A Phase 2b Study to Determine the Efficacy of Candidate Influenza Vaccine MVA-NP+M1 in Adults Aged 18 Years and Over
Phase: PHASE2
Conditions: Influenza
Sponsor: Barinthus Biotherapeutics



 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 2 OF 78 
Principal Investigator Agreement: 
I, the undersigned, have reviewed this protocol and agree to conduct this protocol in accordance 
with International Council on Harmonisation Good Clinical Practice (ICH GCP), the ethical 
principles set forth in the Declaration of Helsinki, and with local regulatory requirements.   
 
Signature 
 
 
 
 
 
 
 
Date 
 
 
Printed Name  

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 3 OF 78 
TABLE OF CONTENTS 
TABLE OF CONTENTS ...................................................................................................... 3 
LIST OF TABLES AND FIGURES ..................................................................................... 7 
LIST OF ABBREVIATIONS ............................................................................................... 8 
CONTACTS ........................................................................................................................... 9 
STUDY ABSTRACT ........................................................................................................... 11 
1 
INTRODUCTION ...................................................................................................... 12 
1.1 
Background ......................................................................................................... 12 
1.2 
Non-clinical Studies ............................................................................................ 14 
1.3 
Clinical Experience with MVA-NP+M1 ............................................................ 14 
1.3.1 
Safety and Immunogenicity Summary ................................................. 16 
1.3.2 
Efficacy Summary ................................................................................ 17 
1.4 
Rationale for Study ............................................................................................. 17 
2 
STUDY OBJECTIVES AND DESIGN .................................................................... 19 
2.1 
Objectives and Endpoints.................................................................................... 19 
2.2 
Design 
20 
2.3 
Data Monitoring Committee and Study Pausing and Stopping Rules ................ 26 
3 
STUDY PROCEDURES ............................................................................................ 28 
3.1 
Schedule of Assessments .................................................................................... 28 
3.2 
Participant Selection ........................................................................................... 30 
3.2.1 
Recruitment and Informed Consent ...................................................... 30 
3.2.2 
Assignment of Participant Identification Number ................................ 30 
3.2.3 
Eligibility Criteria ................................................................................. 30 
3.2.3.1 
Inclusion Criteria .................................................................. 30 
3.2.3.2 
Exclusion Criteria ................................................................. 31 
3.2.4 
Screening/Baseline Assessments .......................................................... 32 
3.3 
Study Randomisation .......................................................................................... 33 
3.4 
Investigational Product Administration .............................................................. 33 
3.5 
Participant Follow-up and Contact ..................................................................... 34 
3.5.1 
Follow-up over Influenza Season ......................................................... 34 
3.5.2 
Loss to Follow-up ................................................................................. 35 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 4 OF 78 
3.6 
Study Evaluations ............................................................................................... 35 
3.6.1 
Efficacy Evaluations ............................................................................. 35 
3.6.2 
Immunogenicity Laboratory Evaluations ............................................. 36 
3.6.3 
Safety Evaluations ................................................................................ 36 
3.6.3.1 
Adverse Events ..................................................................... 36 
3.6.3.1.1 
Solicited Adverse Events ................................... 36 
3.6.3.1.2 
Unsolicited Adverse Events .............................. 37 
3.6.3.2 
Laboratory Safety Tests ....................................................... 37 
3.6.3.2.1 
Haematology ..................................................... 37 
3.6.3.2.2 
Biochemistry ..................................................... 37 
3.6.3.3 
Physical Examination ........................................................... 38 
3.6.3.4 
Concomitant Medications .................................................... 38 
4 
STUDY TREATMENTS............................................................................................ 38 
4.1 
Description of Study Treatments ........................................................................ 38 
4.1.1 
MVA-NP+M1 ....................................................................................... 39 
4.1.2 
Placebo .................................................................................................. 39 
4.2 
Blinding 
39 
4.3 
Receipt and Storage ............................................................................................ 39 
4.4 
Accountability ..................................................................................................... 40 
4.5 
Preparation 40 
4.6 
Disposal of Unused Investigational Product ....................................................... 40 
4.7 
Compliance ......................................................................................................... 41 
5 
SAFETY ...................................................................................................................... 42 
