Phase IIb Study of the Efficacy of FLU-v, a Broad Spectrum Influenza Vaccine in an H1N1 Influenza Healthy Human Challenge Model
Phase: PHASE2
Conditions: Influenza
Sponsor: PepTcell Limited

 
Phase IIb Study of the Efficacy of FLU-v, a Broad 
Spectrum Influenza Vaccine in an H1N1 Influenza 
Healthy Human Challenge Model 
 
Clinical Study Protocol 
 
 
 
NCT Number: NCT03180801 
EudraCT Number: 2016-002134-74 
Last date of approval: 19th May 2017 

Sponsor: PepTCell  
Sponsor Protocol No: FLU-v-004 
 
Version: Final v3.0_18APR2017   
 
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hVIVO Protocol Template_HVC and IMP studies_17MAR2015 
CLINICAL STUDY PROTOCOL 
Sponsor’s study number: FLU-v-004 
Phase IIb Study of the Efficacy of FLU-v, a Broad Spectrum Influenza Vaccine 
in an H1N1 Influenza Healthy Human Challenge Model 
Version: 
Final v3.0_18APR2017 
Sponsor: 
 
 
Gregory Stoloff, 
PepTcell Limited (t/a SEEK), 
Central Point, 
45 Beech Street, 
London, 
EC27 8AD  
Senior Clinical & 
Scientific leader 
Dr Matthew J. Memoli 
Director, LID Clinical Studies Unit 
Laboratory of Infectious Diseases NIAID, NIH 
MSC 3203 33 North Drive 
Bethesda, MD 20892.  
Principal 
Investigator: 
Dr Balpreet Matharu 
Principal Investigator  
hVIVO Services Limited (hVIVO), 
Queen Mary BioEnterprises Innovation Centre, 42 New Road, 
London E1 2AX, UK. 
 
Dr Jeremy Dennison 
Principal Investigator  
Hammersmith Medicines Research Ltd  
Cumberland Avenue  
London, NW10 7EW 
Study carried out at 
the facilities of: 
hVIVO Services Limited, 
Queen Mary BioEnterprises Innovation Centre, 42 New Road,  
London. E1 2AX. UK. 
 
hVIVO Services Limited, 
Manchester Science Parks, Kilburn House, Lloyd Street North 
Manchester, M15 6SE. UK 
 
Hammersmith Medicines Research Ltd  
Cumberland Avenue  
London, NW10 7EW 
Research Ethics 
Committee (REC) 
Ref:  
16/NE/0227 
EudraCT Number:  
2016-002134-74 
 

Sponsor: PepTCell 
Sponsor Protocol No: FLU-v-004 
Version: Final v3.0_18APR2017 
 
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DETAILS OF AMENDMENTS 
Number 
Date 
Type 
Brief details 
1.1 
25JUL2016 
Amendment to 
the Protocol in 
response to 
the MHRA 
review dated 
06JUL2016 
 
Clarification on requirement of competent 
authority approval prior to commencement 
of activities for Part B. 
 
Addition of pregnant and breastfeeding 
women to the definition of vulnerable 
population. 
 
Addition of pregnancy as criteria for subject 
discontinuation. 
1.2 
12AUG2016 
Non-
Substantial 
Amendment 
02 
 
Version 
control 
and 
date 
updated 
throughout the document.  
 
Changes to the group orders to harmonise 
with study schematic figure on page 48, at 
pages 32, 48, 56. 
 
Addition of Principal Investigator approval 
section for Dr Dennison as PI at the HMR 
Pharmacy Site.  
 
Section 1: Addition of PI details for Dr 
Dennison. 
 
Section 7.3: Exclusion Criteria: 
1) Amendment to the smoking criteria 
2) Amendment to BMI criteria 
3) Amendment 
to 
the 
reference 
to 
vulnerable populations 
4) Amendment to criteria to prevent 
duplication 
 
Section 9: Clarification on the conditions for 
end of Quarantine phase.  
 
Table 9-2: Removal of LDH and Uric Acid 
from the Biochemistry panel as reflected in 
the Time & Events (T&E) schedule and 
throughout the protocol, as it does not add 
significant safety information in a healthy & 
young population. 
 
Table 9-2: Removal of Biochemistry from 
Day 5 assessments as it does not add 
significant safety information.  
 
Table 9-2: Clarification on the conduct of the 
safety blood analysis on the Follow-Ups 
(Day 35 and 63) will be conducted at PIs 
discretion.  
 
Keynotes for T&E Schedule: 
1) Clarifying the conduct of the FLU-PRO to 
be in line with the Protocol text. 
2) #7: Clarifies that a viral challenge 
serology test may be repeated if required, if 
subjects fall out of the 90-day window. 
Additionally, clarifying that the screening 

Sponsor: PepTCell 
Sponsor Protocol No: FLU-v-004 
Version: Final v3.0_18APR2017 
 
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DETAILS OF AMENDMENTS 
visit includes collection of PBMC and 
PAXgene from subjects invited to receive 
IMP before their vaccination visit.  
 
Section 10 & 13: Clarification that HMR 
SOPs will be followed when appropriate.  
Section 13.2.3: Clarification that no protocol 
deviation will be recorded due to missing 
diary card data. Furthermore, the diary card 
data will be reviewed by a physician in 
retrospect and complete the information as 
accurately as possible by asking the subject 
about symptoms for the missing data sets. 
 
Grammatical and formatting changes have 
been made throughout the document.  
1.3 
26Aug2016 
Non-
Substantial 
Amendment 
03 
 
Section 5.3, page 32 -  updated the order of 
group numbering  
 
Section 9, page 47, updated the order of 
group numbering and removed the Figure 1  
 
Section 10,  page 56,  updated the order of 
group numbering 
 
Exclusion criteria 1 -  clarified exclusion 
criteria 1 
2.0 
26SEP2016 
Substantial 
Amendment 
01 
 
Section 7.2; Inclusion Criteria 9: Clarification 
to participant asthma history prior to entry 
into study. 
 
Section 
7.2; 
Inclusion 
Criteria 
11: 
Clarification on the time-point for acquiring a 
subject’s medical history from their GP. 
 
Section 
18.7.1; 
Informed 
consent 
procedure: Amended to include Investigator 
or 
delegate 
to 
conduct 
participant 
consenting.    
 
Section 18.7.3; Information for General 
Practitioners: 
Amendment 
to 
the 
requirement for participant’s medical history 
from their GP. 
2.1 
09DEC2016 
Non-
Substantial 
Amendment 
04 
 
Protocol has been clarified throughout to 
allow variable entry to the Quarantine unit 
on Day -2 or Day -1. The changes are 
further reflected in the study design, Time & 
Events 
schedule 
and 
individual 
assessments where appropriate. 
 
Sections 7.2 & 18.7.1: Clarification on the 
responsibilities 
of 
the 
Investigator 
or 
delegate in the consenting process for 
participants.  
 
Keynotes to the Time & Events schedule & 
Section 
14.1.3: 
Clarification 
on 
the 
collection of pre-vaccination PAXGene and 
PBMC samples in the Time & Events 
schedule.  

Sponsor: PepTCell 
Sponsor Protocol No: FLU-v-004 
Version: Final v3.0_18APR2017 
 
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DETAILS OF AMENDMENTS 
 
Section 
18.7.3: 
Clarification 
on 
the 
confirmation of volunteers’ medical history 
from their medical practitioner.  
2.2 
31JAN2017 
Non-
Substantial 
Amendment 
05 
 
Correction of Section 7.2; Inclusion Criteria 
9: Participant asthma history prior to entry 
into study to match the wording included in 
the MHRA and Research Ethics Committee 
-approved version 2.0 of the study protocol, 
which was incorrectly reverted to the original 
wording in protocol version 2.1. 
3.0 
18APR2017 
Substantial 
Amendment 
02 
 
Pages 1, 6 and 12 updated to reflect change 
in PI. 
 
Section 6.3.1 and throughout updated to 
reflect 
exploratory 
endpoints 
may 
be 
reported separately from CSR. 
 
Section 9.3.1 correction for consistency that 
subjects will be admitted to the Quarantine 
unit with a minimum 20 days not 21 days 
post second vaccination. 
 
Section 9.3.1 and throughout a clarification 
that serology test and result must be 
available within 90 days of Day 0 inoculation 
 
Section 13.1.2 inspection of the eyes 
removed from mandatory list in directed 
physical examination. 
 
Section 13.2.2 language inserted to state 
how missing Flu-PRO data will be handled. 

Sponsor: PepTCell 
Sponsor Protocol No: FLU-v-004 
Version: Final v3.0 18APR2017 
PRINCIPAL INVESTIGATOR'S AGREEMENT 
hvtvo 
I have read the protocol, and agree to conduct the trial in accordance with the approved 
protocol, the Declaration of Helsinki 19961, the principles of ICH GCP2, the current regulatory 
requirements as detailed in the Medicines for Human Use (Clinical Trial) Regulations 
(Statutory instrument [SI] 2004/1031 )4 and all subsequent amendments, the UK Data 
Protection Act 19985, any other applicable laws and guidance, and any Sponsor requirements . 
. , 
I agree to conduct the procedures described in this protocol according to these guidelines and 
·to appropriately direct and assist the staff under my control. 
SIGNATURE OF THE PRINCIPAL INVESTIGATOR 
' SIGN 
DATE 
[ J I q ! J l ljl P .j.( It l2l 0 ! 1 111 
Dr Balpreet Matharu 
Senior Investigator, hVIVO 
SIGNATURE OF THE PRINCIPAL INVESTIGATOR 
_ 0 ...---.eATE 
SIGN ::,/\ ( .:S. 
:::::::::--
! 1 I q It I A-1 f [ n Jt l 1...lo I t 111 
Dr Jeremy Dennison 
Senior Research Physician, HMR 
Note: The term 'Investigator' includes appropriately qualified persons to whom the PI has 
formally delegated his/her Investigator roles and responsibilities. 
CONFIDENTIAL 
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Sponsor: PepTCell 
Sponsor Protocol No: FLU-v-004 
Version: Final v3.0_18APR2017 
 
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Contents 
1 
STUDY PERSONNEL CONTACT LIST .................................................................... 12 
2 
PROTOCOL SYNOPSIS .......................................................................................... 14 
3 
GLOSSARY OF ABBREVIATIONS.......................................................................... 20 
4 
DEFINITIONS ........................................................................................................... 24 
4.1 General ....................................................................................................... 24 
4.2 Study definitions of infection and illness ..................................................... 25 
5 
BACKGROUND AND INTRODUCTION ................................................................... 26 
5.1 Information about Influenza ........................................................................ 26 
5.2 Information about FLU- v ............................................................................ 27 
5.2.1 Product description .......................................................................... 27 
5.2.2 Non-clinical studies .......................................................................... 27 
5.2.3 Clinical studies ................................................................................. 29 
5.3 Rationale for the study design .................................................................... 33 
5.3.1 Overall benefit/risk assessment ....................................................... 34 
6 
STUDY OBJECTIVES .............................................................................................. 37 
6.1 Primary objective ........................................................................................ 37 
6.1.1 Primary endpoint .............................................................................. 37 
6.2 Secondary objectives ................................................................................. 37 
6.2.1 Secondary endpoints ....................................................................... 37 
6.3 Exploratory objectives ................................................................................ 37 
6.3.1 Exploratory endpoints ...................................................................... 37 
6.4 Safety objectives ........................................................................................ 38 
6.4.1 Safety endpoints .............................................................................. 38 
7 
STUDY POPULATION ............................................................................................. 39 
7.1 Number of subjects ..................................................................................... 39 
7.2 Inclusion criteria .......................................................................................... 39 
7.3 Exclusion criteria ........................................................................................ 41 
7.4 Discontinuation of a subject’s participation ................................................. 44 
7.4.1 Subject withdrawal ........................................................................... 44 
7.4.2 Subject discontinuation .................................................................... 44 
7.4.3 Pregnancy ........................................................................................ 45 
7.5 Replacements and reserve subjects ........................................................... 45 
7.6 Subject numbering ...................................................................................... 46 
8 
STUDY RESTRICTIONS .......................................................................................... 47 
8.1 Concomitant therapies ................................................................................ 47 
8.2 Strenuous exercise ..................................................................................... 47 
8.3 Tobacco ...................................................................................................... 47 
8.4 Alcohol, caffeine and xanthine-containing food and beverages .................. 47 
8.5 Contraception ............................................................................................. 47 
8.6 Contact with vulnerable populations ........................................................... 48 
9 
STUDY DESIGN ....................................................................................................... 49 
9.1 Screening phase ......................................................................................... 54 
9.1.1 Visit 1 - Study specific screening ..................................................... 54 
9.2 Vaccination Phase ...................................................................................... 54 
9.2.1 Visit 2 - Day -43 ............................................................................... 54 
9.2.2 Visit 3 - Day -22 (minimum 21 days post first vaccination +7 days) . 54 

Sponsor: PepTCell 
Sponsor Protocol No: FLU-v-004 
Version: Final v3.0_18APR2017 
 
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9.3 Quarantine and Challenge .......................................................................... 54 
9.3.1 Visit 4 - Admission (Day -2 or Day -1 up to 40 days post second 
vaccination) ...................................................................................... 54 
9.3.2 Virus Inoculation (Day 0) .................................................................. 55 
9.3.3 Day 1 through 7 ............................................................................... 55 
9.3.4 Discharge ......................................................................................... 55 
9.3.5 Day 8 through 15 (if required) .......................................................... 55 
9.4 Visit 5 & 6 - Follow-up phase ...................................................................... 56 
9.4.1 Lost to follow-up ............................................................................... 56 
9.5 End of trial .................................................................................................. 56 
9.5.1 End of Trial Report ........................................................................... 56 
10 
RANDOMISATION AND BLINDING ......................................................................... 57 
10.1 Route of administration, dosage, dose regimen and treatment period ....... 57 
10.2 Randomisation for the study ....................................................................... 57 
10.3 Blinding ....................................................................................................... 58 
10.4 Unblinding................................................................................................... 58 
11 
CHALLENGE VIRUS ................................................................................................ 60 
11.1 Description .................................................................................................. 60 
11.2 Supply and accountability ........................................................................... 60 
11.3 Storage ....................................................................................................... 60 
11.4 Preparation and administration ................................................................... 60 
12 
INVESTIGATIONAL MEDICINAL PRODUCT .......................................................... 61 
12.1 Description .................................................................................................. 61 
12.1.1 FLU-v ............................................................................................... 61 
12.1.2 Placebo ............................................................................................ 61 
12.2 Supply and accountability ........................................................................... 61 
12.3 Packing and labelling .................................................................................. 61 
12.4 Administration ............................................................................................. 62 
12.5 Compliance ................................................................................................. 63 
12.6 Overdose .................................................................................................... 63 
12.7 Disposal ...................................................................................................... 63 
13 
CLINICAL ASSESSMENTS AND PROCEDURES ................................................... 65 
13.1 Clinical assessments .................................................................................. 65 
13.1.1 Complete physical examination ....................................................... 65 
13.1.2 Directed physical examination ......................................................... 65 
13.1.3 Vital signs ......................................................................................... 66 
13.1.4 Temperature .................................................................................... 66 
13.1.5 ECG ................................................................................................. 67 
13.1.6 Spirometry ........................................................................................ 67 
13.1.7 Adverse events ................................................................................ 68 
13.1.8 Concomitant medications ................................................................. 68 
13.2 Efficacy assessments ................................................................................. 68 
13.2.1 Directed physical examination ......................................................... 68 
13.2.2 FLU-PRO Symptom Severity Assessment Tool and Physician 
assessment of Influenza Symptoms ................................................ 69 
13.2.3 Adverse events diary cards (Diary report cards) .............................. 69 
13.2.4 Nasopharyngeal swab...................................................................... 70 
14 
LABORATORY ASSESSMENTS ............................................................................. 71 

Sponsor: PepTCell 
Sponsor Protocol No: FLU-v-004 
Version: Final v3.0_18APR2017 
 
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14.1 Blood  ......................................................................................................... 71 
14.1.1 Blood volume ................................................................................... 71 
14.1.2 Routine blood analysis ..................................................................... 71 
14.1.3 Whole blood and Serum analysis ..................................................... 71 
14.2 Nasopharyngeal swab ................................................................................ 72 
14.2.1 Respiratory virus screen .................................................................. 72 
14.2.2 Viral shedding .................................................................................. 72 
14.3 Urine  ......................................................................................................... 72 
14.3.1 Urinalysis ......................................................................................... 72 
14.3.2 Pregnancy ........................................................................................ 73 
14.3.3 Drugs of abuse ................................................................................. 73 
15 
ADVERSE EVENTS AND TOXICITY MANAGEMENT ............................................. 74 
15.1 Definitions ................................................................................................... 74 
15.1.1 Adverse event .................................................................................. 74 
15.1.2 Adverse reaction .............................................................................. 75 
15.1.3 Unexpected adverse (drug) reaction ................................................ 75 
15.1.4 Serious adverse event, serious adverse drug reaction and unexpected 
serious adverse (drug) reaction ....................................................... 75 
15.1.5 Suspected unexpected serious adverse reaction ............................. 76 
15.2 AE reporting ................................................................................................ 76 
15.2.1 Challenge Virus symptoms .............................................................. 77 
15.2.2 IMP related adverse events symptoms ............................................ 77 
15.2.3 Complete Physical examination ....................................................... 78 
15.2.4 Directed physical examination ......................................................... 78 
15.2.5 Vital signs ......................................................................................... 78 
15.2.6 Temperature .................................................................................... 78 
15.2.7 Spirometry ........................................................................................ 78 
15.2.8 Laboratory values ............................................................................ 78 
15.3 Classification of adverse events ................................................................. 79 
15.3.1 Seriousness ..................................................................................... 79 
15.3.2 Severity ............................................................................................ 79 
15.3.3 Frequency ........................................................................................ 80 
15.3.4 Relationship ..................................................................................... 80 
15.3.5 Action taken ..................................................................................... 81 
15.3.6 Outcome .......................................................................................... 81 
15.3.7 Follow-up ......................................................................................... 82 
15.4 Serious adverse event reporting ................................................................. 82 
15.4.1 Reporting of SUSARs ...................................................................... 83 
15.4.2 Adverse reactions to non-IMPs ........................................................ 83 
15.4.3 Post-quarantine AEs and SAEs ....................................................... 84 
15.4.4 Pregnancy ........................................................................................ 84 
16 
STATISTICAL METHODS AND PLANNED ANALYSES ......................................... 85 
16.1 Study Hypothesis ........................................................................................ 85 
16.2 Sample size ................................................................................................ 85 
16.3 Interim analysis ........................................................................................... 85 
16.4 FLU-v Statistical Analysis Plan ................................................................... 86 
16.4.1 Subject accountability ...................................................................... 86 
16.4.2 Protocol deviations ........................................................................... 86 

Sponsor: PepTCell 
Sponsor Protocol No: FLU-v-004 
Version: Final v3.0_18APR2017 
 
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16.4.3 Demographic and baseline characteristics ....................................... 86 
16.5 Primary analysis ......................................................................................... 86 
16.6 FLU-v Secondary analysis .......................................................................... 87 
16.7 Safety Analyses .......................................................................................... 87 
16.7.1 Adverse events ................................................................................ 87 
16.7.2 Laboratory parameters ..................................................................... 87 
16.7.3 Physical examination ....................................................................... 87 
16.7.4 Concomitant medications ................................................................. 88 
17 
STUDY FILES AND CLINICAL SOURCE DOCUMENTATION ................................ 89 
17.1 Investigator’s Study File ............................................................................. 89 
17.2 Clinical source documentation .................................................................... 89 
17.3 Data capture ............................................................................................... 89 
17.4 Data quality assurance and quality control ................................................. 90 
17.5 Data coding ................................................................................................ 90 
17.6 Database lock ............................................................................................. 90 
17.7 Data protection ........................................................................................... 90 
18 
STUDY MANAGEMENT AND ETHICAL RESPONSIBILITIES ................................ 91 
18.1 Regulatory approval and Good Clinical Practice ........................................ 91 
18.2 Deviations from the protocol ....................................................................... 91 
18.2.1 Protocol amendments ...................................................................... 91 
18.2.2 Urgent Safety Measures .................................................................. 92 
18.3 Serious breach of the protocol or GCP ....................................................... 92 
18.3.1 Protocol waivers ............................................................................... 93 
18.4 Discontinuation of the study........................................................................ 93 
18.4.1 Stopping criteria ............................................................................... 94 
18.5 Study records retention and direct access to source documents ................ 95 
18.5.1 Archiving .......................................................................................... 96 
18.6 Sponsor responsibilities .............................................................................. 96 
18.6.1 General ............................................................................................ 96 
18.6.2 Ethical considerations ...................................................................... 96 
18.6.3 Laboratory certification and normal values ....................................... 97 
18.6.4 No-fault compensation and indemnity .............................................. 97 
18.6.5 Monitoring ........................................................................................ 98 
18.6.6 Audits and inspections ..................................................................... 98 
18.6.7 Annual Safety Report and Development Safety Update Report ....... 99 
18.7 Investigator responsibilities......................................................................... 99 
18.7.1 Informed consent procedure ............................................................ 99 
18.7.2 Delegation of Investigator responsibilities ........................................ 99 
18.7.3 Information for General Practitioners ............................................. 100 
18.7.4 Payments ....................................................................................... 100 
18.7.5 Liability and insurance.................................................................... 100 
18.7.6 Investigator’s Protocol Agreement ................................................. 100 
18.7.7 Quality assurance .......................................................................... 100 
18.8 Study termination ...................................................................................... 100 
19 
DISCLOSURE OF DATA ........................................................................................ 101 
19.1 Subject confidentiality ............................................................................... 101 
19.2 Sponsor confidentiality ............................................................................. 101 
19.3 Publication ................................................................................................ 101 

Sponsor: PepTCell 
Sponsor Protocol No: FLU-v-004 
Version: Final v3.0_18APR2017 
 
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20 
REFERENCES ....................................................................................................... 103 
21 
APPENDICES ........................................................................................................ 108 
 
LIST OF TABLES  
Table 9-2: Time & Events Schedule…………………………................................................................48 
Table 15-1: Classification of adverse event severity .................................................................... 80 
Table 15-2: Classification of adverse event relationship .............................................................. 80 
Table 15-3: Classification of adverse event outcome ................................................................... 82 
Table 15-4: Contact details for reporting SAEs ............................................................................ 83 
Table 18-1: Study stopping criteria ............................................................................................... 95 
 
LIST OF APPENDICES 
Appendix 1: FLU-PRO Symptom Questionnaire ........................................................................ 109 
Appendix 2: Vital signs: Study specific normal ranges and abnormalities ................................. 111 
Appendix 3: ECG: Study specific abnormalities ......................................................................... 112 
Appendix 4: Division of Microbiology and Infectious Diseases (DMID) Adult 
Toxicity Table November 2007 ....................................................................... 113 
 

Sponsor: PepTCell 
Sponsor Protocol No: FLU-v-004 
Version: Final v3.0_18APR2017 
 
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1 
STUDY PERSONNEL CONTACT LIST 
CONTACT 
DETAILS 
SPONSOR 
PepTcell Limited (t/a SEEK) 
SPONSOR’S 
REPRESENTATIVE 
Gregory Stoloff, 
PepTcell Limited (t/a SEEK), 
Central Point, 
45 Beech Street, 
London, 
EC27 8AD 
 
Phone/Mobile: +44 (0)207 153 6575 
Email: gregory.stoloff@seekacure.com 
SPONSOR'S MEDICAL 
EXPERT 
Dr. Bryan Murray, 
Boyd Consultants Limited, 
3a, Station Cottages, 
St Neots, 
Cambrigdeshire, 
PE19 1QF 
 
Phone: +44 (0)7833 204296 
Email: bryan.murray@seekacure.com 
SENIOR CLINICAL & 
SCIENTIFIC LEADER 
Dr Matthew J. Memoli 
Director, LID Clinical Studies Unit 
Laboratory of Infectious Diseases NIAID, NIH 
MSC 3203 33 North Drive 
Bethesda, MD 20892. 
 