5.1 
Responsibilities for Ensuring the Safety of Study Participants .......................... 42 
5.1.1 
Principal Investigator ............................................................................ 42 
5.1.2 
Study Sponsor ....................................................................................... 42 
5.1.3 
Local Medical Monitor ......................................................................... 42 
5.1.4 
Data Monitoring Committee ................................................................. 42 
5.1.5 
Institutional Review Boards and Ethics Committees ........................... 43 
5.1.6 
National Regulatory Authority ............................................................. 43 
5.2 
Definition of Adverse Event ............................................................................... 43 
5.3 
Assessing Severity .............................................................................................. 44 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 5 OF 78 
5.3.1 
Solicited Adverse Events ...................................................................... 44 
5.3.2 
Unsolicited Adverse Events .................................................................. 44 
5.4 
Assessing Causal Relationship (Relatedness) ..................................................... 45 
5.5 
Assessing "Seriousness" and Serious Adverse Events ....................................... 46 
5.6 
Definition of Adverse Reaction .......................................................................... 46 
5.7 
Assessing Expectedness of Adverse Events ....................................................... 46 
5.8 
Definition of Suspected Unexpected Serious Adverse Reaction ........................ 47 
5.9 
Definition of an Adverse Event of Special Interest ............................................ 47 
5.10 Reporting of Serious Adverse Events ................................................................. 47 
5.10.1 
Reporting to the Sponsor ...................................................................... 47 
5.10.2 
Expedited Reporting ............................................................................. 48 
5.11 Other Events Requiring Immediate Reporting .................................................... 48 
5.12 Adverse Event Treatment, Follow-up, and Outcome ......................................... 48 
5.13 Follow-up of Participants Who Become Pregnant .............................................. 49 
6 
DATA COLLECTION, MONITORING AN RECORD RETENTION ............... 51 
6.1 
Source Documentation ........................................................................................ 51 
6.2 
Data Management ............................................................................................... 51 
6.3 
Monitoring 52 
6.4 
Record Retention................................................................................................. 52 
7 
STATISTICAL CONSIDERATIONS ...................................................................... 53 
7.1 
Participant Analysis Sets ..................................................................................... 53 
7.2 
Disposition, Demographics and Protocol Compliance ....................................... 53 
7.3 
Efficacy Analyses ............................................................................................... 53 
7.4 
Immunogenicity and Other Immunology Analyses ............................................ 54 
7.4.1 
Immune Response Determined by Intracellular Cytokine Staining 
Assay ..................................................................................................... 54 
7.4.2 
ELISpot Assay ...................................................................................... 54 
7.5 
Safety Analyses ................................................................................................... 54 
7.5.1 
Adverse Events ..................................................................................... 54 
7.5.2 
Injection Site Reactions ........................................................................ 55 
7.5.3 
Clinical Laboratory Parameters ............................................................ 55 
7.6 
Sample Size Considerations ................................................................................ 55 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 6 OF 78 
7.7 
Plan for Statistical Summaries and Analyses ...................................................... 56 
7.7.1 
Preliminary Data Reviews .................................................................... 56 
7.7.2 
Final Study Report ................................................................................ 56 
7.8 
Computer Methods .............................................................................................. 56 
8 
ETHICS ....................................................................................................................... 57 
8.1 
Regulatory Considerations .................................................................................. 57 
8.2 
Institutional Review Board or Independent Ethics Committee .......................... 57 
8.3 
Informed Consent ................................................................................................ 58 
9 
STUDY COMPLETION ............................................................................................ 60 
10 
PUBLICATION .......................................................................................................... 61 
11 
CHANGES IN THE PROTOCOL............................................................................ 62 
12 
REFERENCES ........................................................................................................... 63 
APPENDICES ...................................................................................................................... 65 
Appendix 1 
Detailed Description of Study Visits................................................ 65 
Appendix 2 
Adverse Events of Special Interest .................................................. 68 
Appendix 3 
Toxicity Table for Clinical and Laboratory Abnormalities ............. 69 
 