Phone: +1 301-443-5971 
Email: memolim@niaid.nih.gov 
PRINCIPAL INVESTIGATOR 
(PI) AND TRIAL SITE 
Dr Balpreet Matharu 
hVIVO Services Limited, 
Queen Mary BioEnterprises Innovation Centre, 
42 New Road, 
London E1 2AX. 
 
Phone: +44 (0) 20 7756 1396 
Email: b.matharu@hvivo.com  
Dr Jeremy Dennison 
Principal Investigator  
Hammersmith Medicines Research Ltd  
Cumberland Avenue  
London, NW10 7EW 
 
Email: jdennison@hmrlondon.com 

Sponsor: PepTCell 
Sponsor Protocol No: FLU-v-004 
Version: Final v3.0_18APR2017 
 
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IMP CONTACT 
Olga Pleguezuelos / Gregory Stoloff, 
SEEK, 
Central Point, 
45 Beech Street, 
London, 
EC27 8AD 
 
Phone/Mobile: +44 (0) 207 153 6575 
Email: gregory.stoloff@seekacure.com 
Email: olga.pleguezuelos@seekacure.com 
PHARMACY AND 
ADMINISTRATION 
hVIVO External Pharmacy Vendor, 
Hammersmith Medicines Research Ltd,  
Cumberland Avenue,  
London, NW10 7EW 
OTHER PARTIES 
The Investigator Site File (ISF)/Trial Master File (TMF) 
contains details of third party contractors, sub-
investigators, laboratories, data management suppliers, 
statisticians and all other service providers. 
 
 

Sponsor: PepTCell 
Sponsor Protocol No: FLU-v-004 
Version: Final v3.0_18APR2017 
 
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2 
PROTOCOL SYNOPSIS 
SYNOPSIS 
TITLE 
Phase IIb Study of the Efficacy of FLU-v, a Broad Spectrum 
Influenza Vaccine in an H1N1 Influenza Healthy Human 
Challenge Model  
SPONSOR  
PepTcell Limited (t/a SEEK)  
SPONSOR 
PROTOCOL NO. 
FLU-v-004 
PHASE 
Phase IIb 
INDICATION 
Prophylaxis of Influenza  
EUDRACT NUMBER 
2016-002134-74 
STUDY DESIGN 
A randomized, double-blind, placebo-controlled efficacy and 
safety trial of FLU-v administered as 2 vaccinations or 1 
vaccination vs placebo prior to intranasal challenge with the 
Influenza A 2009 H1N1 human virus.   
 
In this study, the main efficacy comparisons are for each of the 
FLU-v groups to placebo. The study will also compare the two 
FLU-v dosing arms but will only have power to detect a significant 
difference in Mild to Moderate Influenza Disease (MMID) rates 
between the FLU-v groups and placebo and not against each 
other.  
 
Assuming significant efficacy of at least one dose of FLU-v 
against placebo is demonstrated in the current protocol (Part A), 
when the primary efficacy endpoint and key safety results are 
available, the protocol may be amended to include a second part 
(Part B) which will test the optimal FLU-v dose from Part A (in 
terms of efficacy and safety) versus current standard of care 
seasonal influenza vaccine. Details of Part B will be determined 
and documented in a future protocol amendment following the 
availability of the unblinded key efficacy and safety results from 
Part A. Approval will be sought via a substantial amendment from 
the competent authority before part B can commence. 
SAMPLE SIZE 
Up to 123 participants inoculated with the challenge virus  
RANDOMISATION 
AND BLINDING 
Randomisation will occur on day -43.  
 
Part A 
 
FLU-v 1 or 2 doses and placebo treatment arms will be double-
blinded and randomised 1:1:1. 
 

Sponsor: PepTCell 
Sponsor Protocol No: FLU-v-004 
Version: Final v3.0_18APR2017 
 
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SYNOPSIS 
Randomisation numbers will follow a 3 digit format e.g., 101-1NN. 
A copy of the randomisation code list will be sent to the unblinded 
pharmacist preparing the vaccines, so that vaccine or placebo 
doses can be prepared for each subject as appropriate.  A 
designated unblinded statistician will be responsible for the 
computer generated randomisation schedule. Sealed copies of 
the randomisation code will be stored in a secure place. Following 
database lock, on receipt of authorisation from the Sponsor, a 
copy of the randomisation code list will be sent to the Study 
Statistician to conduct study unblinding. 
 
Part B 
 
Assuming significant efficacy of at least one dose of FLU-v 
against placebo is demonstrated in Part A, Part B  will be 
conducted and test the optimal FLU-v dose from Part A (in terms 
of efficacy and safety) versus a current standard of care seasonal 
influenza vaccine. Details of Part B randomisation and blinding 
will be determined and documented in a future protocol 
amendment following the availability of the unblinded key efficacy 
and safety results from Part A. Approval will be sought via a 
substantial amendment from the competent authority before part 
B can commence. 
CHALLENGE VIRUS  
Live, recombinantly derived A/Ca/04/2009-like flu virus 
CHALLENGE VIRUS 
ROUTE 
Intranasal (both nostrils) 
IMP SUPPLIER 
PepTcell Limited (t/a SEEK) 
IMP  
FLU-v 
IMP DOSE(S) 
500 micrograms suspended in 0.5ml volume of water and 
adjuvant 
PHARMACEUTICAL 
FORM 
Lyophilised powder to be suspended for injection 
IMP ROUTE 
Subcutaneous Injection 
CONTROL 
COMPOUND 
Placebo (adjuvant Montanide ISA-51)  
STUDY POPULATION 
Healthy males and females aged 18 to 55 years of age 
REPLACEMENT 
POLICY 
Subjects will not be replaced post-influenza challenge on Day 0 
PRIMARY 
OBJECTIVE  
To determine the effect of FLU-v on reducing the incidence of Mild 
to Moderate Influenza Disease (MMID) defined as detectable viral 
shedding plus at least one symptom of influenza  

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SYNOPSIS 
PRIMARY ENDPOINT 
Incidence of MMID  
SECONDARY 
OBJECTIVES 
To determine the overall effect of FLU-v on measurements of 
disease severity 
SECONDARY 
ENDPOINTS 
 
Viral shedding duration 
 
Viral shedding quantitation 
 
Symptom duration 
 
Total number of symptoms experienced 
 
Symptom severity score as measured by FLU-PRO 
Symptom Questionnaire 
 
Incidence of vaccine related adverse events (diary card 
for 21 days after each vaccine) 
EXPLORATORY 
OBJECTIVES  
To explore the immunological responses to FLU-v 
EXPLORATORY 
ENDPOINTS 
 
Immunogenicity of FLU-v as measured by 
o B-cell and T-cell responses to FLU-v both after 
vaccination as well as influenza challenge 
o Immunophenotyping 
 
Broadness of protection as measured by culturing PBMCs 
pre-influenza virus inoculation in study with PBMCs (same 
subject) infected with influenza and assess killing of 
infected cells by PBMCs from vaccinated subjects and 
use sera containing non-neutralising antibodies and test 
killing of human influenza infected cells by complement 
activation or ADCC assays 
SAFETY 
OBJECTIVES  
To determine the safety and tolerability of FLU-v after vaccination 
in healthy subjects subsequently challenged with Influenza A 
2009 H1N1 human challenge virus  
SAFETY ENDPOINTS 
 
Incidence of treatment-emergent AEs (TEAE), severity, 
seriousness and causality 
 
Absolute values and change from baseline in routine 
clinical and laboratory parameters  
 
Vaccine related physical examination findings  
 
Concomitant medications 
STUDY DESIGN 
 
 
Study-specific screening (SSS) within 90 days prior to 
challenge  
 
Vaccination on Day  - 43 
 
Vaccination on Day  - 22 

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SYNOPSIS 
 
Entry to quarantine on Day  -2 or Day -1 
 
Challenge Virus inoculation on Day  0 
 
Subjects will be resident in the Quarantine Unit for a total 
of approximately 10 days (from Day -2 or Day -1 to Day 7) 
 
End of quarantine phase is achieved on Day 7 or until two 
negative diagnostic tests for influenza on two separate but 
consecutive days and are otherwise clinically stable.  
 
Follow-up visits: Day 35 (+/- 3) and Day 63 (+/- 5) days.  
PROCEDURES AND 
ASSESSMENTS 
During the study the following assessments and procedures will 
be performed: 
 
Written informed consent 
 
Eligibility criteria 
 
Height, body weight, body mass index (BMI),  
 
Medical history 
 
Demographics 
 
Prior medications 
 
Randomisation Dosing with FLU-v-004 or placebo  
 
Challenge Virus inoculation 
 
Complete physical examination 
 
Directed physical examination 
 
Vital signs (blood pressure [BP], respiratory rate [RR], 
heart rate [HR], peripheral arterial oxygen saturation 
[SpO2]) 
 
Tympanic temperature 
 
12-lead ECG 
 
Spirometry 
 
FLU-PRO Symptom Questionnaire  
 
Bloods:  
o Challenge Virus serology  
o Haematology 
o Biochemistry 
o Cardiac enzymes 
o Hepatitis A, B and C and human 
immunodeficiency virus (HIV) serology 
o Serum follicle stimulating hormone (FSH) (post-
menopausal females) 
o Beta-human chorionic gonadotropin (β-hCG) 
pregnancy test (females).  
o Whole and serum blood collection for immune 
response analysis 
 
Nasopharyngeal swab 
o Respiratory virus screen  
o Viral load (TCID50 and/or RT-qPCR). 

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SYNOPSIS 
 
Breath alcohol test 
 
Urine: 
o Urinalysis (dipstick) 
o Pregnancy test 
o Drugs of abuse. 
 
Adverse events 
 
Concomitant medications  
END OF STUDY 
The last subject’s last scheduled visit (LSLV). 
EXPECTED 
DURATION OF 
SUBJECT 
PARTICIPATION 
Approximately 153 days or 22 weeks from screening to LSLV 
OVERALL DURATION 
OF CLINICAL PHASE 
Approximately 18 months  
STATISTICS 
The hypothesis is that vaccination with 1 dose or two doses of 
FLU-v + adjuvant will significantly reduce MMID when compared 
to individuals vaccinated with placebo.   
 
The primary objective of this study is to examine whether there is 
a difference in the MMID post inoculation rates between either of 
the 2 FLU-v arms and placebo. A sample size of 41 subjects per 
arm (total 123) will provide 80% power to detect a difference in 
MMID rates of 0.70 versus 0.40 (ie difference of 0.30) using a one 
sided 0.05 significance level.  
 
In this study, the main comparisons are for each of the FLU-v 
dose groups to placebo. The study will also compare the two FLU-
v dosing arms but the study will not have adequate power to 
detect a significant difference in MMID rates at the predicted 
treatment rates. This study does not control for multiple 
comparisons since we are trying to maintain a small sample size 
but have high power to detect the predefined primary objective of 
efficacy versus placebo when FLU-v is truly beneficial. All 
comparisons will be made at the one sided 0.05 significance level.  
 
FLU-v Statistical Analysis Plan 
 
MMID rates in the 2 FLU-v groups and placebo group will be 
compared using a Fishers exact test. 95% confidence intervals 
around the difference in rates between the FLU-v groups will be 
presented. Adverse event rates between groups will also be 
compared using Fishers exact test.  The secondary endpoints will 
be examined by calculating the median and interquartile range 

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SYNOPSIS 
and then performing a two-sided Wilcoxon Rank Sum Test at the 
0.05 significance level. 
STOPPING CRITERIA 
The study will be terminated if: 
 
One or more subjects experience a vaccine related SAE 
or two or more subjects experience severe or clinically 
significant AEs within same organ class and confirmed by 
repeat sample if considered to be at least possibly related 
to the FLU-v vaccine. 
 
One or more subjects experience any severe clinically 
significant illness from influenza challenge. 

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3 
GLOSSARY OF ABBREVIATIONS  
Abbreviation 
Term 
ABPI 
Association of British Pharmaceutical Industries 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AP 
Analytical Plan 
API 
Active Pharmaceutical Ingredients 
APTT 
Activated partial thromboplastin time 
APTTR 
Activated partial thromboplastin time ratio 
AR 
Adverse reaction 
ASR 
Annual Safety Report 
AST 
Aspartate aminotransferase 
ATS 
American Thoracic Society 
AUC 
Area under (the) curve 
BD 
Twice daily 
BDRM 
Blinded Data Review Meeting 
β-hCG 
Beta human chorionic gonadotropin 
BMI 
Body mass index 
bpm 
Beats per minute 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CHMP 
Committee for Medicinal Products for Human Use 
CK 
Creatine kinase 
COPD 
Chronic obstructive pulmonary disease 
CPE 
Complete Physical Examination 
CRF 
Case report form 
CRP 
C-reactive protein 
CSR 
Clinical study report 
CTA 
Clinical Trial Agreement 
CTL 
Cytotoxic T lymphocytes 
DMID 
Division of Microbiology and Infectious Diseases 
DMP 
Data Management Plan 
DPE 
Directed Physical Examination 
DSUR 
Development Safety Update Report 
DTA 
Data Transfer Agreement 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ECSC 
European Coal and Steel Community 
EMA 
European Medicines Agency 
ERS 
European Respiratory Society 
ESI 
Event of Special Interest 

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ESR 
Erythrocyte sedimentation rate 
EU 
European Union 
FDA 
Food & Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FI 
Febrile illness 
Fmoc 
Fluorenylmethoxycarbonyl 
FSH 
Follicle stimulating hormone 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte-colony stimulating factor 
GGT 
Gamma glutamyl transferase 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
GP 
General Practitioner 
HA 
Haemagglutinin 
HAI 
Haemagglutinin inhibition 
HBsAg 
Hepatitis B surface antigen 
HepA IgM 
Hepatitis A antibody Immunoglobulin M 
HCAb 
Hepatitis C antibodies 
HIV 
Human Immunodeficiency Virus 
HR 
Heart rate 
HRT 
Hormone replacement therapy 
HVC 
Human Viral Challenge 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
ICF 
Informed consent form 
Ig 
Immunoglobulin 
IL 
Interleukin 
ILI 
Influenza-like illness 
IMP 
Investigational medicinal product  
IMPD 
Investigational Medicinal Product Dossier 
INR 
International normalised ratio 
IP 
Induced protein 
ISF 
Investigator Site File 
ITT 
Intention-to-treat 
ITT-I 
Intention-to-treat- Infected 
IUD 
Intra-uterine device 
IUS 
Intra-uterine system 
kg 
Kilogram 
KC 
Keratinocyte-derived cytokine 
LDH 
Lactate dehydrogenase 
LRT 
Lower respiratory tract 
LSLV 
Last subject last (scheduled) visit 

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MCH 
Mean corpuscular haemoglobin 
MCHC 
Mean corpuscular haemoglobin concentration 
MCP 
Monocyte chemotactic protein 
MCS 
Microscopy, sensitivity and culture 
MCV 
Mean corpuscular volume 
MDA 
Melanoma differentiation-associated 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MIP 
Macrophage inflammatory protein 
mm Hg 
Millimetres of mercury 
MMID 
Mild to Moderate Influenza Disease 
MTD 
Maximum tolerated dose 
NA 
Neuraminidase 
NPS 
Nasopharyngeal Swab 
OTC 
Over-the-counter 
PBMC 
Peripheral blood mononuclear cell 
PCR 
Polymerase chain reaction  
PHQ 
Patient Health Questionnaire  
PI 
Principal Investigator 
PP 
Per protocol 
PT 
Prothrombin time 
QA 
Quality assurance 
QC 
Quality control 
QIV 
Quadrivalent Influenza Vaccine 
QP 
Qualified Person 
RANTES 
Regulated on Activation, Normal T Cell Expressed and Secreted 
RBC 
Red blood cell 
REC 
Research Ethics Committee 
RIG 
Retinoic acid inducible gene 
RNA 
Ribonucleic acid 
RR 
Respiratory rate 
RVAT 
Rapid virus antigen test 
RT-qPCR 
Reverse Transcription quantitative PCR 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAR 
Serious adverse drug reaction 
SI 
Statutory Instrument 
SME 
Sponsor’s Medical Expert 
SOC 
System, Organ, Class 
SOP 
Standard operating procedure 
SpO2 
Peripheral arterial oxygen saturation 
SSS 
Study-specific screening 

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SUSAR 
Suspected unexpected serious adverse reaction 
SVS 
Systemic viral symptoms 
TCID50 
Tissue culture infective dose (50%) 
TEAE 
Treatment emergent adverse event 
TLR 
Toll-like receptor 
TMF 
Trial Master File 
TNF 
Tumour necrosis factor 
TSH 
Thyroid stimulating hormone 
UK 
United Kingdom 
URT 
Upper respiratory tract  
US/USA 
United States of America 
USM 
Urgent safety measures 
VCU 
Viral Challenge Unit 
VIS 
Volunteer information sheet 
WBC 
White blood cell 
WHO 
World Health Organization 
 

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4 
DEFINITIONS 
4.1 
General 
TERM 
hVIVO DEFINITION 
Completion (of a subject’s 
participation in the study) 
A subject is considered to have completed the study after 
his/her attendance at the last planned study visit on Day 63.  
Enrolment (of a subject into 
the study) 
A subject will be considered to be ‘enrolled’ into the study 
once he/she has signed the consent form.  
Events of Special Interest 
(ESI) 
Significant adverse events that are judged to be of special 
interest in a clinical trial because of their clinical importance, 
known class effects, or based on preclinical signals (e.g., 
nasal irritation). 
Human 
Viral 
Challenge 
(HVC) study 
A study to determine how a virus and the human body 
interact. Subjects are isolated in a hVIVO Quarantine Unit 
and infected (challenged) with a respiratory virus. 
hVIVO 
hVIVO acting as Site (including Manchester Screening, 
Whitechapel Screening and/or Whitechapel Quarantine)  
Infectious titre 
The titre of virus inoculum producing viral infection in a 
subject. 
Investigator 
The term ‘Investigator’ includes appropriately qualified 
persons to whom the PI has formally delegated his/her 
Investigator roles and responsibilities. 
Quarantine group 
A group of subjects who are admitted to and are resident in 
the Quarantine Unit for a particular quarantine period. 
Quarantine period 
The period of time when clinical trial subjects are isolated in 
the Quarantine Unit during a HVC study. 
Quarantine Unit 
A hVIVO isolation facility for HVC studies. 
Randomisation (of a subject 
into the study) 
A subject will be considered to be ‘randomised’ into the study 
once he/she has been allocated a randomisation number 
and dosed with study drug.  
Randomisation number 
The number allocated to a subject at randomisation. 
Screening 
A process of active consideration of potential subjects for 
enrolment in a trial.  
Sponsor  
Clinical Trial Sponsor  
Subject number 
The unique number assigned to a volunteer on the hVIVO 
volunteer database, which is used to identify the volunteer 
prior to randomisation. 
FLU-PRO survey 
A document in which the subject records his/her assessment 
of symptoms related to the study. 
Titre 
The term ‘titre’ applies to the quantity or concentration of 
virus inoculum or antibody. 
Treatment group 
A group of individuals who either receive the study drug,  or 
the placebo  or combinations of the aforementioned 

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TERM 
hVIVO DEFINITION 
Viral 
Challenge 
(or 
Challenge) 
The inoculation of a subject with virus inoculum. By 
definition, the day of Viral Challenge is Day 0. 
4.2 
Study definitions of infection and illness  
Illness/infection 
type 
  
  
Definition 
  
  
Viral shedding 
A positive molecular test for influenza 
MMID 
(Mild 
to 
moderate 
influenza 
induced disease) 
Detectable viral shedding plus at least one of the following 
symptoms or signs or tests determined by the investigator to be 
related to influenza: 
         Arthralgia
         Chills
         Conjunctivitis
         Coryza
         Diarrhoea
         Dry Cough
         Dyspnea/Shortness of Breath
         Fatigue/Tiredness
         Fever (>38.0°C)
         Headache
         Myalgia
         Nausea
         Oxygen Saturation Decrease by ≥3% from baseline
         Productive Cough
         Rhinorrhea
         Sore Throat
         Sweats
 

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5 
BACKGROUND AND INTRODUCTION  
5.1 
Information about Influenza  
The high morbidity and mortality associated with both pandemic and seasonal influenza and 
the threat of new pandemic strains emerging continues to keep influenza at the forefront of 
infectious disease and public health research.  Mean annual estimates of influenza deaths 
due to seasonal influenza alone attributes up to 49,000 deaths in the US and 250,000 to 
500,000 deaths in industrialized countries to influenza 44-46. Pandemics can have an even more 
devastating effect.  Public health agencies must continue to be prepared by attempting to 
reduce the public health impact of this important virus. 
Currently, influenza vaccination is the cornerstone of prophylaxis and the most effective 
method available now to reduce the impact of influenza on the world’s population each year.  
Current vaccines target the major surface protein, hemagglutinin (HA), and are standardized 
as stimulating anti-HA antibodies as the primary correlate of protection.  Measurements of 
these serum antibodies to this surface protein have become the gold standard for evaluating 
vaccines.  The Federal Drug Administration (FDA) and the European Medicines Agency (EMA) 
Committee for Medicinal Products for Human Use (CHMP) both define “protective titre” as a 
haemagglutination inhibition (HAI) titre of > 4044. 
In recent years epidemiologic evaluations however, have questioned if such antibody titres 
are the sole correlate of protection.  Since the 2009 pandemic more questions have arisen 
regarding the performance of these types of vaccines, and epidemiologic data from as recently 
as the 2013 influenza season suggest that current seasonal vaccines targeting the HA are 
greatly underperforming especially in those that really need protection such as the elderly, 
young, and infirm46. 
Novel correlates of protection are being explored and the role of other aspects of the immune 
system, such as cellular immunity, has come to the forefront.  Influenza specific cytotoxic T 
lymphocytes (CTL) have been shown to be involved in killing and removing cells that are 
infected with influenza viruses 49-54. These cells may play an important role in the clearance of 
influenza virus both before and after clinical symptoms appear.  Influenza has been shown to 
stimulate CTL responses not only specific to the surface proteins which may be subtype 
specific, but also to the internal proteins PB1, PB2, PA, NP, and M155-58, which may be more 
broad spectrum, in action since these proteins are not as variable as viral surface proteins. 
Influenza virus is a highly variable virus. Most of its variability comes from the proteins on its 
surface, NA and HA. Current vaccines use these highly immunogenic proteins to induce 
production of neutralising antibodies, however because these proteins change from strain to 
strain, the antibody response is only efficient against the strain present in the vaccine and if 
the circulating strain is different to that in the deployed vaccine, it will not be protective.  
 

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5.2 
Information about FLU- v  
FLU-v, a novel peptide vaccine, aims to provide a broad-spectrum response and for that it 
uses as antigens viral proteins that are conserved throughout the different strains. These 
proteins are not located on the surface of the influenza virus like NA and HA are, but internally. 
These antigens are not capable of producing neutralising antibodies but can induce cytotoxic 
T cell responses and non-neutralising antibodies. When cells are infected with influenza, these 
internal viral antigens are presented on the surface of infected cells.  Vaccination with FLU-v 
generates a population of T cells and non-neutralising antibodies that can recognise these 
antigens on the surface of infected cells. On recognition, T cells are activated and secrete Th1 
cytokines such as INF-, TNF-α, and IL2 and release granzyme and perforin. Non-neutralising 
antibodies will activate complement and/or induce cytotoxic responses led by Natural Killer 
cells (NK cells). These T cells and antibody actions will result in the destruction of infected 
cells. 
5.2.1 
Product description 
FLU-v is a lyophilised product composed of four short peptidic active pharmaceutical 
ingredients (APIs) (FLU-5, FLU-7, FLU-8N and FLU-10). The APIs are manufactured by 
fluorenylmethoxycarbonyl (Fmoc) chemistry before reconstituting them in 50% acetic acid and 
mixed to prepare an equimolar solution of the four peptides. Glass vials are then filled with the 
solution under sterile conditions. Water and acetic acid are removed from the preparation by 
lyophilisation. The end product is a white to off white lyophilised solid that will need 
reconstitution prior administration by injection. 
5.2.2 
Non-clinical studies 
(1) FLU-v 
A series of pharmacology, safety and toxicology studies have been carried out in two animal 
species, the mouse and the rat. Pharmacology studies have demonstrated that FLU-v is able 
to generate both a cell mediated and humoral response in vaccinated animals and that the 
cell mediated response is enhanced when FLU-v is injected together with an adjuvant. A safety 
pharmacology study demonstrated that FLU-v had no biologically relevant effects on 
cardiovascular or respiratory parameters when administered subcutaneously alone or in 
combination with the adjuvant, in rats.  
 
Toxicology studies have demonstrated evidence of injection site responses and microscopic 
and macroscopic changes in animals receiving FLU-v and it is thought that these were likely 
to be due to the effects of the adjuvant used in the studies, ISA-51. In general, FLU-v was 
clinically well tolerated with no signs of systemic toxicity. FLU-v was also well tolerated in a 
local tolerance study in rabbits, with no local or systemic sign of reaction to treatment.  
 
A safety pharmacology study in rats, under Good Laboratory Practice (GLP) principles, was 
carried out to measure potential side effects of FLU-v on cardiovascular and respiratory 
parameters. FLU-v was administered subcutaneously alone or in combination with the 

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adjuvant, ISA 51, to rats and was found to have no biologically relevant effects on 
cardiovascular or respiratory parameters. 
 
Key messages from FLU-v non-clinical studies: 
 
FLU-v generates both cell mediated and antibody responses in mice and rats and cell-
mediated responses are enhanced when FLU-v is given with adjuvant. 
 
Injection site responses and microscopic and macroscopic changes in animals 
receiving FLU-v likely to be due to the effects of the adjuvant, ISA 51. 
 
FLU-v was well tolerated with no signs of systemic toxicity. 
 
In animal models vaccination with FLU-v has been shown to reduce viral titre and severity of 
illness (please refer to section 5.2.2 in the IB v4.0 7th June 2016). 
(2) ISA-51  
A number of potential adjuvants for use with the FLU-v vaccine were tested for their ability to 
enhance the immune response. In a number of experiments, the adjuvants ISA 51, 
Montanide® ISA 720 (ISA 720) and Quill saponin (QS 21) all boosted the cellular immune 
response to FLU-v, as measured by IFN- γ, although they had no effect on the antibody 
response. 
 
ISA 51 in a final vaccine dose, prepared as instructed, is an emulsion of oil in water in which 
the micelles have an average diameter of approximately four μm. As particles between two 
and 5 μm are preferentially taken up by phagocytic cells and most antigen presenting cells 
(e.g. dendritic cells) have phagocytic capacity, this peptide adjuvant combination increases 
the delivery of antigen to cells capable of triggering an immune response. In addition, these 
micelles contain, in themselves, both hydrophilic and hydrophobic environments and thus can 
accommodate, and efficiently carry, peptides of very different hydrophilic potentials. 
Therefore, ISA 51 was chosen to test the ability of FLU-v as an adjuvant to enhance the 
immunogenicity of the FLU-v vaccine in clinical studies in humans. 
 
5.2.2.1 Pharmacokinetics and metabolism 
A number of ex vivo pharmacology studies have been conducted in transgenic and non-
transgenic mice demonstrating the generation of an effective immune response following 
subcutaneous administration of FLU-v. Most of the studies that were conducted demonstrated 
the ability of FLU-v to generate a cell mediated Th1 type response to the influenza virus. In 
contrast, FLU-v did not generate a Th2 type response in any of the studies conducted. FLU-v 
vaccination was shown to generate both human and murine MHC class I specific immunity to 
influenza virus in a number of studies. Humoral immunity was investigated by measuring the 
levels of total IgG and IgG2a responses to each FLU-v peptides. A weak response to each 
peptide was detected and this was not dose dependent in all but one of the studies, nor was 
it boosted by adjuvant. One study demonstrated weak IgG and IgG2a responses that were 
inversely dose dependent. When FLU-v was administered subcutaneously alone or in 
combination with the adjuvant, ISA 51, to rats, it was found to have no biologically relevant 
effects on cardiovascular or respiratory parameters. ISA 51 was chosen to test the ability of 

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an adjuvant to enhance the immunogenicity of the FLU-v vaccine in clinical studies in humans 
because this peptide adjuvant combination increases the delivery of antigen to cells capable 
of triggering an immune response. 
Standard pharmacokinetic studies were not performed as it was not possible to measure an 
intact test substance in the systemic circulation since the FLU-v peptides are processed 
rapidly by the immune system. Therefore, the cellular immune response was seen as a 
surrogate measure of exposure and an indication of the biological response to treatment with 
the peptides. 
5.2.2.2 Toxicology 
In repeat dose toxicity studies conducted in mice and rats to investigate the systemic toxicity 
potential and immunogenicity of FLU-v, all the studies demonstrated that following 
subcutaneous vaccination with FLU-v alone or with the adjuvant, ISA 51, at doses of up to 553 
μg, there was no effect on the following parameters: bodyweight gain, food consumption, 
organ weight or ophthalmology. In one repeat dose toxicity study in the mouse, where FLU-v 
was administered alone, there was evidence of a cell mediated response (as measured by 
increase in IFN-γ) but no Ab response to FLU-v at doses of up to 553 μg. In other repeat dose 
toxicity studies, FLU-v, in combination with adjuvant, showed an increase in cell mediated 
response with limited evidence of a weak Ab response which was observed in a small number 
of animals immunised with 11.1 μg or more of peptide. However, due to the small number of 
responders, the weak response and the absence of a dose relationship or peak effect it was 
not possible to conclude that FLU-v with adjuvant elicited a humoral response in mice when 
administered subcutaneously on Days 1 and 15. All studies demonstrated evidence of an 
injection site response in animals receiving FLU-v either with or without adjuvant and adjuvant 
alone, although the response was more marked in those groups receiving both FLU-v and 
adjuvant compared to FLU-v alone. There were gross observations at the parenteral sites 
included inflammation, cystic spaces, fibrosis and necrosis and vacuolation and increase in 
paracortex cellularity was observed in the lymph nodes and the lungs. These effects were 
likely to be due to the adjuvant used in the studies, ISA 51, which contains a mixture of mineral 
oil and surfactant and is known to cause inflammation at the injection site. For more 
information on ISA 51, see ‘Adverse Reactions’ above and Investigator’s Brochure for 
Montanide® ISA 51, 2008. Treatment with FLU-v up to four doses of 263 μg/occasion or up 
to two doses of 553 μg/occasion with or without adjuvant, was well tolerated with no signs of 
systemic toxicity. 
5.2.3 
Clinical studies 
5.2.3.1 Pharmacology and Safety 
Two Phase I studies of FLU-v have completed and enrolled 82 subjects of whom 56 have 
been exposed to FLU-v. 
 
 

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Phase I study (FLU-v-001) 
FLU-v-001 was a first-in-man, single-centre, randomised, double-blinded, placebo-controlled 
study. A total of 48 healthy adult males were to be enrolled, 51 subjects were enrolled. There 
were 2 groups with 24 subjects in each group. The first group received 250μg (Dose Level 1), 
and the second group received 500μg (Dose Level 2) FLU-v.  48 subjects were planned to be 
enrolled but 51 subjects were enrolled due to a dosing error with 3 of the subjects. 
The study demonstrated a good safety profile as well as similar good immune responses in 
humans as those seen in animal models. No safety or tolerability concerns were identified at 
the doses administered to the subjects in the study. No safety or tolerability concerns were 
identified following administration of the adjuvant to the subjects in this clinical study.  
Pharmacodynamics results: 
FLU-v was shown to be immunogenic in humans, as measured by ex vivo INF- production. 
Strong IFN-γ responses were seen in six of nine subjects in the 250μg adjuvanted cohort and 
in eight of ten subjects in the 500μg adjuvanted cohort, indicating a potential dose-response 
to the vaccine. There were no significant responses in the unadjuvanted cohorts. No 
immunoglobulin production was seen in any of the vaccinated subjects. (See Section 6.3 in 
the IB v4.0 7th June 2016). 
Safety results: 
There were no deaths during the study. There was one SAE of appendicitis considered not to 
be related to study treatment. 
Three subjects were excluded from the protocol and the total treated analysis sets as the dose 
of FLU-v they received could not be determined. A total of 129 TEAEs (treatment emergent 
adverse events) were reported by 36 subjects receiving 250 or 500 μg FLU-v and 20 TEAEs 
were reported by 8 subjects receiving placebo. There was no apparent increase in the 
incidence of TEAEs at Dose Level 2 (500 μg) compared with Dose Level 1 (250 μg). 
The majority of TEAEs were reported in the system organ class of general disorders and 
administration site conditions; 15 TEAEs reported by subjects receiving 250 μg FLU-v without 
adjuvant, 29 TEAEs reported by subjects receiving 250 μg FLU-v with adjuvant, 15 TEAEs 
reported by subjects receiving 500 μg FLU-v without adjuvant and 34 TEAEs reported by 
subject receiving 500 μg FLU-v with adjuvant. Injection site pain was the most frequently 
reported TEAE and subjects receiving FLU-v with adjuvant reported more events of injection 
site pain (approximately 2-fold difference) than subjects receiving FLU-v without adjuvant. 
Within this system organ class, injection site pruritus (6 events), injection site swelling (6 
events) and pyrexia (1 event) were only reported by subjects receiving adjuvant. 
Adverse events of headache, malaise, fatigue, myalgia, nausea, vomiting diarrhoea, chills 
fever and other (as reported by the subject) were assessed for systemic tolerability. Neither 
vomiting nor chills were reported by subjects during the trial. The most commonly reported 
TEAEs by subjects receiving FLU-v were headache (11 events), fatigue (9 events), malaise 

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(7 events), myalgia (7 events) and nausea (4 events). One event each of diarrhoea and 
pyrexia were reported. 
Assessment of local tolerability (itching, pain and tenderness) indicated that the majority of 
reactions were reported at the 0.08 h (5 minute) post dose time point. Most reactions were 
reported as mild and there were no reported severe reactions. 
There were no clinically significant findings in either the individual or mean laboratory 
measurements, vital signs or ECG measurements. 
In conclusion, no safety or tolerability concerns were identified at the doses administered 
(250μg and 500μg FLU-v) to the subjects in the study. No safety or tolerability concerns were 
identified following administration of the adjuvant to the subjects in the study.  
The FLU-v vaccine candidate was demonstrated to be immunogenic in humans, as measured 
by ex vivo INF- production. 
Phase Ib study (FLU-v-002) 
FLU-v-002 was a single-centre, randomised double-blind, placebo-controlled, Phase Ib trial to 
evaluate the safety, tolerability and protective efficacy of the influenza vaccine candidate, FLU-
v, in an influenza challenge model. 32 subjects were vaccinated, 28 were quarantined and 27 
completed the study. 16 subjects FLU-v 500 μg + adjuvant and the other 16 received placebo 
+ adjuvant. Subjects were healthy males aged 18 to 45 years, who had not had seasonal 
influenza vaccination since 2006 or a known influenza infection in the 12 months prior to study 
entry, who were serosusceptible to Influenza A/Wisconsin/67/2005 (H3N2) virus at screening, 
and in good health as determined by past medical history, physical examination, vital signs, 
electrocardiogram (ECG), and laboratory tests at screening. 
Efficacy 
The study demonstrated similar good immune responses to the previous Phase I study 
following FLU-v treatment (see Section 6.3.2 in the IB v4.0 7th June 2016). The dose of 
Challenge Virus used in the study was intended to cause mild symptoms in volunteers, and 
an attack rate of approximately 70% to 80% in the placebo group, which was not achieved. 
It is possible that in this study, the low rates of infectivity in the placebo group and the resulting 
apparent lack of efficacy of FLU-v may have been related to pre-existing multi-strain (i.e., 
heterologous) cellular immunity arising from previous asymptomatic exposure of the 
population to viral infection during a recent Influenza pandemic between June 2009 and 
February 2010. In addition, pre-existing T cells responding to Influenza internal proteins may 
have been associated with lower virus shedding and a less severe illness. 
As a result of these potential unforeseen circumstances, there was no statistical evidence that 
FLU-v conferred clinical protection to subjects or reduced illness subsequent to being 
challenged with intranasal Influenza A/Wisconsin/67/2005 (H3N2). However, when looking at 
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strain, the subjects in the control group were more symptomatic and ‘ill’ compared to the 
subjects in the vaccinated group who did not become significantly symptomatic. (see Section 
page 12 in the IB v4.0 7th June 2016). 
Live virus challenge studies can play a pivotal role in developing novel vaccine such as this 
one.   Through a well-controlled challenge study, the time and number of patients needed to 
evaluate such a vaccine can be greatly decreased, and a more thorough analysis of the 
immune response to such a vaccine in the presence of infection can be observed.   
Safety Results: 
16 FLU-v and 16 Placebo subjects were included in the safety analysis. 
Adverse events: 
All subjects reported AEs. 32 subjects reported mild AEs (16 FLU-v: 16 Placebo), 10 reported 
moderate AEs (6 FLU-v: 4 Placebo) and 1 subject had a severe adverse event (AE) 
(presyncope- Placebo). There were no serious adverse events (SAEs). 
Injection site AEs related to the investigational medicinal product (IMP) were frequently 
reported and most were mild. Pain, swelling and erythema were most commonly reported by 
the FLU-v group within 24 hours post-vaccination. AEs related to the injection site 
corresponded with those reported for Montanide ISA-51-VG (Seppic), used as an adjuvant in 
the vaccine and Placebo preparations. One FLU-v subject had an injection site lump removed 
6 months following the study. It is likely that this was related to the site and volume injected 
which has been amended for this study. (see IB section 6.3.2)” 
FLU-v appeared to be generally safe, although AEs associated with the adjuvant Montanide 
ISA-51-VG (Seppic) at the injection site were frequently reported. It was suspected that this is 
due to the large 1mL volume being injected into the forearm where there is little skin depth. In 
the current study the site chosen this time is the upper arm and with a reduced volume of 
0.5mL. 
 
4 FLU-v (25%) and 3 Placebo (18.8%) subjects reported rhinorrhoea which 
was considered IMP related. 
 
In general, changes in complete physical examination, clinical chemistry, 
haematology and urinalysis, vital signs, ECG, oral temperature or concomitant 
medications were not clinically significant and were resolved by the end of the 
study. 
 
2 Placebo subjects had abnormal spirometry results at the Day 28 follow-up, 
which were followed up post-study and resolved. 
In conclusion, the dose of Challenge Virus used in this study was intended to cause mild 
symptoms in volunteers, and an attack rate of approximately 70% to 80% in the Placebo 
group, which was not achieved. It is possible that in the study, the low rates of infectivity in the 
Placebo group and the resulting apparent lack of efficacy of FLU-v may have been related to 
pre-existing multi-strain (i.e., heterologous) cellular immunity arising from previous 

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asymptomatic exposure of the population to viral infection during a recent Influenza pandemic 
between June 2009 and February 2010. 
It is also possible that pre-existing T cells responding to Influenza internal proteins may have 
been associated with lower virus shedding and less severe illness. This was determined by 
looking at pre-vaccinated PBMC’s from volunteers and looking for responses to pandemic 
strain flu viruses including the swine flu circulating at that time. It was found that the majority 
of volunteers in the placebo group had PBMC’s against the pandemic while the minority in the 
vaccinated group had such pre-exposure. It has been clearly established by other researches 
that exposure to the swine flu produced cross protection against other strains of flu for a period 
of time.  
5.3 
 Rationale for the study design 
Current Phase IIb Study 
The doses selected for the Phase IIb  study have been chosen based on the best results seen 
from previous Phase I human trial studies. 
This is a randomised, double-blind, placebo-controlled, single-centre, Phase 2b study of FLU-
v administered at Day -43 and Day -22 prior to intranasal challenge at Day 0 with the Influenza 
A 2009 H1N1 human challenge virus. Subjects will be randomised 1:1:1 to three treatment 
arms: 
 
Group 1: adjuvanted placebo on Day -43 and on Day -22  
 
Group 2: 500 mcg adjuvanted FLU-v vaccine on Day -43 and 1 dose of adjuvanted 
placebo on Day -22 
 
Group 3: 500 mcg adjuvanted FLU-v vaccine on Day -43 and on Day -22  
A placebo control will be used to establish the frequency and magnitude of changes in 
endpoints that may occur in the absence of active treatment. Randomisation will be used to 
minimize bias in the assignment of participants to treatment groups, to increase the likelihood 
that known and unknown participant attributes (e.g., demographic and baseline 
characteristics) are evenly balanced across treatment groups, and to enhance the validity of 
statistical comparisons across treatment groups. Blinded treatment will be used to reduce 
potential bias during data collection and evaluation of endpoints. Due to the local injection site 
reactions likely from Montanide ISA-51 adjuvant, masking of syringe barrels is deemed 
superfluous. However, the blinded study personnel will remain blinded to the presence or 
absence of FLU-v vaccine.  
In this study, the main efficacy comparisons are for each of the FLU-v groups to placebo. The 
study will also compare the two FLU-v dosing arms but the study will only have power to detect 
a significant difference in MMID rates between the FLU-v groups and placebo and not against 
each other.  

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Assuming significant efficacy of at least one dose of FLU-v against placebo is demonstrated 
in the current protocol (Part A), when all the primary efficacy endpoint and key safety results 
are available, the protocol may be amended to include a second part (Part B) which will test 
the optimal FLU-v dose from Part A (in terms of efficacy and safety) versus current standard 
of care seasonal influenza vaccine. Details of Part B will be determined and documented in a 
future protocol amendment following the availability of the unblinded key efficacy and safety 
results from Part A. Approval will be sought via a substantial amendment from the competent 
authority before part B can commence 
5.3.1 
Overall benefit/risk assessment 
Based on the available data and proposed safety measures, the overall risk/benefit 
assessment for this study is considered acceptable. 
Influenza (flu) is an infectious disease of birds and mammals caused by an RNA virus of the 
family Orthomyxoviridae (the influenza viruses). In humans, common symptoms of influenza 
infection are fever, sore throat, muscle pains, severe headache, coughing, and weakness and 
fatigue. In more serious cases, influenza causes pneumonia, which can be fatal, particularly 
in young children and the elderly. 
Typically, influenza is transmitted from infected people through the air by coughs or sneezes, 
creating aerosols containing the virus. Influenza can also be transmitted by saliva, nasal 
secretions, faeces and blood. Infections occur through contact with these bodily fluids or with 
contaminated surfaces. Flu viruses can remain infectious for about one week at human body 
temperature, over 30 days at 0°C (32°F), and indefinitely at very low temperatures. Most 
influenza strains can be inactivated easily by disinfectants and detergents. 
Flu spreads around the world in seasonal epidemics. This was the situation during the 
influenza pandemic of 1918-19, when a completely new influenza virus subtype (influenza 
A/H1N1) emerged and spread around the globe in around four to six months. Several waves 
of infection occurred over two years, killing an estimated 40-50 million people. Since then there 
have been two subsequent influenza pandemics, in 1957 and 1968. In 2009, the swine flu 
(H1N1) was the cause of a pandemic that reached a phase 6 pandemic alert and was 
moderate in severity. Currently available influenza vaccines utilise a Quadrivalent killed 
vaccine, incorporating two A strains (H1N1 like and H3N2 like) and a two B strains. Whilst 
these vaccines confer a degree of immunity; antigenic drift, together with the emergence of 
newer strains, limit their usefulness  to  a  single season, and the need for annual manufacture 
has considerable impact on cost, as well as the risk that an incorrect prediction of the virus 
types will lead to an unacceptable level of protection. There is a need for a “universal” vaccine 
that would be available on an annual basis for winter influenza, but would also have the ability 
to be rapidly deployed in the face of a pending pandemic, without the need to identify the novel 
strain and develop a novel vaccine. 
PepTcell have developed a novel approach to this problem by developing a vaccination  that 
contains  four  polypeptides,  each  of  which  contains  multiple  epitopes  thought  to  generate  
a significant cell-mediated and antibody immune response to the influenza virus, named FLU-

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v. Importantly, however, PepTcell have shown that these polypeptide sequences are relatively 
conserved between different strains and are therefore likely to provide a more consistent 
immune response, even in the face of a variety of viral strains. 
FLU-v has undergone comprehensive testing in a number of non-clinical studies including 
safety pharmacology, repeat dose toxicology, four-week repeat dose toxicology and local 
tolerance tests conducted in rats, mice and rabbits. Overall, the vaccine and vaccine/adjuvant 
combinations were safe and had no significant toxicity at the doses tested. Safety 
pharmacology studies in rats showed only minor and transient changes in cardiovascular and 
respiratory parameters that were not considered biologically relevant.  In addition, local 
tolerance of FLU-v administered subcutaneously with or without adjuvant (ISA 51), was 
assessed in rabbits each receiving a single subcutaneous injection of 502.7 µg FLU-v. 
Following observation for five days, the animals showed no sign of local reaction to treatment 
and no clinical signs or treatment-related bodyweight changes during the study period. 
Subcutaneous injection of FLU-v or FLU-v with adjuvant was well tolerated with no local or 
systemic sign of reaction to treatment. Although there were some histological findings, these 
were considered to be due to treatment with adjuvant or were procedural. There were no 
treatment related findings associated with FLU-v observed in the study. Two Phase I studies 
have demonstrated good safety , tolerability and good immunological responses in human 
subjects 
In summary, the clinical and non-clinical studies completed with Flu-v suggest that this  
vaccine has an acceptable safety profile, well tolerated and suitable for ongoing development 
in human studies. In addition, PepTCells novel approach identifying conserved epitopes of the 
influenza vaccine differs from approaches used previously. Given these factors and the fact 
that a vaccination treatment is likely to represent an important option not only for seasonal 
influenza, but also as an important public health treatment in the event of a pandemic, the 
potential benefits of this study outweigh the risks. 
5.3.1.1 Vulnerable populations 
To reduce the risk of passing the Challenge Virus to others, subjects will be asked to avoid 
contact with vulnerable people for 2 weeks after they leave quarantine. For the purposes of 
this protocol, a vulnerable individual is a person who:  
 
Is a child under five years old 
 
Is elderly (aged 65 years or older) 
 
Pregnant or breastfeeding women 
 
Has known immunodeficiency 
 
Is receiving immunosuppressant medications 
 
Is undergoing or soon to undergo cancer chemotherapy within 28 days of Viral 
Challenge  
 
Has been diagnosed with chronic obstructive pulmonary disease (COPD) or other 
severe lung or heart disease  
 
Has received a bone marrow or solid organ transplant. 