 
 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 7 OF 78 
LIST OF TABLES AND FIGURES 
Table 1-1 
Summary of MVA-NP+M1 Clinical Studies ................................................... 15 
Table 2-1 
Treatment Groups and Number of Participants ................................................ 21 
Table 3-1 
Schedule of Assessments (Main Cohort) ......................................................... 28 
Table 3-2 
Schedule of Assessments (Immunogenicity Cohort) ....................................... 29 
Table 7-1 
Sample Size Calculations (80% power, two-sided alpha levels) ..................... 55 
Figure 1-1 
Immunogenicity of MVA-NP+M1 in Older Adults (FLU001) ....................... 16 
Figure 1-2 
Area under the Curve Responses for Patricipants Vaccinated using 
MVA-NP+M1 (1.5 × 108 pfu) Manufactured on AGE1.CR.pIX® and Chicken 
Embryo Fibroblasts .......................................................................................... 17 
Figure 2-1 
Study Flow Diagram ........................................................................................ 20 
Figure 2-2 
Follow-up Procedures for the Main Cohort (Participants Vaccinated early in 
the Influenza Season) ....................................................................................... 23 
Figure 2-3 
Follow-up Procedures for the Main Cohort (Participants Vaccinated later in 
the Influenza Season) ....................................................................................... 24 
Figure 2-4 
Follow-up Procedures for the Immunogenicity Cohort (Participants Vaccinated 
early in the Influenza Season) .......................................................................... 25 
Figure 2-5 
Follow-up Procedures for the Immunogenicity Cohort (Participants Vaccinated 
later in the Influenza Season) ........................................................................... 26 
 
 
 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 8 OF 78 
LIST OF ABBREVIATIONS 
AUC 
Area under the curve 
CEF 
Chicken embryo fibroblasts 
CRO 
Contract research organisation 
DMC 
Data monitoring committee 
DMSO 
Dimethyl sulfoxide 
EDTA 
Ethylenediaminetetraacetic acid 
ELISpot 
Enzyme linked immunosorbent spot 
eDiary 
Electronic diary 
GMO 
Genetically modified organism 
HA/H 
Haemagglutinin 
HIV 
Human immunodeficiency virus 
ICH GCP 
International Council on Harmonisation Good Clinical Practice 
ICS 
Intracellular cytokine staining 
IEC 
Independent ethics committee 
IFN- 
Interferon gamma 
ILI 
Influenza like illness 
IRB 
Institutional review board 
MedDRA 
Medical dictionary for regulatory activities 
M1 
Matrix 1 
MVA 
Modified vaccinia virus Ankara 
NA/N 
Neuraminidase 
NP 
Nucleoprotein 
pfu 
Plaque forming units 
QIV 
Quadrivalent influenza vaccine 
RT-PCR 
Reverse transcription polymerase chain reaction 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
TCID50 
Tissue culture infectious dose 
 
 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 9 OF 78 
CONTACTS 
Sponsor 
 Vaccitech Ltd 
The Schrodinger Building 
Heatley Road 
The Oxford Science Park 
Oxford, OX4 4GE 
UK 
Tel: +44 (0)1865 818808 
Local Medical Monitor 
 Dr John Gillies MBChB, FRACP, FRCPC, FAAP 
 
 Clinical Network Services (CNS) 
Contract Research Organisation 
 Clinical Network Services Pty Ltd 
(CRO) 
 Level 4 
 