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Should any new information relevant to the subjects’ participation in the study and their safety 
become available, a member of the hVIVO medical staff will notify subjects in a timely manner. 
If appropriate, subjects will be asked to reconfirm their consent to their participation in the 
study. 

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6 
STUDY OBJECTIVES 
6.1 
Primary objective 
To determine the effect of FLU-v in reducing the incidence of Mild to Moderate Influenza 
Disease (MMID) defined as detectable viral shedding plus at least one symptom of influenza 
Assuming significant efficacy of at least one dose of FLU-v against placebo is demonstrated 
in the current protocol (Part A) when all the primary efficacy endpoint and key safety results 
are available, the protocol may be amended to include a second part (Part B) which will test 
the optimal FLU-v dose from Part A (in terms of efficacy and safety) versus current standard 
of care seasonal influenza vaccine. Details of Part B will be determined and documented in a 
future protocol amendment following the availability of the unblinded key efficacy and safety 
results from Part A.  Approval will be sought via a substantial amendment from the competent 
authority before part B can commence  
6.1.1 
Primary endpoint 
Incidence of MMID.  
6.2 
Secondary objectives 
To determine the overall effect of FLU-v on measurements of disease severity. 
6.2.1 
Secondary endpoints 
 
Viral shedding duration 
 
Viral shedding quantitation 
 
Symptom duration 
 
Total number of symptoms experienced 
 
Symptom severity score as measured by FLU-PRO Symptom Questionnaire  
 
Incidence of vaccine related adverse events (diary card for 21 days after each vaccine)  
6.3 
Exploratory objectives 
To explore the immunological responses to FLU-v 
6.3.1 
Exploratory endpoints 
 
Immunogenicity of FLU-v as measured by 
o B-cell and T-cell responses to FLU-v both after vaccination as well as influenza 
challenge 
o Immunophenotyping 
 
Broadness of protection as measured by culturing PBMCs pre-influenza virus 
inoculation in study with PBMCs (same subject) infected with influenza and assess 
killing of infected cells by PBMCs from vaccinated subjects and use sera containing 

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non-neutralising antibodies and test killing of human influenza infected cells by 
complement activation or ADCC assays. 
Exploratory endpoints may be reported separately from the clinical study report (CSR). 
6.4 
Safety objectives 
To determine the safety and tolerability of FLU-v after vaccination in healthy subjects 
subsequently challenged with Influenza A 2009 H1N1 human challenge virus 
6.4.1 
Safety endpoints 
 
Incidence of treatment-emergent AEs (TEAE), severity, seriousness and causality 
 
Absolute values and change from baseline in routine clinical and laboratory parameters  
 
Vaccine Related Physical examination findings  
 
Concomitant medications. 
 

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7 
STUDY POPULATION 
Participants will be carefully selected using the inclusion and exclusion criteria described here 
to select the optimum participants for completing the study objectives and minimize the risk of 
adverse events (AEs).  
7.1 
Number of subjects 
Up to 123 subjects will be inoculated with the influenza challenge virus at a dose of 107 TCID50 
after being randomised 1:1:1, and dosed with FLU-v 1 dose plus placebo, 2 doses, or placebo 
7.2 
Inclusion criteria 
Each potential subject must satisfy all of the following criteria to be enrolled in the study.  
NO 
INCLUSION CRITERIA 
1 
Healthy males and females aged ≥18 and ≤55 years of age at the point of 
enrolment.  
2 
Willingness to remain in isolation for the duration of viral shedding and to comply 
with all study requirements. 
3 
The following criteria are applicable to subjects in a heterosexual relationship and 
female subjects in a same sex relationship (i.e., the criteria do not apply to male 
subjects in a same sex relationship): 
- 
True abstinence- when this is in line with the preferred and usual lifestyle of 
the subject. (Periodic abstinence [e.g. calendar, ovulation, symptothermal, 
post-ovulation methods] and withdrawal are not acceptable methods of 
contraception). 
Or 
- 
Two forms of effective contraceptive methods among (between) the couple, 
which are defined as: 
o For males: condom with spermicidal foam/gel/film/cream, 
sterilisation (with the appropriate post-vasectomy documentation of 
the absence of sperm in the ejaculate. This applies only to males 
participating in the study). 
o For females: 
 
Women no longer of child bearing potential (post-
menopausal females are defined as having a history of 
amenorrhea for at least 2 years, otherwise they should have 
documented status as being surgically sterile or post 
hysterectomy. The latter applies only to females participating 
in the study). 

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NO 
INCLUSION CRITERIA 
 
If of childbearing potential, then acceptable forms of 
contraception include: 
 
Established (a minimum of 2 weeks prior to admission) use 
of oral, injected or implanted hormonal methods of 
contraception. 
 
Placement of an intrauterine device (IUD) or 
intrauterine system (IUS). 
 
Barrier methods of contraception or occlusive cap 
(diaphragm or cervical/vault caps), both with one of 
the following - spermicidal 
foam/gel/film/cream/suppository. 
o The longevity of contraception is as follows: 
 
Males: 
 
Comply with agreed contraception at entry to 
quarantine, and continuing until 90 days after the 
date of viral challenge/last dosing with IMP 
(whichever occurs last).  
 
Must not donate sperm following discharge from 
quarantine until 90 days after the date of viral 
challenge/last dosing with IMP (whichever occurs 
last). 
 
Females: 
If of childbearing potential must have a negative pregnancy test at screening and 
just prior to the date of Viral Challenge, and must be using contraception 
consisting of two forms of birth control (one of which must be a barrier method) 
starting from at least 2 weeks prior to the first vaccination and continuing until 90 
days after the date of Viral Challenge/last dosing with IMP (whichever occurs last). 
4 
Willing to have samples stored for future research. 
5 
Sero-suitable to the study challenge virus within 90 days of Day 0. 
6 
Agrees to abstain from alcohol intake 24 hours before admission on Day -2 or Day 
-1 and all other outpatient visits.  
7 
Agrees to not use prescription or over-the-counter medications (including aspirin, 
decongestants, antihistamines, and other NSAIDs), and herbal medication 
(including, but not limited to, Vitamin C, Vitamin D, immune booster products, 
herbal tea, St. John’s Wort), within 14 days prior to study vaccine administration 
through the final follow-up visit, unless approved by the investigator and sponsor 
medical monitor.  
8 
An informed consent document signed and dated by the subject and the 
Investigator or delegate. 

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NO 
INCLUSION CRITERIA 
9 
A history of childhood asthma before the age of 12 years is acceptable provided 
the subject is asymptomatic without treatment. Subjects with a single episode of 
wheezing (lasting less than 2 weeks) after the age of 12 years can be included at 
the Investigator’s discretion provided the episode was more than 1 year ago and 
did not require a hospital admission and/or oral/intravenous steroids. 
10 
In good health with no history of major medical conditions that will interfere with 
subject safety, as defined by medical history, physical examination, and routine 
laboratory tests and determined by the Investigator at a screening evaluation.  
 
A subject with a history of Herpes type 1 or 2 infection may be included if 
there are no active lesions present and the subject is not taking active 
medication.  
 
A subject with or without any evidence of atopy including any history of 
allergic rhinitis, dermatitis, and conjunctivitis will be included as long as they 
do not conflict with exclusion criteria.  
Mild to moderate arthritis of non-inflammatory origin may be allowed if the subject 
is not at risk from relative immobility in the Quarantine Unit and does not require 
regular medication.  
11 
A documented medical history for a minimum of the last 2 years prior to inoculation.  
7.3 
 Exclusion criteria 
NO 
EXCLUSION CRITERIA 
1 
Any subjects who have smoked 10 pack years at any time.  
Of those subjects that have smoked less than 10 pack years at any time, a subject 
will be excluded:  
If regular smokers (e.g., smoking every day) at the time of enrolment.  
 
If current casual smoker or use of smoking / nicotine-related products, they must 
agree to refrain from smoking during the in-patient stay 
2 
Presence of self-reported or medically documented significant medical condition 
including but not limited to: 
a. Chronic pulmonary disease (e.g., asthma (except what is stated in 
inclusion criteria 9), COPD) 
b. Chronic cardiovascular disease (e.g., cardiomyopathy, congestive heart 
failure, cardiac surgery, ischemic heart disease, known anatomic 
defects). 
c. Chronic medical conditions requiring close medical follow-up or 
hospitalisation during the past 5 years (e.g., insulin dependent diabetes 
mellitus, renal dysfunction, haemoglobinopathies). 
d. Immunosuppression, or immunodeficiency or ongoing malignancy. 

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NO 
EXCLUSION CRITERIA 
e. Neurological and neurodevelopmental conditions (e.g., cerebral palsy, 
epilepsy, stroke, seizures). 
f. Post infectious or post vaccine neurological sequelae. 
g. Hyperlipidemia requiring medical therapy per current American College 
of Cardiology (ACC) and American Heart Association (AHA) guidelines 
published in 2013. 
3 
Individual with body mass index (BMI) <18 and >35. 
4 
Acute illness within 7 days of first vaccine administration day  
5 
Clinically significant abnormal electrocardiogram (ECG) and/or parameters, as 
determined by the Investigator 
6 
Subjects with clinically significant abnormal systolic and diastolic blood pressure or 
clinically significant abnormal pulse rate. 
7 
Subject has abnormal pulmonary function as measured by spirometry defined as a 
forced vital capacity or forced expiratory volume in 1 second (FEV1) < 80% of 
predicted or peripheral arterial oxygen saturation (SpO2) < 92% on room air. 
8 
Known allergy to treatments for influenza (including but not limited to oseltamivir, 
nonsteroidals).  
9 
Known allergy to 2 or more classes of antibiotics (e.g. penicillins, cephalosporins, 
fluoroquinolones, or glycopeptides).  
Known allergy to excipients in the challenge virus inoculum 
10 
Daily or household contact with vulnerable populations as defined by 5.3.1.1 
11 
a) Receipt of any investigational drug within 3 months prior to the planned date of 
Viral Challenge/first dosing with IMP (whichever occurs first). 
b) Receipt of three or more investigational drugs within the previous 12 months prior 
to the planned date of Viral Challenge/first dosing with IMP (whichever occurs first). 
c) Prior inoculation with a virus from the same virus-family as the Challenge Virus. 
d) Prior participation in another Human Viral Challenge study with a respiratory virus 
in the preceding 12 months taken from the date of Viral Challenge/first dosing with 
IMP (whichever occurs first) in the previous study to the date of expected Viral 
Challenge in this study. 
12 
Receipt of any vaccine within 6 months of enrolment. 
13 
Self-reported or known history of alcoholism or drug abuse (including marijuana) 
within 6 months prior to enrolment, or positive urine/serum test for drugs of abuse 
during the study  

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NO 
EXCLUSION CRITERIA 
14 
Self-reported or known history of psychiatric or psychological issues that require 
treatment and are deemed by the PI to be a contraindication to protocol participation. 
15 
History of a previous severe allergic reaction with generalized urticaria, angioedema, 
or anaphylaxis. 
16 
History or evidence of autoimmune disease or known immunodeficiency of any 
cause – with the exception of atopic dermatitis/eczema and atopic rhinitis. 
17 
Subjects with any history of physician diagnosed and/or objective test confirmed 
asthma (except as per inclusion criteria 9), reactive airway disease, COPD, 
pulmonary hypertension, or chronic lung condition of any aetiology. 
18 
Positive human immunodeficiency virus (HIV) within 60 days of first vaccination visit, 
active hepatitis A (HAV), B (HBV), or C (HCV) test. 
19 
Any significant abnormality altering the anatomy of the nose or nasopharynx 
(including significant nasal polyps). 
20 
Venous access deemed inadequate for the phlebotomy and cannulation demands 
of the study. 
21 
Any nasal or sinus surgery within 6 months of Viral Challenge. 
22 
Recurrent history of fainting. 
23 
Those employed or immediate relatives of those employed at hVIVO or the Sponsor. 
24 
Any clinically significant history of epistaxis (nosebleeds) within the last 12 months 
and/or history of being hospitalized due to epistaxis on any previous occasion. 
25 
Females who:  
 
Are breastfeeding, or  
 
Have been pregnant within 6 months prior to the study, or  
Have a positive pregnancy test at any point during screening or prior to first dosing 
with IMP. 
26 
Presence of fever, defined as subject presenting with a temperature reading of > 
38.0°C on Day -43  

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NO 
EXCLUSION CRITERIA 
27 
Receipt of blood or blood products, or loss (including blood donations) of 470 mL or 
more of blood during the 3 months prior to the planned date of first dosing with IMP 
or planned during the 3 months after the final visit. 
28 
Receipt of systemic (intravenous and/or oral) glucocorticoids or systemic antiviral 
drugs within 6 months prior to the planned date of first dosing with IMP. 
29 
Any other finding that, in the opinion of the Investigator, deems the subject 
unsuitable for the study. 
7.4 
Discontinuation of a subject’s participation 
7.4.1 
Subject withdrawal 
A subject can withdraw from the study at any time, for any reason, without prejudice to his/her 
future medical care. Subjects do not have to give a reason for their withdrawal.  
However, subjects would be counselled that early withdrawal from the challenge isolation 
portion of the trial is strongly discouraged, as it may pose a risk both to the subject and his/her 
contacts outside of the Quarantine Unit. 
In the event of a subject insisting on early withdrawal following Viral Challenge, the subject 
would be encouraged to stay and would be advised of the potential risks of carrying an 
Influenza virus infection into the community, and to vulnerable groups (Section 5.3.1.1) in 
particular. The subject would be referred to his/her GP and wherever possible, followed up at 
home. Each subject would be counselled regarding their consent and asked to return for a 
follow-up visit. 
All subjects will be advised that for 2 weeks following discharge from the Quarantine Unit they 
should avoid close contact with vulnerable people, as described in Section 5.3.1.1. 
If a subject withdraws before completing the study, the reason for withdrawal should be 
documented in the electronic case report form (eCRF) and in the source document. Study 
drug assigned to the withdrawn subject will not be assigned to another subject. In case 
subjects withdraw from the study after receiving vaccination(s) but prior to influenza challenge, 
replacement subjects will be recruited. 
In the case, that a participant is withdrawn from the study after receiving vaccination(s) but 
prior to influenza challenge, all efforts will be made to follow these patients at the outpatient 
visits as outlined in the T&E. 
7.4.2 
Subject discontinuation 
A subject's participation may be stopped for any of the following reasons 
 
Withdrawal of subject consent. 

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 
Clinically significant abnormal laboratory findings, which in the opinion of the 
Investigator(s) and/or Sponsor precludes further participation in the study. 
 
Consumption of homeopathic or pharmaceutical remedies for the symptomatic 
treatment of an upper respiratory tract (URT) infection (e.g., decongestants, 
antipyretics, etc.), unless prescribed by the Investigator after consultation with the 
Sponsor and Investigators. 
 
Development of inter-current illness which, in the opinion of the Investigator(s), would 
compromise the health of the subject or the study objectives. 
 
Pregnancy 
 
Investigator’s decision that withdrawal from further participation would be in the 
subject’s best interests. 
 
Non-compliance with study requirements. 
 
Termination of the study at the discretion of the Investigator(s) or Sponsor for safety 
behavioural or administrative reasons. 
 
The PI or the study-site personnel break the randomisation code. 
 
The subject experiences an acute systemic allergic reaction ≥ Grade 3. 
 
Lost to follow-up (every reasonable effort must be made by the study-site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. The 
measures taken to follow up must be documented). 
Suitability check will be conducted by the study physician to confirm that subject is still suitable 
to continue with study participation, on Day -22, Day -2 /-1 and Day 0. This will include but not 
limited to the following assessments: 
 
Acute illness within 7 days of any vaccine administration day or admission to 
quarantine. Subjects can be rescheduled for another Viral challenge admission day if 
possible and the protocol window permitting. 
 
Presence of fever, defined as subject presenting with a temperature reading of > 38.0 
°C on Day -22 and/or Viral Challenge on Day 0. Subjects can be rescheduled for 
another Viral challenge day if possible and the protocol window permitting. 
 
Known close contact with anyone known to have a positive test for influenza in the 7 
days prior to virus inoculation. 
7.4.3 
Pregnancy 
In the event of a subject discontinuing the study prematurely due to pregnancy, or if pregnancy 
in a subject’s partner becomes known, the procedure outlined in Section 15.4.4 should be 
followed. 
7.5 
Replacements and reserve subjects 
If a subject is withdrawn from the study prior to influenza challenge, replacement subjects will 
be recruited. Once a subject is challenged with influenza virus he/she will not be replaced.  

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7.6 
Subject numbering 
hVIVO assigns a subject number to each volunteer in the hVIVO volunteer database. This 
subject number will be used to identify a volunteer up to the point of randomisation (Section 
10.1), on source documents, on all study correspondence and in the study database. 
For volunteers who subsequently do not enter the study, a reason will be documented in the 
source documentation and the subject’s medical notes.  
For subjects who are subsequently enrolled into the study, the PI will keep an identification 
code list and enrolment log, listing initials of each subject alongside the subject number 
assigned and the date enrolled. This log will remain in the ISF at the study site. Replacement 
subjects will be assigned a new, unique subject number (Section 10.1).  

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8 
STUDY RESTRICTIONS 
8.1 
Concomitant therapies 
All concomitant prescription medications (including vaccines but with the exception of post-
exposure prophylaxis), over-the-counter medications, or herbal remedies taken during study 
participation must be approved by the PI and will be recorded in the participant’s source 
documents. For this protocol, a prescription medication is defined as a medication that can be 
prescribed only by a properly authorised/licensed clinician. Symptomatic treatment 
(antipyretics, antitussives, decongestants, etc.) in individuals not requiring an increased level 
of care will be administered at the discretion of the PI and recorded carefully in the source 
documents.   
8.2 
Strenuous exercise 
Subjects will refrain from strenuous activities for the duration of the quarantine period and for 
3 days prior to screening and follow-up visits. .  
8.3 
Tobacco  
Subjects should abstain from smoking or using nicotine products or e-cigarette products prior 
to assessment visits to the research facility. 
8.4 
Alcohol, caffeine and xanthine-containing food and beverages 
Subjects should abstain from alcohol, caffeine and xanthine-containing food and beverages 
(e.g., coffee, tea, energy drinks, cola, chocolate) between 24 hours prior to vaccine and dosing 
as well as prior to admission to quarantine.  They will continue to abstain until after discharge 
from quarantine unit. Decaffeinated drinks will be provided during the quarantine period. 
8.5 
Contraception  
Male and female subjects of childbearing potential who engage in heterosexual intercourse 
must agree to utilize protocol-recommended methods of contraception. The required 
contraceptive measures are outlined in the study eligibility criteria (Section 7.2).  
Postmenopausal women (no spontaneous menses for at least 2 years), women with surgical 
sterilisation (documented GP evidence of a total hysterectomy, bilateral oophorectomy, 
bilateral tubal ligation/bilateral tubal clips without reversal operation), and women who are 
otherwise incapable of becoming pregnant must use a condom when having heterosexual 
intercourse from 2 weeks prior to entry to quarantine and continuing until 90 days after the 
date of Viral Challenge / last dosing with IMP (whichever occurs last). 
Study approved contraceptive methods 
Established use of oral, injected or implanted hormonal methods of contraception. 

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Placement of an intrauterine device or intrauterine system. 
Barrier 
methods 
of 
contraception: 
Condom 
or 
diaphragm 
with 
spermicidal 
foam/gel/film/cream/suppository. 
Male sterilisation (with the appropriate post-vasectomy documentation of the absence of 
sperm in the ejaculate). [For female subjects on the study, the vasectomized male partner 
should be the sole partner for that subject]. 
True abstinence: When this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception. 
Subjects should be advised that a male and female condom should not be used together due 
to risk of breakage or damage caused by latex friction.  
8.6 
 Contact with vulnerable populations 
Subjects should avoid close contact with people who are known to be vulnerable to Challenge 
Virus infection (Section 5.3.1.1) for 2 weeks following discharge from the Quarantine Unit. 

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9 
STUDY DESIGN 
This is a randomised, double-blind, placebo-controlled, single-centre, phase IIb study of FLU-
v administered at Day -43 and Day -22  prior to intranasal challenge at Day 0 with the Influenza 
A 2009 H1N1 human challenge virus. Subjects will be randomised 1:1:1 to: 
 
Group 1: adjuvanted placebo on Day -43 and on Day -22 
 
Group 2: 500 mcg adjuvanted FLU-v vaccine on Day -43 and 1 dose of adjuvanted 
placebo on Day -22 
 
Group 3: 500 mcg adjuvanted FLU-v vaccine on Day -43 and on Day -22 
A placebo control will be used to establish the frequency and magnitude of changes in 
endpoints that may occur in the absence of active treatment. Randomisation will be used to 
minimize bias in the assignment of participants to treatment groups, to increase the likelihood 
that known and unknown participant attributes (e.g., demographic and baseline 
characteristics) are evenly balanced across treatment groups, and to enhance the validity of 
statistical comparisons across treatment groups. Blinded treatment will be used to reduce 
potential bias during data collection and evaluation of endpoints. Due to the local injection site 
reactions likely from Montanide ISA-51 adjuvant, masking of syringe barrels is deemed 
superfluous. However, the blinded study personnel will remain blinded to the presence or 
absence of FLU-v vaccine.  
The follow-up visit will be up to approximately 153 days or 22 weeks from screening within 90 
days of viral challenge to the last follow up visit on Day 63 (± 5 days). 
The total duration of the clinical phase of the study, from the start of volunteer screening to 
the last subject’s last scheduled visit (LSLV) is expected to be approximately 18 months.  
The timings of study procedures relative to each phase are shown in table 9.2 and the 
procedures and assessments which will be undertaken to evaluate safety and efficacy are 
described in Sections 13. 
Subjects will: 
 
Attend study-specific screening (SSS) within -90 days prior to viral challenge 
 
Vaccination on Day -43 
 
Vaccination on Day -22 
 
Entry to quarantine on Day -2 or Day -1 
 
Challenge Virus inoculation on Day 0 
 
Subjects will be resident in the Quarantine Unit for a total of approximately 10 days 
(from Day  -2/-1 to Day 7) 
 
End of quarantine phase starting from Day 7 when 2 negative diagnostic tests for 
influenza on two separate days are achieved 
 
Follow-up visits: Day 35 (+/- 3) and Day 63 (+/- 5) days

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Table 9-2: Time & Events Schedule  
Visits 
Visit 1 
Visit 2 
21 days post vaccination 1 
Visit 3 
21 days post vaccination 2 
Visit 4 
Visit 5 
Visit 6 
Study Phase > 
Screen 
IMP 
DOSING 
IMP 
DOSING 
Quarantine 
Admission 
Inpatient 
Follow-
Up 
Follow-Up 
Study Day > 
~ DAY --
90  to -
43 
D-43 
D-22 
D-2 
D-1 
D0 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 - 
15 
D35 (+/- 
3 days) 
D63 (+/- 5 
days) 
Challenge 
or  Early 
withdrawa
l visit 
Inpatient 
hospitalisation 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical & 
Medication History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outpatient Visit 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Eligibility Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Suitability check4 
 
 
 
X 
 
X6 
X 
 
 
 
 
 
 
 
 
 
 
Written Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events & 
Concomitant 
Medication review 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
X 
Distribution and 
collection of 
Adverse Events 
diary card post 
vaccination visit 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Completion of 
Adverse Events 
diary card post 
vaccination visit 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physician 
Assessment and 
CPE 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
(X) 
X 
X 
Physician 
Assessment and 
DPE 
 
 
 
 
 
 
X1 
X 
X 
X 
X 
X 
X 
 
(X) 
 
 
Self-administered 
FLU-PRO 
Symptom 
Questionnaire§ 
 
 
 
 
 
X6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 

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Visits 
Visit 1 
Visit 2 
21 days post vaccination 1 
Visit 3 
21 days post vaccination 2 
Visit 4 
Visit 5 
Visit 6 
Study Phase > 
Screen 
IMP 
DOSING 
IMP 
DOSING 
Quarantine 
Admission 
Inpatient 
Follow-
Up 
Follow-Up 
Study Day > 
~ DAY --
90  to -
43 
D-43 
D-22 
D-2 
D-1 
D0 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 - 
15 
D35 (+/- 
3 days) 
D63 (+/- 5 
days) 
Challenge 
or  Early 
withdrawa
l visit 
Physician 
assessment of 
Influenza 
Symptoms 
 
 
 
 
 
X6 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
 
 
Vital signs † 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
X 
Pregnancy test‡ 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Urine drugs of 
abuse 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
(X)2 
(X)2 
Alcohol Breath 
Testing 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Nasal swab 
 
X 
 
 
 
 
X6 
 
X 
X 
X 
X 
X 
X 
X 
(X) 
 
 
Respiratory 
pathogen screen 
 
 
 
 
 
X6 
 
 
 
 
 
 
 
 
 
 
 
Spirometry 3 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
(X)2 
 
 
Height, Weight 
and BMI (Height 
performed only at 
screening) 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
ECG† 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
(X)2 
X 
X 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccination visit 
and clinic 
observation 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Challenge virus 
inoculation 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
CBC + diff 
(Haematology) 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
(X)2 
X 
X 
Biochem: Acute 
Care, Mineral, and 
Hepatic Panels 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
(X)2 
(X)2 
(X)2 

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Visits 
Visit 1 
Visit 2 
21 days post vaccination 1 
Visit 3 
21 days post vaccination 2 
Visit 4 
Visit 5 
Visit 6 
Study Phase > 
Screen 
IMP 
DOSING 
IMP 
DOSING 
Quarantine 
Admission 
Inpatient 
Follow-
Up 
Follow-Up 
Study Day > 
~ DAY --
90  to -
43 
D-43 
D-22 
D-2 
D-1 
D0 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 - 
15 
D35 (+/- 
3 days) 
D63 (+/- 5 
days) 
Challenge 
Or Early 
withdrawa
l visit 
Biochem: Creatine 
Kinase, and Total 
Protein 
X 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
(X)2 
(X)2 
(X)2 
Serum / Whole 
Blood Collection7 
X 
 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
(X)2 
X 
X 
HIV, Hepatitis 
A/B/C 
X 
 
 
 
 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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KEY NOTES FOR TIME AND EVENTS SCHEDULES 
Symbol 
Notes 
Results of tests or examinations performed under other ethically approved hVIVO protocols, and within 90 days prior to admission to quarantine, 
may be used to determine eligibility without the need to repeat the assessment at study specific screening. 
* 
If continued viral shedding is detected on Day 7, the participant(s) will remain in quarantine as an inpatient and will continue 
to have nasal swabs and physician assessment and exams.  In addition FLU-PRO symptom questionnaires will continue 
up to day 15. Any other procedures will be performed if deemed necessary by the study physician. 
† 
Vital Signs and ECG’s:  participants must be supine for a minimum of 5 minutes prior to these procedures being performed; 
vital signs include blood pressure, mean blood pressure, heart rate, respiratory rate, temperature, pulse oximetry.  During 
the quarantine confinement vital signs will be taken 3 times a day at the same time +/- 1 hour except on Day -2, when it will 
be conducted once and on discharge day when it will be performed once or twice depending on discharge time. ECG should 
be performed once daily 
‡ 
Females only - Serum pregnancy testing at the screening visit and, urine pregnancy testing on Days -43, -22, -2, 35 and 
63.  
§ 
FLU-PRO Symptom Questionnaire(s) will be filled out daily in the evening on Days -2 or-1, 0 through to Day 15, and on 
Day 35  
 
 
NP nasal sampling will take place 2 times a day at the same time +/- 1 hour, except on Day -2 / -1 where there is 
one baseline sampling and on discharge day. No nasal sampling will take place on Day 0.   
 
NPS - tolerance only at screening  
(X) 
Optional - Only for subjects kept in VCU after D7.  If the subject is not discharged on day 7, they will continue to have vital 
signs, physical assessments, nasal swabs, adverse event s & concomitant medication check, and FLU-PRO questionnaires 
performed daily. 
1 
DPE to be performed before and after inoculation at D0 
2 
These assessments will be performed at the PI’s discretion 
3 
Spirometry will be performed during the inpatient phase in presence of lower respiratory tract symptoms 
4 
A continued suitability check will be conducted by the physician to determine if subject is suitable to continue study 
participation 
5 
Repeat HIV test if screening results are more than 60 days prior to entry to Quarantine  (on Day -2 or Day -1) 
6 
Assessments will be performed once, either on Day -2 or Day -1 
7 
Challenge virus Serology will be performed only at Screening visit. A repeat may be requested before admission if required, 
however, the serology test and result must be dated within 90 days of Day 0. PBMC & PAXgene samples will be collected 
from subjects, either at their screening visit or at a planned PBMC sampling visit prior to their vaccination. 

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9.1 
Screening phase 
9.1.1 
Visit 1 - Study specific screening  
Screening will be performed within 90 days of inoculation and prior to Day -43.  The 
participants will sign the informed consent document prior to any study procedures. Study 
screening procedures will be conducted as detailed on the Time and Events, table 9.2.  
  
9.2 
Vaccination Phase 
9.2.1 
Visit 2 - Day -43 
The first vaccine or placebo administration will take place on Day -43, 43 days prior to virus 
challenge. Study procedures will be conducted as detailed on the Time and Events, table 9.2 
Once it is determined that the participant still meets Inclusion/Exclusion criteria for the 
research study, participants will receive the first of two injections of FLU-v 500mcg+adjuvant 
2 doses, FLU-v 500mcg 1 dose + 1 dose placebo , or 2 doses of placebo.  The study team will 
thoroughly discuss the consent with the volunteer. The study team will issue and explain the 
completion of self-reported adverse events in a 21-day diary card. This diary card will be used 
to record vaccine-related local and systemic events post first vaccination. 
9.2.2 
Visit 3 - Day -22 (minimum 21 days post first vaccination +7 days) 
The second study drug administration will take place if the participant continues to meet all 
inclusion and none of the exclusion criteria. Study procedures will be conducted as detailed 
on the Time and Events schedule  
The study team will issue and explain the completion of self-reported adverse events in a 21-
day diary card. This diary card will be used to record vaccine-related local and systemic events 
post second vaccination. 
9.3 
Quarantine and Challenge 
9.3.1 
Visit 4 - Admission (Day -2 or Day -1 up to 40 days post second vaccination) 
Subjects will be admitted to the Quarantine unit on day -2 or day -1 (minimum 20 days post 
second vaccination). If subject is not available to attend admission on the Day -2/Day -1 due 
date, the visit can be scheduled up to 40 days post second vaccination.  
The admission procedures/assessments and testing will be performed after admission and 
before challenge virus administration. Study procedures will be conducted as detailed on the 
Time and Events schedule  
As determined by the PI, results of standard procedures performed in the process of admission 
to the Quarantine unit may be used to determine suitability, including but not limited to vital 
signs, height, weight, etc. They can also be used to extend eligibility beyond 90 days from 

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screening if the participant has been vaccinated but his admission has fallen out of the 90 
days window. A Viral Challenge serology test can be repeated if required before Quarantine if 
the participant has been vaccinated but the admission date has fallen out of the 90 days 
window. However, the serology test and result must be dated within 90 days of Day 0. 
9.3.2 
Virus Inoculation (Day 0) 
All baseline procedures and tests will be performed prior to challenge virus administration. 
Once it has been determined that the participant still meets eligibility criteria for the study and 
that he/she is comfortable in the unit, administration of the challenge virus will proceed at a 
dose of 107 TCID50 on Day 0. Once the influenza challenge virus has been administered, 
participants will remain hospitalized in isolation on the unit for a minimum of 8 additional days 
and will be discharged only after they meet the discharge criteria described below.  
9.3.3 
Day 1 through 7 
While admitted to the Quarantine Unit, participants will remain in isolation in their room. 
Participants will undergo study procedures which will be conducted as detailed on the Time 
and Events table 9.2 
Participants will be discharged when they meet the following discharge criteria: 2 consecutive 
negative morning nasal swabs (that occur on 2 different but consecutive days) for influenza 
A, are afebrile, show no signs of significant influenza symptoms, and are clinically and 
hemodynamically stable. It is expected that participants will shed virus for 3 to 5 days post 
inoculation; therefore, we expect most participants to have 2 consecutive negative 
nasopharyngeal swabs by Day 7 of the study. 
The FLU-PRO questionnaires will be completed in paper form.  
9.3.4 
Discharge 
Starting from Day 7 subjects will be discharged from the Quarantine Unit if the morning 
nasopharyngeal swab sample is negative (on two separate but consecutive days) for 
Challenge Virus. If the test is positive or the subject remains symptomatic, the subject will be 
asked to remain in the Quarantine Unit for further observation at the discretion of the PI.  
9.3.5 
Day 8 through 15 (if required) 
All subjects will complete diary card up to Day 15 while at home.  
All subjects remaining in quarantine unit will follow assessments as detailed in the T&E  

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9.4 
Visit 5 & 6 - Follow-up phase 
All participants will be followed for a minimum of 8 weeks after completing the inpatient portion 
of the study. Any participant who experiences complications due to challenge virus 
administration or study drug will be followed until resolution of such complications or 
appropriate referral to the necessary medical care has been made.  
Follow-up visits will take place on Day 35 (+/-3 days) and Day 63 (+/-5) days or more often if 
deemed medically necessary; the procedures/evaluations to be conducted at these visits are 
shown in T&E schedule.  Day 63 will be the final study visit unless the participant requires 
additional follow-up of study-related complications. 
Participants will be asked to report to the study team if any close contacts become ill with an 
influenza-like illness. If a close contact becomes ill with an influenza-like illness during the 
follow-up period, the participant will be asked to contact that individual and have them contact 
the hVIVO study team. The possibly infected person will be asked to come to the hVIVO facility 
for an assessment.  
9.4.1 
Lost to follow-up 
In the event that a subject does not return for the final follow-up visit post-Viral Challenge; the 
Investigator will make every reasonable effort to contact the subject to review all AEs. In the 
event that a subject drops out of the study at any time, the reason for discontinuation, if known, 
must be fully documented in the source data. The site personnel will document the AEs and 
any other assessments and will make every effort to complete all required end of study 
assessments. 
9.5 
End of trial
The end of the trial is defined as the last subject’s last scheduled visit (LSLV). If an additional 
visit is required after the last scheduled visit, this will be at the PI’s discretion, for example, 
repeat spirometry or laboratory tests. Such discretionary follow-up visits will not be considered 
part of the trial data unless they represent follow-up and closure on an AE or SAE identified 
during the trial period. 
AEs that are unresolved at the follow-up visit may necessitate further follow-up visits if 
required. 
9.5.1 
End of Trial Report  
It is the Sponsor’s responsibility to send the End of Trial Report to the Medicines and 
Healthcare products Regulatory Agency (MHRA) and Research Ethics Committee (REC) 
within 1 year of the end of the trial.  

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10 
RANDOMISATION AND BLINDING 
123 subjects will be randomised 1:1:1 to: 
 
Group 1: adjuvanted placebo on Day -43 and on Day -22 
 
Group 2: 500 mcg adjuvanted FLU-v vaccine on Day -43 and 1 dose of adjuvanted 
placebo on Day -22 
 
Group 3: 500 mcg adjuvanted FLU-v vaccine on Day -43 and on Day -22 
10.1 
Route of administration, dosage, dose regimen and treatment period 
The route of administration was chosen based on the animal data and on the adjuvant 
manufacturer. The mechanism of action of and oil adjuvant-based vaccines includes the 
formation of a depot at the injection site, enabling the slow release of the antigen and the 
stimulation of antibody-producing plasma cells. These formulations promote antigen uptake 
by APCs. Formulated antigens are concentrated and protected against degradation, while 
phagocytosis is stimulated by different ligand/receptor interactions. Subcutaneous injection is 
ideal for that. 
The dosage selection is supported by animal data and also previous clinical trial showing that 
500ug was better than 250ug. In clinical trials we have only given a single dose of FLU-v but 
animal data (presented in IB), shows that a second dose boosts the response. The two doses 
are given 3 weeks apart because that is the necessary length of time required for the immune 
system to mature the response to the antigen administered. 
 
10.2 
Randomisation for the study 
Potential subjects will be assigned a unique hVIVO subject number that will be used to identify 
them prior to entry to the study and during the study until the point of randomisation.  Once a 
subject in randomised they will be allocated a randomisation number.  
Randomisation will occur on Day -43 Randomisation numbers will be assigned sequentially in 
ascending order, and once assigned, a randomisation number shall not be reassigned. The 
study site will keep a log of the randomisation number assigned to each subject. 
The assigned randomisation number and the randomisation schedule will determine which 
arm the participant will be in. Treatments will be assigned in a ratio of 1:1:1. 
Randomisation numbers will follow a 3 digit format e.g., 101-1NN. A copy of the randomisation 
code list will be sent to the unblinded pharmacist preparing the vaccines, so that vaccine or 
placebo doses can be prepared for each subject as appropriate. 

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A designated unblinded statistician will be responsible for the computer generated 
randomisation schedule. Sealed copies of the randomisation code will be stored in a secure 
place. Following database lock, on receipt of authorisation from the Sponsor, a copy of the 
randomisation code list will be sent to the Study Statistician to conduct study unblinding.  
10.3 
Blinding 
The PI will be provided with a tamper evident sealed envelope containing details of the 
treatment for each subject. All opened and unopened envelopes will be collected after the end 
of the subject’s participation in the study. 
With the exception of the manufacturer’s pharmacy department, the independent statistician 
preparing the randomisation code list, the unblinded Clinical Research Associate (CRA) and 
the Quality Assurance (QA) auditors where necessary, the Investigator and all other clinical 
and non-clinical staff, including the Study Statistician, data management staff, and subjects, 
will remain blinded to the treatment allocation until after the database has been locked and 
approval for study unblinding has been given. The confidentiality of the randomisation code 
list and study blinding will be maintained. 
10.4 
Unblinding 
Randomisation codes will be provided to the Pharmacist or designee at the start of the study. 
Individual emergency code break envelopes will be provided to hVIVO should it be necessary 
to break the blind for a subject. The Investigator will ensure there is an appropriate procedure 
in place to allow access to the code break envelopes in case of an emergency arising during 
the quarantine period, as per hVIVO's or HMR’s standard operating procedures (SOPs). In 
the event of such an ‘emergency’, the relevant medical decision on the further care of a subject 
would depend on the actual identity of the study treatment that the subject received. 
The emergency code break envelopes will contain information stating either ‘This subject was 
on active drug’ or ‘This subject was on placebo’. Any premature code breaking will be 
explained and justified by the Investigator and hVIVO, and the Sponsor must be promptly 
informed. If possible, the Sponsor should be consulted before the code is broken.  
When the code break envelope is opened, the Investigator must note the date, time, reason 
for unblinding and personnel details and record this information according to hVIVO SOPs. 
The Investigator must also immediately notify the Sponsor’s Medical Expert (SME) that the 
code has been broken. 
Even if the code is broken, blood samples for safety, efficacy, and other parameters 
assessments will continue to be drawn for the remainder of the planned study period following 
the last dose as long as doing so will not compromise subject welfare. 
In the event of unblinding, the subject will still be followed up until resolution of any AEs. 

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If a subject’s randomisation code is unblinded by the PI or study site personnel, the subject 
must be withdrawn from the study and followed up as appropriate. If the Sponsor breaks the 
code for safety reporting purposes, the subject may remain in the study. 
 

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11 
CHALLENGE VIRUS  
11.1 
Description  
Using reverse genetics, an investigational live Influenza A 2009 H1N1 human challenge virus 
similar to the wild-type strain A/Ca/04/2009 was manufactured in certified Vero cells under 
Good Manufacturing Practice (GMP) conditions by Charles River Laboratories in Malvern, PA 
from a seed stock produced by Dr. Matthew Memoli and his laboratory team in the Viral 
Pathogenesis and Evolution Section of the LID. It will be vialed at a maximum dose level of 
1012TCID50. This virus has been demonstrated to be sensitive to standard FDA-approved 
neuraminidase inhibitors such as oseltamivir and zanamivir. Similar to current seasonal H3N2 
and all 2009 H1N1 pandemic viruses, it is resistant to the adamantanes. 
11.2 
Supply and accountability 
hVIVO is obliged to establish a system for control of Challenge Virus, to ensure all supplies 
are received by a responsible person, and all deliveries and returns are documented and 
signed for.  
The PI will maintain accurate records of receipt and condition of all Challenge Virus inoculum 
stock, including dates of receipt, and details and dates of the quantities dispensed and used 
in the study. Any departures from the protocol-dispensing regimen will be fully documented. 
Challenge inoculum accountability records will be available for verification by the Study 
Monitor.  
11.3 
Storage 
The Influenza A 2009 H1N1 human challenge virus will be stored at -60°C to -90°C in single-
use vials. Multiple doses of virus may be prepared from the same vial after it is opened. Once 
opened, each vial will be discarded appropriately after use. Preparation and administration 
procedures will be documented in a laboratory analytical plan. 
11.4 
Preparation and administration 
Challenge virus preparation and administration procedures will be documented in a laboratory 
analytical plan. This will be performed by trained personnel in the hVIVO laboratory.  
 
 

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12 
INVESTIGATIONAL MEDICINAL PRODUCT 
12.1 
Description  
12.1.1 FLU-v 
FLU-v is a lyophilised product composed of four short peptidic active pharmaceutical 
ingredients (APIs) (FLU-5, FLU-7, FLU-8N and FLU-10). The APIs are manufactured by 
fluorenylmethoxycarbonyl (Fmoc) chemistry before reconstituting them in 50% acetic acid and 
mixed to prepare an equimolar solution of the four peptides. Glass vials are then filled with the 
solution under sterile conditions. Water and acetic acid are removed from the preparation by 
lyophilisation. The end product is a white to off white lyophilised solid that will need 
reconstitution prior administration by injection. It is subcutaneously administered and supplied 
in single-use vials as a dose of 500 micrograms suspended in 0.5ml volume of water and 
adjuvant.The intended application of the investigational medicinal product is as a prophylactic 
vaccine to prevent influenza virus infection by inducing an enhanced immune response. 
12.1.2 Placebo 
The placebo is adjuvant (Montanide ISA-51)   
12.2 
Supply and accountability 
hVIVO external pharmacy vendor will only receive supplies of FLU-v and adjuvant once it has 
Qualified Person (QP) sign off by the GMP Pharmacy provider, and the IMP has been verified 
ready for dispatch. All IMP supplies will be used only for this protocol and for no other purpose.  
Once received at hVIVO external pharmacy vendor, will perform stock level accountability. 
Vaccine accountability will be controlled by hVIVO external vendor and monitored by the Study 
Monitor throughout the study and at study closeout.  
The Investigator will ensure that a responsible person receives all supplies, all deliveries and 
returns are documented and signed for, and the condition of the vaccine is monitored. 
Accurate records will be kept of when and how much vaccine is dispensed and used in the 
study. Any reasons for departure from the dispensing protocol will also be recorded. 
FLU-v or placebo will be supplied only to subjects participating in the study. It must not be 
relabelled or reassigned for use by other subjects.  
Accountability records will be available for verification by the Study Monitor at each monitoring 
visit. At the completion of the study, there will be a final reconciliation of all IMP. 
12.3 
Packing and labelling 
FLU-v-004 and placebo will be packed under the responsibility of the Sponsor.  

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FLU-v-004 and placebo will be packed per subject according the randomisation list, assuring 
double-blindness for the FLU-v-004 versus placebo part of the study. All supplies will be 
packaged and received in accordance with Annex 13 of Eudralex volume 4 and the current 
version of the ‘Rules and Guidance for Pharmaceutical Manufacturers and Distributors’30. 
Blinding, randomisation, and labelling will be performed at a GMP Pharmacy. 
A release document signed by a legally authorised QP will be kept in the Trial Master File to 
document labelling and dispensing of the IMP to the subject. All documents required to 
perform GMP activities will be supplied as per the Technical Agreement.  
Labelling and packing of study medication will be in accordance with current regulatory 
standards.3,31-33 
No medication can be relabelled without prior approval from PepTcell (t/a SEEK).  
Storage 
FLU-v vials will be stored at -15 to -25oC. The determination of the shelf life for the IMP is on-
going. Stability studies of previous batches indicate that it should remain stable for 2 years 
when stored at -20oC.  
The vials ofwater for injection, Montanide ISA-51 should be stored at room temperature.  
None of the materials can be dispensed beyond the expiry date. 
Provision must be in place to store the IMP within the permitted temperature range. 
Temperature must be monitored regularly, ideally using a continuing electronic monitoring 
system (24/7) is expected. However, it is acceptable to use a well-maintained system of max 
min thermometer recording at least once per working day. Diligence is expected in checking 
that at the time of dispensing, the IMP has always been stored in the permitted range.   
Whichever system is adopted the equipment must be regularly calibrated and a certificate of 
recalibration be available to the Sponsor / monitor to review.    
Temperature logs should be maintained at all times and be available for inspection by the 
monitoring team, when requested at monitoring visits.  
Should there be a deviation in the storage temperature of the IMP, it must be immediately 
quarantined. The deviation must be recorded on the Temperature Deviation Form, The 
Investigator should be immediately contacted and eventual IMP already dispensed recalled. 
Subject safety should be managed according to GCP. 
12.4 
Administration 
The IMP will be administered in accordance with the study Pharmacy manual.  

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The investigator or delegate will be responsible for the administration of the vaccine to subjects 
enrolled into the study according to the procedures in the Pharmacy Manual.  
Precautions:  
Study vaccines should not be administered to individuals with known hypersensitivity to any 
component of the vaccines.  
Any temperature > 38.0 oC or active infection is reason for delaying vaccination or according 
to eligibility and other criteria in section 7.4.2.  
Standard immunization practices should be observed and care taken to administer the 
injection avoiding intravascular injection.  
Subjects will be observed for 60 minutes after each injection for any immediate reactions. All 
subjects will be instructed to complete an adverse event diary card for 21 days for local 
symptoms (i.e., ecchymosis, erythema, induration, swelling and pain at the injection site) and 
systemic symptoms (i.e., chills, malaise, myalgia, arthralgia, nausea, headache, sweating, and 
fatigue) after each injection. Additional monitoring may be required for clinically significant 
reported events.   
Appropriate medical treatment and supervision should be readily available in the case of rare 
anaphylactic reactions following administration of the study vaccine. Adrenaline 1:1000, 
Chlorpheniramine and Hydrocortisone, as per the Resuscitation Council (UK) should be 
readily available in case of any anaphylactic reactions.   
12.5 
Compliance 
The exact times of dosing will be recorded in the relevant dispensing/ administration logs and 
subject’s source notes. Any non-compliance or problems with the administration of the IMP 
will be recorded in the subject’s source notes and reported to the Sponsor if appropriate. 
12.6 
Overdose 
In the event of an IMP overdose, the Sponsor is responsible for notifying the MHRA and REC 
of the potential serious breach (see Section 18.3) within 7 days of becoming aware of it. The 
SME will be contacted before the next scheduled dose time (see the Pharmacy Manual for 
further procedural details). General supportive measures will be taken to manage any AEs 
associated with overdose and subjects will be clinically followed up until the AE has resolved.  
12.7 
Disposal 
All study drugs will be disposed of according to the Sponsor's instructions. Study-site 
personnel must not combine contents of the study drug containers. 

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All used medication packages and unused study medication will be collected by the monitor 
and returned to the Sponsor unless other arrangements have been agreed to with the 
Sponsor. This must be documented on the Investigational Product Destruction Form.  

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13 
CLINICAL ASSESSMENTS AND PROCEDURES 
Assessments will be performed as detailed in Time and Events, Table 9.2 and in accordance 
with hVIVO’s OIs, (unless stated otherwise). The Investigator may perform additional 
assessments in order to evaluate or manage clinical illness. 
13.1 
Clinical assessments 
Where applicable, unless otherwise stated:  
 
Normal ranges will be identified in the Investigator Site File (ISF). 
 
Baseline measurements  will be those taken pre-IMP administration  
13.1.1 Complete physical examination 
A complete physical examination will include an evaluation of the following body systems 
(these are not exclusive) and a skin examination: 
 
General appearance 
 
Eyes 
 
Ears 
 
Nose 
 
Throat 
 
Heart 
 
Lungs 
 
Chest (via stethoscope) 
 
Abdomen 
 
Peripheral pulses 
 
Lymph nodes 
 
Neurologic 
 
Musculoskeletal 
 
Head, neck, and thyroid 
13.1.2 Directed physical examination 
Directed physical examinations will be conducted as deemed appropriate by the Investigator 
and will include examination of the: 
 
Ear 
 
Nose 
 
Throat 
 
Chest (via stethoscope) 

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Assessment and grading of any URT (nasal discharge, otitis, pharyngitis, sinus tenderness) 
and LRT symptoms (abnormal breath sounds externally [e.g. stridor, vocal cord dysfunction] 
and on chest auscultation [new wheezing or rhonchi, crepitations] will be performed. 
Physician-reported assessments of viral challenge related illness will be graded in accordance 
with their intensity as absent, mild, moderate or severe documented in the source data. 
Following viral challenge, URT and LRT symptoms (as described above) will be expected and 
presumed to represent virus infection consequent to viral challenge, and will not be additionally 
captured as AEs unless they meet the definition of an AE, and are deemed to be clinically 
significant (in the opinion of the Investigator) to be classed as AEs. 
Following viral challenge all unexpected (in the opinion of the Investigator) directed physical 
examination findings will be captured as AEs, along with all other occurrences that meet the 
criteria for an AE.   
13.1.3 Vital signs 
Vital signs assessments will be recorded in accordance with hVIVO or HMRs operating 
instructions,: 
Heart rate (HR) will be recorded in beats per minute (bpm).  
Respiratory rate (RR): respirations will be counted and recorded as breaths per minute. 
Blood pressure: systolic blood pressure and diastolic blood pressure will be measured in 
mmHg;  
Peripheral arterial oxygen saturation (SpO2 %) will be assessed using pulse oximetry.  
In the event of a subject having an unexpected abnormal or out of normal range result, the 
assessment may be repeated after at least 2 minutes to exclude a technical fault and confirm 
the original reading. The assessment may then be repeated at the PI’s discretion and in 
accordance with hVIVO or HMR’s SOPs.  
Study specific normal ranges and abnormalities are defined in Appendix 2: Vital signs: Study 
specific normal ranges and abnormalities, The Investigator will judge if the abnormalities are 
clinically significant. The severity of clinically significant out of normal range values will be 
assigned as per Appendix 4: Division of Microbiology and Infectious Diseases (DMID) Adult 
Toxicity Table November 2007. 
13.1.4 Temperature 
Tympanic temperature will be recorded using a digital thermometer.  

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Temperature is related to definitions of illness (Section 4.2) and to symptomatic and specific 
therapy criteria; therefore temperatures > 38.0 ºC must be confirmed by a repeat 
measurement not less than 20 minutes and not more than 60 minutes after the first reading. 
The first temperature measurement will be used if confirmed by the second reading; both 
readings will be recorded in the source document.  
Pyrexia will be defined as temperature > 38.0oC. 
Following Viral Challenge, pyrexia will be presumed to represent Challenge Virus infection 
consequent to challenge. Section 15.2.6 describes the circumstances in which pyrexia would 
be recorded as an AE. 
The study specific normal range for tympanic temperature is detailed in Appendix 2: Vital 
signs: Study specific normal ranges and abnormalities. 
13.1.5 ECG 
Twelve-lead electrocardiograms (ECG) will be obtained to evaluate cardiac function, and will 
be read on site by an appropriately qualified investigator. Wherever possible the same 
investigator will review subsequent ECGs from the same subject for the assessment of any 
change from baseline while in inpatient stay.  
ECG abnormalities are detailed in Appendix 3: ECG: Study specific abnormalities. Any 
changes from screening during the study will be assessed for their clinical significance. Any 
clinically significant (in the Investigator’s opinion) changes will be recorded as an AE and 
reported as described in Section 15.1.1. 
13.1.6 Spirometry 
Spirometry will be performed according to hVIVO’s standard procedures. 
Spirometry should meet the American Thoracic Society (ATS)/European Respiratory Society 
(ERS) guidelines criteria (as per ATS/ERS guidelines for standardisation of spirometry36). For 
forced expiratory volume in 1 second (FEV1), the highest value from 3 technically satisfactory 
attempts will be considered. The chosen value should not exceed the next one by more than 
150 mL or 5%. If the difference is larger, up to 8 measurements will be made if appropriate. 
Predicted values will be calculated according to the formula of the European Coal and Steel 
Community (ECSC). For Caucasians of non-European descent and non- Caucasians, 
predicted values for FEV1 and FVC will be adjusted for race as per the ECSC guidelines.  
Any clinically significant changes from baseline will be assessed and recorded as described 
in Section 15.2.7.  

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Spirometry will be performed at baseline and may be repeated at any time in the inpatient 
phase of the study in the event of lower respiratory signs or symptoms (e.g. repeated 
coughing, dyspnoea, bradypnoea, tachypnoea, râles and rhonchi) or respiratory distress of 
any kind. 
A 15% drop in FEV1 value (compared to baseline) will be a Grade 1 (mild) AE. The PI will use 
his/her clinical judgement to assign severity to drops in FEV1values of greater than 15%, 
based on evaluation of clinical signs and symptoms. 
13.1.7 Adverse events  
Adverse events will be recorded from the point of signature of the Informed Consent Form 
(ICF) to the last study follow-up visit (see Section 15). 
Subjects will record any symptoms that they experience after administration of the IMP. These 
symptoms will be classified as AEs and graded by the Investigator/research nurse according 
to the tables provided in Appendix 4: Division of Microbiology and Infectious Diseases (DMID) 
Adult Toxicity Table November 2007 as a reference. 
13.1.8 Concomitant medications  
All concomitant prescription medications (including vaccines but with the exception of post-
exposure prophylaxis), over-the-counter medications, or herbal remedies taken during study 
participation must be approved by the PI and will be recorded in the participant’s source 
documents. For this protocol, a prescription medication is defined as a medication that can be 
prescribed only by a properly authorised/licensed clinician. Symptomatic treatment 
(antipyretics, antitussives, decongestants, etc.) in individuals not requiring an increased level 
of care will be administered at the discretion of the PI and recorded carefully in the source 
documents.  The PI must consult with the sponsor medical monitor before an exclusion based 
on concomitant medication is made in order to determine level of deviation. 
13.2 
Efficacy assessments 
Assessments to determine the efficacy of the IMP will be performed at the times detailed in 
T&E. Unless otherwise indicated, the value obtained at screening will be used as the baseline 
for efficacy assessments. 
13.2.1 Directed physical examination 
Directed physical examinations will be conducted as deemed appropriate by the Investigator.  
Daily assessment of any upper and lower respiratory symptoms (nasal discharge, otitis, 
pharyngitis, sinus tenderness, new wheezes, râles and rhonchi) will be performed. All 
assessment outcomes including incidence and severity will be documented in the source data. 
Changes in physical examination will be reported as detailed in Section 15.2.  

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13.2.2 FLU-PRO Symptom Severity Assessment Tool and Physician assessment of 
Influenza Symptoms 
Subjects will report and assess any Challenge Virus related signs and symptoms and assess 
their associated severity using the FLU-PRO Symptom Severity Assessment.   The physician 
assessment will be performed daily to determine the presence or absence of influenza 
symptoms.  The following mild (Grade 1) to moderate (Grade 2) signs or symptoms are 
induced by or associated with influenza, and any combination of these is expected to occur 
with virus challenge. These symptoms will not be reported as adverse events unless they are 
associated with administration of FLU-v and deemed possibly, probably, or definitely related 
to FLU-v by the PI.  If deemed related to influenza by the PI they will be recorded as Adverse 
Events of influenza infection per protocol, only if deemed a risk to the participants’ rights or 
wellbeing or as deemed appropriate by the Principal Investigator. The study team on a daily 
basis will check these events. 
In the event of missing FLU-PRO Symptom Severity Assessment Tool data, the physician will 
review the data in retrospect, and complete the information as accurately as possible by asking 
the subject about any symptoms during the missing day. However, no protocol deviation will 
be recorded for missing FLU-PRO Symptom Severity Assessment Tool data. 
 
Arthralgia 
 
Chills 
 
Conjunctivitis 
 
Coryza 
 
Diarrhea 
 
Dry Cough 
 
Dyspnea/Shortness of Breath 
 
Fatigue/Tiredness 
 
Fever (>38.0°C) 
 
Headache 
 
Myalgia 
 
Nausea 
 
Oxygen Saturation Decrease by ≥3% from baseline 
 
Productive Cough 
 
Rhinorrhea 
 
Sore Throat 
 
Sweats 
13.2.3 Adverse events diary cards (Diary report cards)  
To look at expected (solicited) local and systemic signs of reactogenicity, 2 AE diary cards will 
be issued to all study subjects. The cards will need to be completed by the subjects from Day 
-43 and returned on D-22 and D-2 or D-1. In the event of missing diary card data, the physician 
will review the AE diary cards in retrospect, and complete the information as accurately as 

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possible by asking the subject about any symptoms during the missing day. No protocol 
deviation will be recorded for the missing diary card data. 
13.2.4 Nasopharyngeal swab 
Nasopharyngeal swab samples will be collected to evaluate the parameters described in 
Section 14.2. 

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14 
LABORATORY ASSESSMENTS 
The following assessments will be performed as detailed in Time and Events, table 9.2. The 
Investigator may request additional safety assessments in order to evaluate or manage clinical 
illness.  
Any laboratory abnormalities will be determined according to the Division of Microbiology and 
Infectious Diseases (DMID) grading table and in accordance with the normal ranges of the 
clinical laboratory. 
The PI or delegate must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the Adverse Event Section of the 
eCRF. 
14.1 
Blood  
14.1.1 Blood volume 
No more than 470 mL will be taken from each subject in a 6-month period (which includes the 
Screening visit to final scheduled follow up visit). 
14.1.2  Routine blood analysis 
The routine blood tests that will be performed as detailed Table 9.2 and in the laboratory 
analytical plan. The tests will include, but not limited to, haematology, biochemistry and cardiac 
enzymes. Additional safety assessments will be conducted at the discretion of the PI as 
required.  
 
14.1.3 Whole blood and Serum analysis 
1) These samples will be collected to perform research studies to better understand the 
pathogenesis of influenza, the immune response after influenza inoculation, and to 
further explore FLU-v’s efficacy in vitro.  Studies may include flow cytometric  analysis, 
cytokine measurements, influenza antibody titre assays, host transcriptomics, and viral 
neutralization assays.  Host genomic assays will not be performed as part of this study.  
At screening visit a serum sample will be collected to assess the Viral Challenge 
serology. A Viral Challenge serology test can be repeated if require before Quarantine if 
the participant has been vaccinated but the admission has fallen out of the 90 days 
window, however, the serology test and result must be dated within 90 days of Day 0. 
PBMC & PAXgene samples will be collected from subjects, either at their screening visit 
or at a planned PBMC sampling visit prior to their vaccination. 
 

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14.2 
Nasopharyngeal swab 
14.2.1 Respiratory virus screen 
On admission to quarantine, a respiratory viral screen will be performed to detect the presence 
of a number of respiratory viruses that could potentially contraindicate a volunteer’s 
participation in the study.   
14.2.2 Viral shedding 
Viral shedding will be confirmed by positive polymerase chain reaction (PCR) of 
nasopharyngeal swab samples.  
RT-qPCR will use nucleic acids extracted from the samples taken at the times shown in T&E.  
An infectivity assay might also be used to quantify the amount of virus in the sample. 
14.3 
Urine 
14.3.1 Urinalysis 
Clinical urine safety analysis will be undertaken using commercially available urine test strips 
that provide an instant result. Results will be documented in the source data.  
 
The following parameters will be evaluated:  
 
Colour  
 
Specific gravity  
 
 
Appearance  
 
 
pH. 
and the presence of the following will be detected:  
 
Blood  
 
Glucose  
 
Leukocytes 
 
Ketones  
 
Nitrite  
 
Protein 
 
 
Bilirubin 
 
Urobilinogen.  
If the dipstick yields abnormal results, a urine sample may be sent for microscopy, culture and 
sensitivity (MCS), at the Investigator’s discretion. MCS will include but is not limited to RBC, 
WBC, epithelial cells, crystals, casts, and bacteria.  
Urine safety analysis values will be evaluated by the Investigator. Those deemed to be 
clinically significant will be reported as AEs as defined in Section 15.1.1. 

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14.3.2 Pregnancy  
During the study, females will undergo pregnancy testing of serum B-HCG/urine samples.  
14.3.3 Drugs of abuse  
Urine will be tested for drugs of abuse using commercially available kits that provide an instant 
result. The test will include (but is not limited to) amphetamines, barbiturates, cocaine, opiates, 
cannabinoids and benzodiazepines. A positive result must be repeated on a different sample 
to confirm or dispute a false positive before exclusion / screen fail. Results will be documented 
in the source data. 

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15 
ADVERSE EVENTS AND TOXICITY MANAGEMENT 
The PI is responsible for ensuring that all AEs, SAEs and pregnancies are identified, 
evaluated, recorded and reported in a timely manner as per hVIVO’s, HMR’sor Sponsor’s 
SOPs (as required), and also for ensuring that the medical management (including follow-up) 
of AEs, SAEs and, where appropriate, pregnancy symptoms/complications is provided by 
competent Investigator Site staff. 
15.1 
Definitions  
15.1.1 Adverse event 
Defined as 'any untoward medical occurrence in a subject to whom a medicinal product has 
been administered, including occurrences which are not necessarily caused by or related to 
that product’4.  
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an 
investigational medicinal product, whether or not considered related to the investigational 
medicinal product’, (or for the purposes of Human Viral Challenge studies, the Challenge 
Virus). 
An AE includes: 
 
Exacerbation of a pre-existing illness. 
 
Increase in frequency or severity of a pre-existing episodic condition. 
 
A condition detected or diagnosed after IMP or inoculum administration even though it 
may have been present prior to the start of the study. 
 
Any malfunction or deterioration in the characteristics and/or performance of a device, 
and any inadequacy in the labelling or the instructions for use, which might lead to or 
might have led to endangering the health of a patient or the device user. 
 
A complication that occurs during a hospitalisation. 
An AE does not include: 
 
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
transfusion); the condition that leads to the procedure are an AE. 
 
Pre-existing disease or conditions present or detected prior to start of IMP (when 
applicable) or Challenge Virus inoculation administration that does not worsen 
(including screening findings such as abnormal laboratory results). 
 
Hospitalisation for elective surgery, social and/or convenience admissions provided 
they are arranged before the start of IMP administration. 
 
Overdose of either study treatment or concomitant medication without any signs or 
symptoms. 
 
Typical/normal viral symptoms on FLU-PRO Symptom Questionnaire (see Section 
15.2.1). 

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15.1.2 Adverse reaction 
An adverse reaction (AR) is any untoward and unintended response in a subject to an IMP 
which is related to any dose administered to that subject. 
‘Response’ in this context means that a causal relationship between a medicinal product and 
an adverse event is at least a reasonable possibility37. 
All AEs judged by either the reporting investigator or the Sponsor as having a reasonable 
causal relationship to a medicinal product qualify as adverse reactions. The expression 
‘reasonable causal relationship’ means to convey in general that there is evidence or argument 
to suggest a causal relationship. 
15.1.3 Unexpected adverse (drug) reaction 
An ‘unexpected adverse (drug) reaction’ is an ‘adverse reaction, the nature and severity of 
which is not consistent with the information about the medicinal product in question set out-: 
(a) In the case of a product with a marketing authorisation, in the summary of product 
characteristics for that product, 
(b) In the case of any other investigational medicinal product, in the Investigator’s Brochure 
relating to the trial in question’4. 
15.1.4 Serious adverse event, serious adverse drug reaction and unexpected serious 
adverse (drug) reaction  
A serious adverse event (SAE), serious adverse (drug) reaction (SAR) or unexpected serious 
adverse reaction is any AE, adverse reaction or unexpected adverse reaction, respectively, 
that - 
(a) results in death, 
(b) is life-threatening, 
(c) requires hospitalisation or prolongation of existing hospitalisation, 
(d) results in persistent or significant disability or incapacity, or 
(e) consists of a congenital anomaly or birth defect  
The above characteristics/consequences have to be considered at the time of the 
event, for example: 

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The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the subject 
was at risk of death at the time of event; it does not refer to an event which, hypothetically, 
might have caused death if it were more severe39. 
‘Important medical events’ - some medical events may jeopardise the subject or may require 
an intervention to prevent one of the above characteristics/consequences. Such events should 
also be considered as ‘serious’ in accordance with the above definition.  
Medical judgement should be exercised in deciding whether an adverse event/reaction is 
serious. Important adverse events/reactions that are not immediately life threatening or do not 
result in death or hospitalisation, but may jeopardise the subject or may require intervention 
to prevent one of the other outcomes listed in the definition above occurring, should also be 
considered serious. Details of the SAE must be provided. 
15.1.5  Suspected unexpected serious adverse reaction  
A suspected unexpected serious adverse reaction (SUSAR) is ‘a serious adverse reaction, 
the nature and severity* of which is not consistent with the information about the medicinal 
product in question, as defined in the Summary of Product Characteristics for that product in 
the case of a product with authorisation, or in the Investigator’s Brochure relating to the trial in 
question in the case of any other investigational medicinal product’. 
*The term ‘severity’ is used here to describe the intensity of a specific event. This is not the 
same as ‘serious’ which is based on subject/event outcome or action criteria. 
15.2 
AE reporting 
AEs will be captured from the time informed consent has been signed by the subject until the 
subject’s last study follow-up visit. 
Periodically during the study, the Investigator should enquire about the occurrence of AEs and 
use of concomitant medication. 
The following are examples of open ended, non-leading questions that may be used to obtain 
this information:  
How are you feeling? 
Have you had any medical problems since your last visit/assessment?  
Have you taken any new medicines, other than those given to you in this study, since your 
last visit/assessment? 
Following the reporting of AEs and concomitant medication, the Investigator should assess 
the subject’s eligibility to continue in the study.  

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The PI or delegated investigator will record all relevant information regarding an AE/SAE in 
the source documents and evaluate AEs using the following guidelines:  
 
Description of events (if the event consists of a cluster of signs and symptoms, a 
diagnosis should be recorded) 
 
Seriousness 
 
Severity (or grade) 
 
Onset date and time 
 
Frequency 
 
Date and time of resolution (or ‘continuing’ if unresolved) 
 
Action taken  
 
Concomitant medication 
 
Clinical outcome 
 
Relationship or causality (IMP/Challenge Virus/ study procedures/ concomitant 
medication/other). 
Any clinically significant abnormal laboratory result, vital sign, or other measure will be 
followed until it returns to normal or baseline values, stabilises, or is judged by the Investigator 
to be no longer clinically significant.  
If an AE is not resolved at the end of the study, the AE should be followed until it has resolved 
or (in the case of pregnancy) the pregnancy has been terminated (including spontaneous 
abortion)/resulted in a birth, or a decision has been made by the Sponsor that no further follow-
up is required. 
15.2.1 Challenge Virus symptoms  
The Investigator will assess and review Challenge Virus related symptoms recorded on 
subjects’ FLU-PRO Symptom Questionnaire. FLU-PRO Symptoms greater than Grade 0 will 
be expected and presumed to represent virus infection consequent to Viral Challenge, and 
will not be additionally captured as AEs unless they meet the definition of an AE, and are 
deemed to be clinically significant (in the opinion of the Investigator) to be classed as AEs.  
Following Viral Challenge all unexpected (in the opinion of the Investigator), post-Viral 
Challenge symptoms will be captured as AEs, along with all other occurrences that meet the 
criteria for an AE. 
15.2.2 IMP related adverse events symptoms 
Following vaccination with IMP, diary card symptoms are not reported as individual adverse 
events unless they are deemed to be clinically significant (i.e. progress past 7 days) in the 
opinion of the investigator and / or SME.  
 

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15.2.3 Complete Physical examination 
Any clinically significant change in complete physical examination findings during the study 
will be documented as an AE. 
15.2.4 Directed physical examination 
Following Viral Challenge, upper and lower respiratory symptoms (nasal discharge, otitis, 
pharyngitis, sinus tenderness, new wheezes, râles and rhonchi) will be expected and 
presumed to represent virus infection consequent to Viral Challenge and will not be 
additionally captured as AEs unless they meet the definition of an AE, and are deemed to be 
clinically significant (in the opinion of the Investigator) to be classed as AEs. 
Following Viral Challenge all unexpected (in the opinion of the Investigator) post-Viral 
Challenge directed physical examination findings will be captured as AEs, along with all other 
occurrences that meet the criteria for an AE. 
15.2.5 Vital signs 
Deterioration in a vital sign (compared to baseline) should only be reported as an AE if the 
deterioration fulfils the criteria for an AE. If deterioration in a vital sign is associated with clinical 
signs and symptoms, the sign or symptom will be reported as an AE and the associated vital 
sign will be considered as additional information. 
15.2.6 Temperature 
Following Viral Challenge, pyrexia will be expected and presumed to represent virus infection 
consequent to Viral Challenge, and will not be additionally captured as an AE unless it meets 
the definition of an AE, and is deemed to be clinically significant (in the opinion of the 
Investigator) to be classed as an AE.  
Following Viral Challenge all unexpected (in the opinion of the Investigator) post-Viral 
Challenge pyrexia will be captured as an AE, along with all other occurrences that meet the 
criteria for an AE. 
15.2.7 Spirometry 
A 15% drop in a spirometry value (compared to baseline) will be a Grade 1 (mild) AE. The PI 
will use his/her clinical judgement to assign severity to drops in spirometry values of greater 
than 15%, based on evaluation of clinical signs and symptoms.  
15.2.8 Laboratory values 
Deterioration in a laboratory value (compared to baseline) should only be reported as an AE 
if the deterioration fulfils the criteria for an AE and it is clinically significant in the opinion of the 

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Investigator. If deterioration in a laboratory result is associated with clinical signs and 
symptoms, the sign or symptom will be reported as an AE and the associated laboratory result 
will be considered as additional information. 
The Investigator will judge whether abnormal laboratory values are clinically significant or not 
clinically significant, and record this in the source document. This entry should be signed and 
dated by the relevant investigator. Laboratory abnormalities detected at screening will be 
considered as part of the medical history and will not be reported as AEs. 
Challenge Virus associated laboratory abnormalities (e.g., elevated ALT, AST or GGT; 
decreased neutrophils) may be recorded as AEs (at the discretion of the Investigator).   
Any laboratory abnormality that meet the criteria of a Grade 2 AE  or above will be discussed 
with the SME. If a Grade 3 laboratory abnormality occurs (not related to Viral Challenge), a 
confirmatory test should be performed, preferably within 48 hours (if practically feasible) after 
the results have become available. 
15.2.8.1 
C-reactive protein 
Any value above 5 mg/L but less than 60 mg/L will be a Grade 1 (mild) AE (unless deemed 
non clinically significant by the PI). The PI will use his/her clinical judgement to assign severity 
grades above Grade 1, based on evaluation of clinical signs and symptoms.  
15.3 
Classification of adverse events 
15.3.1 Seriousness 
The PI must record whether the AE meets the definition of serious. If the event is serious 
(Section 15.3.1), the PI must initiate reporting to the Sponsor and complete a SAE report form 
(Section 15.4). 
15.3.2 Severity  
The term ’severe’ is often used to describe the intensity (severity) of a specific event. This is 
not the same as ‘serious’ which is based on subject/event outcome or action criteria. 
Appendix 4: Division of Microbiology and Infectious Diseases (DMID) Adult Toxicity Table 
November 2007) will be used to standardise the severity and grading of AEs and anatomical/ 
pathophysiological terms.  
The PI will use these tables as a reference when collecting, reporting and clarifying database 
queries of AEs, SAEs and ARs.  
The severity of an AE that does not appear in the DMID tables should be determined according 
to the definitions in Table 15-1. 

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Table 15-1: Classification of adverse event severity  
Grade 
Classification 
Definition 
Grade 1 
Mild 
Mild level of discomfort, and does not interfere with regular 
activities 
Grade 2 
Moderate 
Moderate level of discomfort and significantly interferes with 
regular activities 
Grade 3 
Severe 
Significant level of discomfort and prevents regular activities 
The DMID AE severity Grade 4 (life threatening) will not be used when assessing AE severity 
in this trial, because the term ‘life threatening’ does not relate to severity but to consequence. 
AEs can be classed, as ‘life threatening’, and all life threatening AEs must be reported to the 
Sponsor and NIH as SAEs (as per the definition of a SAE). DMID is a draft internationally 
recognised tool and is used as best practice guidance. 
15.3.3 Frequency 
The frequency of the AE should be categorised as one of the following: 
 
Single 
 
Intermittent 
 
Continuous. 
15.3.4 Relationship 
The relationship of an AE to the IMP will be categorised as shown in Table 15-2. 
Table 15-2: Classification of adverse event relationship 
Classification 
Definition 
Not related 
The AE is related to an aetiology other than the IMP (the 
alternative aetiology must be documented in the subject’s medical 
record). 
Unlikely to be related 
The AE is unlikely to be related to the IMP and likely to be related 
to factors other than IMP. 
Possibly related 
There is an association between the AE and the administration of 
the IMP, and there is a plausible mechanism for the AE to be 
related to the IMP, but there may also be alternative aetiology, 
such as characteristics of the subject’s clinical status or underlying 
disease. 

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Probably related 
 
A reasonable temporal sequence of the AE and the IMP 
administration exists and, based upon the known pharmacological 
action of the drug, known or previously reported adverse reactions 
to the drug or class of drugs, or judgment based on the 
investigator’s clinical experience, the association of the AE with 
the IMP seems likely. 
Definitely related 
 
A definite causal relationship exists between the AE and the 
administration of the IMP, and other conditions do not appear to 
explain the AE. 
Unless an AE is ‘definitely related’ to the IMP, a causal relationship to one of the following 
should be considered, and full details provided on the AE reporting form as appropriate. 
 
Challenge Virus 
 
Study procedures 
 
Concomitant medication 
 
Other. 
15.3.5 Action taken 
The Investigator should ensure that adequate medical care is provided to subjects for any 
AEs, including clinically significant laboratory values related to the IMP. In addition, the 
Investigator will describe whether any treatment was given for the AE. 
The Investigator will classify the action taken with regard to the AE. The action taken should 
be classified according to the following categories and full details provided as appropriate: 
 
None 
 
Non-drug therapy given 
 
Concomitant medication taken 
 
IMP dose not changed 
 
IMP dose adjusted 
 
IMP administration temporarily interrupted 
 
IMP administration permanently discontinued 
 
Subject withdrawn 
 
Subject hospitalised 
 
Other. 
15.3.6 Outcome 
An AE should be followed until the Investigator has determined and recorded the outcome or 
an alternative explanation. The outcome should be classified according to the categories 
shown in Table 15-3. 

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Table 15-3: Classification of adverse event outcome  
Classification 
Definition 
Resolved 
Resolution of the AE with no residual signs or symptoms 
Resolved with sequelae 
Resolution of the AE with residual signs or symptoms 
Discharged to GP 
AE considered stable or not anymore clinically significant 
and not requiring further follow up 
Ongoing 
Either incomplete improvement or no improvement of the 
AE, such that it remains on-going 
Fatal 
Outcome of the AE was death. ‘Fatal’ should be used when 
death was at least possibly related to the AE. 
Unknown (Lost to follow-up) 
Outcome of the AE is not known 
15.3.7 Follow-up 
Any AEs ongoing at the end of the study will be classed as ongoing and where appropriate 
the subject will be referred to the subject’s GP or other healthcare professional. 
Additional measurements and/or evaluations may be necessary to investigate the nature 
and/or causality of an AE or SAE - this may include additional laboratory tests, diagnostic 
procedures, or consultation with other healthcare professionals. If the subject dies, any post-
mortem findings (including histopathology) will be provided to the Sponsor if possible. 
15.4 
Serious adverse event reporting 
All SAEs must be reported by the PI to the SME as soon as possible, and at the latest within 
24 hours of becoming aware of the event. Upon becoming aware of a SAE, an initial phone 
call should be made as soon as possible by the PI to the SME in order to notify the Sponsor 
and NIH of the occurrence of a SAE.  
Following the telephone notification, the PI must fully and accurately complete the SAE Initial 
Reporting Form. Only one SAE must be recorded on each form. The completed SAE Initial 
Reporting Form (including any supporting documents such as the subject’s notes, concomitant 
medication logs and test results) must be e-mailed by the PI to the SME and the study Project 
Director/Project Manager at the latest within 24 hours of becoming aware of the event.   
The PI must also complete the SAE Follow up Report Form. 
The completed Sponsor Follow up Report Forms (including any supporting documents such 
as the subject’s notes and test results) must be e-mailed by the PI to the SME and study 
Project Director/Project Manager within 5 days of the PI becoming aware of the event. 
Adherence to this timeline is crucial in order to ensure that any required reporting to the 
relevant REC and regulatory authorities takes place in a timely manner. 

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Further Follow Up Report Forms may need to be emailed to the SME and the study Project 
Director/Project Manager by the PI, for data/information collected later than 5 days of the PI 
becoming aware of the event, until: 
The SAE has resolved, or the Sponsor has made a decision that no further follow up is 
required.  
Table 15-4: Contact details for reporting SAEs  
Contact 
Details 
Sponsor’s Medical Expert (SME) 
Dr Bryan Murray 
Email: bryan.murray@seekacure.com 
SME Mobile Number 
+ 44 (0)7833 204296 
15.4.1 Reporting of SUSARs  
The Sponsor is responsible for assessing SUSARs, unblinding potential SUSARs, and 
reporting SUSARs to the MHRA and REC as appropriate. NIH are responsible reporting to 
FDA if related to the virus. 
The Sponsor shall ensure that all relevant information about a SUSAR that occurs during the 
course of a clinical trial in the UK and is fatal or life threatening is reported as soon as possible 
to the MHRA and the REC. This needs to be done within 7 calendar days after the Sponsor 
became aware of the event.  
The Sponsor shall ensure that a SUSAR which is not fatal or life threatening is reported as 
soon as possible and in any event within 15 calendar days after the Sponsor became aware 
of the reaction.  
Any additional relevant information should be sent within 8 days of the first report being sent. 
15.4.2 Adverse reactions to non-IMPs 
A SAE caused by a non-IMP would meet the stopping criteria for the study (Section18.4.1). In 
such a case Table 18.1and the procedure for early termination should be followed in line with 
Section 18.4.1)  
A SAE caused by the Challenge agent would meet the stopping criteria for the study (Section 
18.4.1). In such a case Table 18.1 and the procedure for early termination should be followed 
in line with Section 18.4.1. 

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15.4.3 Post-quarantine AEs and SAEs  
All SAEs that occur during the follow-up period must be reported by the Investigator to the 
Sponsor as soon as possible, in accordance with the Sponsor’s SOPs, and at the latest within 
24 hours of becoming aware of the event.  
15.4.4 Pregnancy 
If a female subject or partner of a male subject becomes pregnant within 3 months after the 
study, the pregnancy must be reported by the Investigator to the Sponsor and Study Monitor 
by telephone as soon as possible, in accordance with the Sponsor’s SOPs, and at the latest 
within 24 hours of becoming aware of the event.  
Following the telephone notification, the Investigator must fully and accurately complete the 
appropriate pregnancy reporting form, which must be e-mailed to the Sponsor and the Study 
Monitor the latest within 24 hours of becoming aware of the pregnancy.  
Subjects will be advised to contact their GP or a specialist, as appropriate.  
Consent for follow-up of the pregnancy and pregnancy outcome will be sought from the 
pregnant study subject or the pregnant partner of the male study subject as applicable. 
Consent for follow-up will be documented on a Sponsor Pregnancy Follow-up ICF.  
Provided that appropriate consent is in place, information related to the pregnancy will be 
collected as per the Sponsor’s SOPs. The completed reporting form(s) will be sent to the 
Sponsor for review and assessment, and subsequent reporting as required. 
A complete evaluation will be documented in the source data to permit transfer to the clinical 
database. The emergency code break envelopes will be requested (Section 10.4) to break the 
blind for the appropriate study subject to ensure that further care can be based on the actual 
identity of the study treatment that the subject received. 
hVIVO will maintain contact with the subject for a protracted period of time, but certainly until 
after the birth, in order to assess for outcomes that may be reportable as related AEs, and for 
reporting to the Sponsor as appropriate.  
hVIVO in consultation with the subject will keep the subject’s GP informed.  
All cases of foetal drug exposure via the parent as a study participant will be reported to the 
Sponsor and the REC.  

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16 
STATISTICAL METHODS AND PLANNED ANALYSES 
The unblinded statistician will perform the statistical analysis for this study. 
16.1 
Study Hypothesis  
The hypothesis is that vaccination with 1 dose or two doses of FLU-v + adjuvant will reduce 
MMID when compared to individuals vaccinated with placebo.   
16.2 
Sample size 
The primary objective of this study is to examine whether there is a difference in the MMID 
rates post inoculation between either of the 2 FLU-v arms and placebo. A sample size of 41 
subjects per arm (total 123) will provide 80% power to detect a difference in MMID rates of .70 
versus .40 using a one sided 0.05 significance level. The table below shows the power that 
the study would have with 41 patients per arm for other MMID rates. The sample size 
calculations do not adjust for multiple comparisons. 
Table 1. Power with 41 subjects per arm with various MMID probabilities 
Probability of MMID in 
placebo 
Probability of MMID in 
Vaccinated arms 
Power 
.70 
.40 
.80 
.70 
.44 
.70 
.70 
.47 
.60 
.60 
.30 
.80 
.60 
.34 
.70 
.60 
.37 
.59 
.50 
.21 
.81 
.50 
.25 
.68 
.50 
.28 
.56 
In this study the main comparisons are for each of the FLU-v dose groups to placebo. The 
study will also compare the FLU-v dosing arms but the study will not have adequate power to 
detect a significant difference in MMID rates at the predicted treatment rates. This study does 
not control for multiple comparisons since we are trying to maintain a small sample size but 
yet have high power to detect the pre-defined primary objective of efficacy versus placebo 
when FLU-v is truly beneficial. All comparisons will be made at the one sided 0.05 significance 
level. 
16.3 
Interim analysis 
No interim analysis is planned for this study 

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16.4 
FLU-v Statistical Analysis Plan 
MMID rates in the 2 FLU-v groups and placebo group will be compared using a Fishers exact 
test. 95% confidence intervals around the difference in rates between the FLU-v groups will 
be presented. Adverse event rates between groups will also be performed using Fishers exact 
test.  The secondary endpoints will be examined by calculating the median and interquartile 
range and then performing a two-sided Wilcoxon Rank Sum Test at the 0.05 significance level. 
The SAP will be developed by the study team prior to locking of each relevant cohort. 
The SAP will give a more detailed description of the report presentations to be 
produced, expanding on the protocol specified analysis. Any deviation from the 
protocol specified analysis will be documented within a protocol or SAP amendment, 
as appropriate. 
The SAP will describe and account for the occurrence of and extent of missing data, 
and its possible impact on the study analysis. All baseline assessments will be 
described in the SAP. 
Analysis and reporting of exploratory endpoints may be separate to the clinical study report. 
16.4.1 Subject accountability 
The number of subjects randomised to  FLU-v-004 or placebo and receiving  FLU-v-004 or 
placebo, receiving Challenge Virus, withdrawing from (also split by reason for withdrawal), and 
completing the study, and the numbers in each analysis set will be summarised by treatment  
group and across all subjects. 
16.4.2 Protocol deviations 
Subject data will be reviewed for major protocol deviations prior to database lock at a planned 
blinded data review meeting (BDRM), and decisions will be documented within the meeting 
minutes. At this meeting, subjects will be reviewed for their inclusion/exclusion from the 
analysis sets.   
16.4.3 Demographic and baseline characteristics 
Demographics and characteristics for each of the three study groups will be summarised in a 
table. 
16.5 
Primary analysis 
The primary analysis will be performed to evaluate the MMID rate in each of the three groups.  
This will be based on the physician assessment (presence or absence of symptoms) and the 
influenza PCR performed on nasal swab (demonstrating viral shedding).  MMID rates in the 2 

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FLU-v groups and placebo group will be compared using a Fishers exact test. 95% confidence 
intervals around the difference in rates between the FLU-v groups will be presented. 
16.6 
 FLU-v Secondary analysis 
A secondary analysis will be performed to examine the secondary endpoints for this study.  
Adverse event rates between the three groups will be compared using Fishers exact test.  The 
days of shedding, days of symptoms, number of symptoms, and FLU-PRO scores between 
will be examined by calculating the median and interquartile range for all three groups and 
then performing a two-sided Wilcoxon Rank Sum Test at the 0.05 significance level. 
16.7 
Safety Analyses 
16.7.1 Adverse events 
Adverse event terms will be coded using MedDRA. Treatment emergent AEs will be separately 
reported within summary presentations, by MedDRA system organ class (SOC) and preferred 
term, and by treatment group. An AE will be classified as treatment emergent if the onset date 
of the AE is on or after the start of IMP dosing. In the case of partial dates being recorded, a 
conservative approach will be adopted for inclusion of such events within these reporting 
periods. These definitions will be further detailed within the SAP. 
If a subject experiences more than one AE with the same preferred term (within reporting 
period being considered) that preferred term will be counted only once in summary 
presentations. It will be assigned the worst observed severity and the strongest relationship to 
IMP among those events for summaries in which those characteristics are considered. 
Summary presentations will be produced for the number and percentage of subjects reporting 
treatment emergent AEs, AEs by severity, and AEs related to IMP. In addition, SAEs and AEs 
directly resulting in withdrawal from study will be listed. 
16.7.2 Laboratory parameters 
Time point and treatment group for absolute laboratory parameters (haematology, 
biochemistry, coagulation, cardiac enzymes, and thyroid function tests) will tabulate summary 
statistics for absolute values and changes from baseline. Laboratory values outside the normal 
range will be identified in subject listings. 
16.7.3 Physical examination 
Physical examination findings (complete and directed examinations) will be included within 
subject listings. 

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16.7.4 Concomitant medications 
Concomitant medication terms will be coded using the WHO Drug Dictionary Enhanced. 
Medications will be assigned as being prior to IMP dosing, or concomitant with IMP dosing 
based on start and stop dates of the medication and the timing of receiving IMP.  
If the medication stop date is before the date of IMP (when applicable), the medication will be 
assigned as being prior to IMP. In all other situations, the medication will be assigned as being 
concomitant with IMP. Prior and concomitant medications (separately identified) will be 
included in subject listings. 

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17 
STUDY FILES AND CLINICAL SOURCE DOCUMENTATION 
17.1 
Investigator’s Study File 
The PI will maintain adequate and accurate records to enable the conduct of the study to be 
fully documented and the study data to be subsequently verified. These documents will be 
managed in accordance with hVIVO’s SOPs. 
17.2 
Clinical source documentation 
Study data management will be conducted in accordance with hVIVO or NIH/Sponsor SOPs 
(as required). 
All data capture will be maintained in a manner compliant with the current regulations and 
guidance.  
In cases where data are captured as hard copy e.g., ECG reports or spirometry read outs, the 
hard copy data will become part of the subject's source documentation. The original paper 
source will be maintained to enable source data verification by the Sponsor’s monitor.  
Source documents will be checked for accuracy and completion and will undergo quality 
control (QC) by hVIVO. 
17.3 
Data capture  
The hVIVO external data management vendor (with input from the appropriate hVIVO site staff 
if required) will prepare and provide an electronic case report form (eCRF) for each study 
subject. hVIVO personnel will transcribe the study data from source documents into the eCRF 
in accordance with the data management vendor’s eCRF completion guidelines and the 
agreed timelines. The eCRF will be transmitted in a secure manner to the Sponsor within the 
agreed timeframe.  
hVIVO staff will ensure that data recorded in the eCRFs (i.e., when there is no prior written or 
electronic record of data) and the source data are available for review at each scheduled 
monitoring visit. 
The Source Data Agreement and Source Data Management Plan will provide details of what 
data is deemed to be source and any specific information of the handling and transcription 
processes performed. 
Data captured in electronic formats (e.g., laboratory results or electronic ECGs) will be 
transferred to the Sponsor’s data management company via secure transfer as outlined in the 
Data Transfer Agreement (DTA). 
All entries, corrections, and alterations of the eCRF or source data will only be made by the 
PI or other authorised study-site personnel.  

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17.4 
Data quality assurance and quality control 
Measures will be taken to ensure the accuracy and reliability of data and will include: 
 
Selection of qualified investigators and appropriate study sites  
 
Review of protocol procedures with the PI and study-site personnel prior to the study 
 
Periodic monitoring visits by the Sponsor 
 
Direct transmission of clinical laboratory data from a central laboratory into the 
Sponsor's database. 
Written instructions will be provided for collection, handling, storage, and shipment of samples.  
The Sponsor’s monitor will review the study data for accuracy and completeness during on-
site monitoring visits. Any discrepancies will be resolved with the PI or designee as 
appropriate. After upload of the data into the clinical study database, data will be verified for 
accuracy and consistency with the data sources. 
17.5 
Data coding 
Adverse events and medical histories will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA) version: 19.0, March 2016. 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary Enhanced version: March 1st, 2016. 
Should a new version of either dictionary be released prior to any coding of the study data, 
the new version will be used for coding and the version number will be documented in the 
DMP.  
If any coding of the study data has already been performed, the existing version of the 
MedDRA will be used and the new version will not be used. 
17.6 
Database lock 
The Sponsor’s database will undergo validation prior to database lock.  
Following the Sponsor’s locking of the database the final database will be transferred to the 
Study Statistician for statistical analysis and reporting. 
17.7 
Data protection 
The study site will comply with the EU Data Protection Directive (95/46/EC)40, as transposed 
into UK legislation via the UK Data Protection Act 19985. The Sponsor agrees to comply by 
the principles of the US – European Safe Harbor Framework41 to bridge the differences in the 
privacy approaches for data protection law. 

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18 
STUDY MANAGEMENT AND ETHICAL RESPONSIBILITIES 
18.1 
Regulatory approval and Good Clinical Practice 
This study will be conducted in accordance with the Ethical Principles for Medical Research 
Involving Human Subjects outlined in the Declaration of Helsinki 19961, the principles of ICH 
GCP2, current regulatory requirements as detailed in the Medicines for Human Use (Clinical 
Trial) Regulations (SI 2004/1031)4 and all subsequent amendments, the UK Data Protection 
Act 19985, any other applicable laws and guidances, and any Sponsor requirements.  
 All ethical and legal requirements will be met before the first subject is enrolled in the study.  
18.2 
Deviations from the protocol  
A protocol deviation log will be used to document any unplanned or unintended departures 
from the study protocol. Protocol deviations should be recorded as soon as possible after they 
occur, and if significant, reported to the Sponsor immediately. 
The PI or delegate will complete the protocol deviation log. 
18.2.1 Protocol amendments 
The Sponsor will not alter the study protocol without obtaining written prior agreement from 
the PI. For all amendments, an evaluation will be made by the Sponsor as to whether the 
amendment is ‘substantial’ or ‘non-substantial’.  
Non-substantial amendments include for example, minor administrative or typographical 
changes to the protocol. 
Amendments are ‘substantial’ where they are likely to have a significant impact on subject risk 
or the clinical trial objectives, specifically the: 
1. 
Safety or physical or mental integrity of the subjects 
2. 
Scientific value of the trial 
3. 
Conduct or management of the trial 
4. 
Quality or safety of the IMP used in the trial. 
Substantial amendments must be reviewed and approved by the MHRA and REC prior to their 
implementation unless subject safety would be otherwise compromised (i.e., Urgent Safety 
Measures [USMs]).  
When a protocol amendment substantially alters the clinical trial design or the potential risks 
or burden to subjects, the VIS/ICF will also be amended and approved by the REC, and all 
active subjects will be asked to reconfirm their continued willingness to participate in the trial. 
A log of all protocol amendments will be maintained together with their designation as 
substantial or non-substantial.  

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18.2.2 Urgent Safety Measures 
The Sponsor, NIH and the Investigator may take appropriate ‘urgent safety measures’ to 
protect clinical trial subjects from any immediate hazard to their health and safety.  
Urgent safety measures should be taken immediately. There is no need to wait for MHRA 
approval before implementing urgent safety measures; however, the MHRA and REC must 
be informed in writing in the form of a substantial amendment within 3 days. 
The Sponsor should telephone the Clinical Trial Unit at the MHRA and discuss the issue with 
a safety scientist immediately. Should further clarification be required the Sponsor will be 
contact by a medical assessor. 
The Sponsor must notify the MHRA and the REC in writing, of the measures taken and the 
reason for the measures within 3 days. This notification should include a covering letter 
detailing the measures taken, the reason for them, an Annex II substantial amendment form 
and any supporting documentation. 
If the PI (and not the Sponsor) has instigated the USM, the Sponsor should be notified 
immediately so that they can assess and report the USM within the timelines required.  
18.2.2.1 
Pandemic 
For any period during which a disease is pandemic and a serious risk to human health or 
potentially a serious risk to human health, notice of USMs taken in order to protect the subjects 
of a clinical trial against any immediate hazard to their health or safety and the circumstances 
giving rise to those measures, may be given ‘as soon as possible’ to the MHRA and the REC.  
Written notification to the MHRA and the REC should be provided within 3 days in the form of 
a substantial amendment and should describe the event, the measures taken and justification 
for the measures taken. 
18.3 
Serious breach of the protocol or GCP 
Regulation 29A of the Medicines for Human Use (Clinical Trials) Regulations 2004 [SI 
2004/1031]4, as amended by SI 2006/192842, contains a requirement for the notification of 
‘serious breaches’ of GCP or the trial protocol: 
 
 

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29A.  
(1) The sponsor of a clinical trial shall notify the licensing authority in writing of any serious 
breach of - 
(a) the conditions and principles of GCP in connection with that trial; or 
(b) the protocol relating to that trial, as amended from time to time in accordance with 
regulations 22 to 25,  
within 7 days of becoming aware of that breach. 
 
(2) For the purposes of this regulation, a ‘serious breach’ is a breach which is likely to effect 
to a significant degree – 
(a) the safety or physical or mental integrity of the subjects of the trial; or 
(b) the scientific value of the trial’. 
Any potential serious breach of the conditions and principles of GCP in connection with the 
study will be escalated within hVIVO as soon as an individual becomes aware of the potential 
breach. Rapid escalation will permit the urgent notification to the Sponsor and allow sufficient 
time for the Sponsor to fulfil the reporting timelines for the potential breach, as specified in UK 
Regulation 29A 42, should reporting be necessary.  
The Sponsor will be responsible for notifying the MHRA within 7 days of becoming aware of 
any potential serious breach.  
18.3.1 Protocol waivers 
Protocol waivers are never acceptable as per all EU competent authorities’ guidance 
(including the MHRA). It is not acceptable to include any subject by protocol waiver – i.e. 
included despite not meeting all inclusion criteria or fulfilling at least one exclusion criteria. 
18.4 
Discontinuation of the study 
The Sponsor reserves the right to temporarily suspend or discontinue the study for any reason 
at any time. In addition, the study may be stopped at any time if, in the opinion of the Sponsor 
or the SME, safety data suggest that the medical safety of subjects is being compromised. 
The Sponsor reserves the right to terminate the study for refusal of the PI to supply source 
documentation of work performed in this clinical study.  
The Sponsor is responsible for informing the REC of the study termination. If the study is 
suspended or terminated for safety reason(s), the Sponsor will promptly inform the PI, and will 
also inform the regulatory authorities of the suspension or termination of the study and the 
reason(s) for the action.  

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If the study is prematurely terminated, all study data must be returned to the Sponsor. In 
addition, the site must conduct final disposition of all unused IMPs in accordance with the 
Sponsor's procedures for the study. 
The study may also be stopped at any time if, in the opinion of the Investigator, or Sponsor, 
safety data suggest that the safety of subjects is being compromised. Study stopping criteria 
are detailed in Section 18.4.1. 
These notifications will occur within 15 days of the termination/suspension. Routine 
termination of the study, in line with the end of trial as defined in Section 9.5, will occur within 
90 days of the termination, with responsibilities for those notifications as outlined above. 
Termination of the clinical trial may also be initiated by the MHRA or the REC. 
18.4.1 Stopping criteria 
The study will be terminated if: 
 
One or more subjects experience any drug related SAEs or 2 or more 
subjects experience severe or clinically significant AEs considered to be at 
least possibly related to the FLU-v-004 therapy. 
 
One or more subjects experience any severe or clinically significant illness 
from Influenza inoculation. 
The PI and the SME will perform safety reviews on available clinical and virology data as 
appropriate during the quarantine period.  
Three clinical scenarios relating to the incidence of AEs and SAEs during the study and the 
procedures that should be performed in each case are presented in Table 18-1: Study 
stopping criteria.

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Table 18-1: Study stopping criteria 
Status 
Criterion 
Procedure 
1 
A report has been received of one (or 
more) IMP-related SAEs in any one (or 
more) subject(s). 
If such a status occurs at any point during 
the study then further administration of 
IMP will not take place and the PI and the 
SME will review the data and make 
decisions on study continuation or 
termination. 
Subject follow-up should continue until 
resolution or stabilisation of AEs. 
2 
No IMP-related SAEs have been 
reported but an overall pattern of 
clinical changes or symptoms exists, 
attributed to the IMP, which may 
appear minor or moderate in terms of 
individual AEs but which collectively 
represent a concern for safety. 
If such a status occurs at any point during 
the study then the PI and the SME will 
review the data and make a decision on 
study continuation or termination. 
Subject follow-up should continue until 
resolution or stabilisation of AEs. 
3 
Virus-related SAEs or virus-related 
AEs of clinical concern have been 
reported 
following 
Human 
Viral 
Challenge. 
Subject follow-up should continue until 
resolution or stabilisation of all such AEs 
and final follow-up on Day 28 (± 5 d). 
In any event, subject follow-up should continue until resolution or stabilisation of AEs and final 
follow-up on Day 63 (± 5 d). The exception to this would be suspension of the study for an 
USM (Section 18.2.2).  
18.5 
Study records retention and direct access to source documents 
Data will be collected, reviewed and managed throughout the study as outlined in Section 17 
and hVIVO’s and Sponsor’s SOPs. The PI shall keep a copy of the source data, the ISF and 
source documents, as specified in the Clinical Trial Agreement (CTA), until notified otherwise 
by the Sponsor. 
hVIVO agrees to allow inspections of the study site and any source documentation by clinical 
research and audit personnel from the Sponsor, external auditors or representatives of the 
MHRA or REC, and will allow direct access to source data and documents. 
Direct access to the subject’s clinical records is necessary to verify and corroborate the data 
recorded in the process of source data verification.  

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During the review of records and documents, the anonymity of the subject will be respected 
with strict adherence to professional standards of confidentiality. All monitoring activities 
should be performed in accordance with the Clinical Monitoring Plan for the study. 
Source documentation management is described in the DMP. The PI must retain all 
documents as listed in Section 8 of the ICH consolidated guideline on GCP (essential 
documents for the conduct of a clinical trial)2. 
18.5.1 Archiving 
Paper and electronic records generated by hVIVO during the study will be archived as agreed 
in the CTA and in accordance with the applicable regulations and Sponsor requirements.  
18.6 
Sponsor responsibilities 
18.6.1 General 
The Sponsor agrees to adhere to the study protocol, and to comply with the principles of ICH 
GCP2, the Declaration of Helsinki 19961, the current regulatory requirements, as detailed in 
the Medicines for Human Use (Clinical Trial) Regulations (SI 2004/1031)4, and all subsequent 
amendments, the UK Data Protection Act 19985 and any other applicable regional and local 
regulations.  
The Sponsor has a legal responsibility to obtain MHRA approval to perform the study and to 
report the results of the study in full to the MHRA. A copy of the MHRA approval will be 
provided to the PI before the start of the study. 
18.6.2 Ethical considerations 
The Sponsor will submit the protocol, VIS/ICF, IB and any recruitment  material  to the REC 
for their review. Written approval of these documents must be received from the REC before 
the first subject is recruited.  
The Sponsor will notify the REC of any protocol amendments as described in Section 18.2.1. 
Written approval must be obtained from the REC for all substantial amendments to the 
protocol, prior to their implementation, except when necessary to eliminate apparent 
immediate hazard to the subject (Section 18.2.2).  
The Sponsor should also obtain a written statement of the composition of the REC. 
Appropriate reports on the progress of the study will be made in accordance with local 
regulatory practices. 
IMP can only be supplied to the PI after documentation of all ethical and legal requirements 
for starting the study has been received by the Sponsor. 
The REC and MHRA will be informed about the end of the trial with the required timelines. 

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In the event of early termination this is 15 days from trial completion and the reason for 
termination is required. 
In the case of routine termination, this is 90 days from the protocol-defined end of trial (Section 
9.5). 
18.6.3 Laboratory certification and normal values 
The Sponsor will provide the PI with the name and location of the clinical laboratory(ies) used 
for laboratory tests, plus a copy of the certification for all laboratory tests included in the 
protocol, certification number(s), date(s) of certification, and a list(s) of the normal values for 
all laboratory tests required by the protocol. These documents must be available prior to any 
subject being treated in the study. Updated versions of these documents must be provided as 
appropriate. 
18.6.4 No-fault compensation and indemnity 
The Sponsor will provide ‘no-fault’ compensation insurance against any risk incurred by a 
subject because of his/her participation in the study. The Sponsor will indemnify the PI (as 
detailed in a separate document). The indemnity will only apply where all study procedures 
have been carried out according to this protocol.  
The PI confirms that he/she holds his/her own professional indemnity insurance, suitable for 
the activities of the Investigator(s) in relation to the study and, in addition, that this insurance 
satisfies any local insurance requirements, or he/she is a member of a medical union which 
provides such cover for its members. 
The Sponsor has made the following arrangements for payment of compensation in the event 
of harm to the subjects, where no legal liability arises as follows: 
If the subject suffers any side effect or other physical injury resulting directly from the study 
medication, the Sponsor will pay for the reasonable costs of necessary medical treatment to 
the extent permitted by the laws of the UK if: 
 
the subject took the study medication as directed by the Investigator 
 
the subject’s injury was not deliberately caused 
 
the Investigator was immediately notified about the subject’s injury; and  
 
the medical advice of the Investigator was followed. 
If the subjects are caused any injury directly by their participation in the study, the Sponsor 
will compensate the subject in accordance with the guidelines laid down by the Association of 
the British Pharmaceutical Industry (ABPI)43 in providing compensation for any harm or ill 
health incurred. The Sponsor has insurance to cover study-related injuries. 

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18.6.5 Monitoring  
The Study Monitor will contact the site prior to the start of the study to discuss the protocol 
and data collection procedures with site personnel. In accordance with applicable regulations, 
ICH GCP, and the procedures of the Sponsor, the Study Monitor will also periodically contact 
the site and conduct on-site visits. The Study Monitor will ensure that all monitoring visits are 
conducted according to protocol and regulatory requirements. 
During contacts with the study site, the Study Monitor’s activities will include: 
 
Checking and assessing the progress of the study 
 
Reviewing study data collected to date for completeness and accuracy 
 
Conducting source data verification 
 
Identifying any issues and addressing resolutions. 
These activities will be done in order to verify that the: 
 
Data are authentic, accurate, and complete 
 
Study documentation is maintained properly 
 
AEs are reported accurately 
 
Safety and rights of the subjects are being protected 
 
Study is conducted in accordance with the currently approved protocol (and any 
amendments), GCP, and all applicable regulatory requirements. 
The PI will allow the Study Monitor direct access to all relevant documents and records, and 
allocate his/her time and the time of his/her staff to the Study Monitor to discuss findings and 
any relevant issues. 
At study closure, study monitors will conduct all activities as indicated in Section 18.6.5.  
18.6.6 Audits and inspections 
At its discretion, the Sponsor may conduct a QA audit of this study. The Sponsor’s auditing 
procedures will be followed in order to comply with GCP guidelines and ensure acceptability 
of the study data for registration purposes. If such an audit occurs, the PI will give the auditor 
direct access to all relevant documents, and will allocate his/her time and the time of his/her 
staff to the auditor as may be required to discuss findings and any relevant issues.  
In addition, regulatory agencies (e.g., MHRA) may conduct an inspection of the study. If such 
an inspection occurs, the PI will allow the inspector direct access to all source documents and 
other study documentation for source data check and/or on-site audit inspection. The PI must 
allocate his/her time and the time of his/her staff to the inspector to discuss findings of any 
relevant issues. 

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18.6.7 Annual Safety Report and Development Safety Update Report  
The Sponsor is required to submit an Annual Safety Report (ASR) and a Development Safety 
Update Report (DSUR) to the MHRA and the REC once a year throughout the clinical trial or 
on request. The DSUR will take into account all new available safety information received 
during the reporting period. 
18.7 
Investigator responsibilities 
18.7.1 Informed consent procedure 
Potential subjects are typically sent a copy of the volunteer information sheet (VIS) and 
informed consent form (ICF) when their screening visit is arranged, and are encouraged to 
read it prior to their appointment.  
Upon arrival at the screening visit, subjects read the information sheet and consent form with 
a study nurse or the Investigator or delegate present. They are given the opportunity to ask 
any questions, and can take the information sheet away for at least 24 hours to consider their 
participation. 
All subjects are required to have a good understanding of English and it is the Investigator or 
delegate’s responsibility to ensure that the subject understands the information contained in 
the VIS/ICF. Once the Investigator or delegate has confirmed that the subject has understood 
the study, including the benefits and risks of participation, the subject and the Investigator are 
able to sign and date the ICF.  
The ICF must be signed and dated by the subject and countersigned by the Investigator or 
delegate (whoever conducted the consent discussion). The VIS/ICF will be copied and filed 
within the subject notes; the original will be held in the ISF and a copy will be given to the 
subject.  
Subjects will be assured that they can withdraw from the study at any time and for any reason 
without prejudice to their future medical care. They will also be informed in a timely manner if 
new information becomes available that may affect their willingness to continue participation 
in the study. The communication of this information must be documented. If the VIS/ICF is 
amended during the study, the PI must follow all applicable regulatory requirements pertaining 
to approval of the amendment by the REC. The site must use the amended VIS/ICF for all 
new subjects and repeat the consent process with the amended VIS/ICF for any on-going 
subjects, if required. 
18.7.2 Delegation of Investigator responsibilities 
The PI should ensure that all persons assisting with the study are adequately informed about 
the protocol, any amendments to the protocol, their study-related duties and functions, and 
the study medication. The PI should maintain a list of sub-investigators and other appropriately 
qualified persons to whom he/she has delegated significant study-related duties. 

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18.7.3 Information for General Practitioners 
Confirmation of the volunteer's medical history will be requested from the volunteer’s GP in 
order for the PI to judge the volunteer’s suitability for the study. Volunteers will be required to 
consent to their GPs being contacted by the hVIVO team.  
18.7.4 Payments 
Subjects will be reimbursed for their inconvenience and out-of-pocket expenses, including 
travelling costs. All proposed payments to subjects will be approved by the REC prior to the 
start of the study and the amount of payment will be specified in the VIS. 
18.7.5 Liability and insurance 
Liability and insurance provisions for this study are specified in the CTA. 
18.7.6 Investigator’s Protocol Agreement 
The Investigator's Protocol Agreement at the front of this document must be signed by the PI. 
The original or a copy must be kept on file by the Sponsor and the PI must retain the original 
or a copy. The completed Protocol Agreement signifies review and acceptance of the protocol 
by the PI prior to initiation of the study. 
18.7.7 Quality assurance 
hVIVO must implement and maintain QA and QC systems which may involve auditing the 
study.  
Any contracted individual or group working on the study must implement QC systems in their 
work on the study. 
18.8 
Study termination 
Upon completion of the study, the following activities, when applicable, must be conducted by 
the Study Monitor in conjunction with the PI, as appropriate: 
 
Review of site study records for completeness and accuracy 
 
Return of all study data to the Sponsor (excluding source data) 
 
Data clarifications and/or resolutions 
 
Accounting, reconciliation, and final disposition of used and unused study 
medication (study drug and/or placebo).  
In addition, the Sponsor reserves the right to temporarily suspend or prematurely terminate 
this study for any reason (see Section 18.4). 

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19 
DISCLOSURE OF DATA 
19.1 
Subject confidentiality 
In line with EU Directive 95/46/EEC40, as transposed into the UK Data Protection Act 19985, 
the PI and hVIVO have a legal obligation to protect at all times the confidentiality of subject 
personal data from the point of capture, through processing, dissemination in line with consent 
from the subject and to its final disposition. 
The PI shall provide assurance to subjects that their confidentiality will be maintained during 
all audits and inspections of the study site and in any documentation by third parties.  
hVIVO investigators, study nurses and other hVIVO personnel will record information about 
the subjects in a computerised database and in an hVIVO medical record. If the subject 
consents to participate in this study, any of their medical records may be reviewed by hVIVO 
staff and auditors for the purposes of checking that the study is being carried out correctly.  
Subjects’ medical records may also be reviewed by representatives from the REC, 
government agencies and the MHRA; all have the same legal obligation in respect of 
confidentiality. Subjects will be assigned a unique number prior to enrolment into the study 
(Section 7.6). Subjects’ names will not be supplied to the Sponsor. 
Any samples taken for analysis during the study will be labelled using the subject number. 
Some laboratories in the UK may require up to two-three identifiers for the accurate tracking 
and processing of samples, such as subject number, and date of birth. Under no 
circumstances will a laboratory involved in the analysis of samples in this study be given 
information regarding the identity of subjects, such as their full name. 
19.2 
Sponsor confidentiality 
As detailed in the CTA, information concerning the IMP and any information such as clinical 
indications for the IMP, its formula, methods of manufacture and other scientific data relating 
to it, that have been provided by the Sponsor and are unpublished, are confidential and must 
remain the sole property of the Sponsor. The PI will agree to use the information only for the 
purposes of carrying out this study and for no other purpose, unless prior written permission 
from the Sponsor is obtained.  
19.3 
Publication 
By signing the study protocol, the PI agrees that the results of this study may be used for the 
purposes of national and international registration, publication, and information for medical 
and pharmaceutical professionals by the Sponsor. 
If necessary, the authorities will be notified of the PI's name, address, qualifications, and extent 
of involvement. In order to allow the use of the information derived from this clinical study, the 

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PI understands that he has an obligation to provide complete test results and all data 
developed during this study to the Sponsor. 
If the study is to be published, the Sponsor will jointly prepare and co-author manuscript(s) 
that may result from the clinical trial. The Sponsor agrees to allow the PI 40 days to review all 
manuscripts and abstracts prior to submission for publication. The Sponsor reserves the right 
to include the report of this study in any regulatory documentation or submission or in any 
informational materials. The Sponsor also reserves the right to delete any confidential 
information from any proposed manuscripts prior to submission for publication.  
Verbal or written discussion of results prior to study completion and full reporting should only 
be undertaken with written consent from the Sponsor. 
 
 

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20 
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40. 
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44.  Cox RJ. Correlates of protection to influenza virus, where do we go from here? Human 
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Stohr K, Esveld M. Public health. Will vaccines be available for the next influenza 
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Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and 
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47.  
Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and 
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Ajc. Cytotoxic T-cell Immunity to influenza McMichael A, Gotch F, Noble G, Beare P: 
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Lukacher AE. In vivo effector function of influenza virus-specific cytotoxic T 
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Jaffe PA, Kuwano K, Yamada A, Scott M, Young JF, Ennis FA. Kinetics and 
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54. 
Ennis FA, Wells MA. Recovery from a Viral Respiratory Tract Infection: III. Specificity 
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Bennink JR, Yewdell JW, Smith GL, Moss B. Anti-influenza virus cytotoxic T 
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Gotch F. Identification of viral molecules recognized by influenza-specific human 
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Bennink JR. Murine cytotoxic T lymphocyte recognition of individual influenza virus 
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Reay PA, Jones IM, Gotch FM, McMichael AJ, Brownlee GG. Recognition of the 
PB1, neuraminidase, and matrix proteins of influenza virus A/NT/60/68 by cytotoxic T 
lymphocytes. Virology. 1989;170(2):477-485. 
 
  

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21 
APPENDICES 
Appendix 1: FLU PRO Symptom Questionnaire ......................................................................... 109 
Appendix 2: Vital signs: Study specific normal ranges and abnormalities ................................. 111 
Appendix 3: ECG: Study specific abnormalities ......................................................................... 112 
 

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Appendix 1: FLU-PRO Symptom Questionnaire
 

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Appendix 2: Vital signs: Study specific normal ranges and abnormalities 
Vital 
signs 
parameters 
Lower limit 
Higher limit 
Units 
Tympanic 
temperature 
35.5 
38.0 
oC 
Oxygen saturation 
Normal is ≥ 95 
 
% 
Respiratory rate 
10 
20 
breaths per minute 
Heart rate 
50 
100 
beats per minute 
Systolic BP 
90 
140 
mmHg 
Diastolic BP 
60 
90 
mmHg 
b The classification of AEs related to hypotension and hypertension will be done according to the DMID 
grading scale. 

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Appendix 3: ECG: Study specific abnormalities  
Ref: The clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-
antiarrhythmic drugs. CHMP/ICH/2/04, May 2005. 
ECG Parameters 
Lower limit 
Higher limit 
Units 
HR 
50 
100 
bpm 
QRS 
60 
109 
ms 
PR interval 
120 
200 
ms 
QT 
320 
450 
ms 
QTc 
Normal for females is ≤ 450 
ms 
Normal for males is ≤ 430 
QTcF 
320 
450 
ms 
QTcB 
320 
450 
ms 
RR 
600 
1200 
ms 
 
 

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Appendix 4: Division of Microbiology and Infectious Diseases (DMID) Adult Toxicity 
Table November 2007 
 
 

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