 88 Jephson Street 
 
 Toowong 
 
 Queensland 
 
 4066 
 
 Australia 
Manufacturing Facility 
 
Emergent BioSolutions 
5901 East Lombard Street 
Baltimore 
MD 21224 
US 
Packaging and Labelling 
 Fisher BioServices 
Woodside Industrial Estate 
 
 Unit 1 
 
 Bishop's Stortford 
 
 Hertfordshire, CM23 5RG 
UK 
 
 Fisher Clinical Services  
 
 Langhurst Wood Road 
 
 Horsham 
 
 West Sussex, RH12 4QD 
 UK 
Distribution Centre 
 PCI Pharma Services 
 
 3/31 Sabre Drive 
 
 Port Melbourne VIC 
 
 Australia 3207 
 
 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 10 OF 78 
Immunogenicity Laboratories 
 Veracity Biolabs 
1 Dalmore Drive 
Scoresby 3179  
Victoria  
Australia 
360biolabs Pty Ltd 
85 Commercial Road 
Melbourne 
Victoria 
Australia, 3004 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 11 OF 78 
STUDY ABSTRACT 
Protocol Title 
A Phase 2b Study to Determine the Efficacy of Candidate Influenza Vaccine 
MVA-NP+M1 in Adults aged 18 years and over 
Protocol Number 
FLU009 
Primary Objective(s) 
To assess the effect of MVA-NP+M1 on the reduction of laboratory confirmed 
influenza when given as an adjunct to licensed quadrivalent influenza vaccine 
(QIV) in adults 
Secondary Objective(s) 
• 
To assess the impact of MVA-NP+M1 on incidence and severity of 
influenza-like symptoms in adults aged 18 years and over when given as 
an adjunct to licensed QIV 
• 
To assess the safety of MVA-NP+M1 or placebo when given as an adjunct 
to licensed QIV in adults aged 18 years and over 
Exploratory Objective(s) 
To assess the immunogenicity of MVA-NP+M1 when given as an adjunct to 
licensed QIV in adults aged 18 years and over 
Design 
This is a Phase 2b, multicentre, randomised, single-blind study in up to 6000 
adults to compare the efficacy, safety and immunogenicity of MVA-NP+M1 
when given as an adjunct to a standard, licensed adult dose of QIV. The study 
will be conducted on an outpatient basis and will run over two consecutive 
influenza seasons. It is aimed to recruit approximately 2200 participants in 
Season 1 and 2800-3800 participants in Season 2. 
Number and Location of 
Clinical Study Site(s)  
Up to 10 Sites in Australia 
Study Population 
Healthy adults 18 years or over who are receiving a licensed QIV vaccine  
Treatment Groups 
MVA-NP+M1 vs. saline placebo 
Single dose of 1.5 x 108 plaque forming units MVA-NP+M1 or saline placebo 
given by intramuscular administration  
2,500-3,000 per study group with approximately 1,100 per study group enrolled 
in Season 1 
Length of Follow-up 
Each participant will be followed for a total of approximately 210 days. 
Primary Endpoint(s) 
Incidence of laboratory confirmed influenza-like illness 
 
 
 
 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 12 OF 78 
1 
INTRODUCTION 
1.1 
Background 
Seasonal influenza has a significant annual global impact accounting for an estimated 1 billion 
illnesses and 250,000 to 500,000 deaths [1] with an estimated annual economic cost of 
$87.1 billion in the US alone [2]. Influenza pandemics also occur occasionally with significant 
health and economic burden [3]. In addition, the unpredictable risk of sporadic outbreaks of 
human infections with avian influenza (H5N1) could trigger a new pandemic if the virus 
acquires the ability to transmit from person to person [4] and make influenza a major global 
public health issue. The major demographic groups at highest risk of influenza infection, severe 
disease and death remain young children, older individuals, pregnant women and those with 
co-morbid conditions such as asthma, chronic respiratory disease, diabetes and 
immunosuppressive conditions.  
Vaccination remains the most cost-effective strategy available to combat influenza. Current 
influenza vaccines work by inducing strain-specific antibodies against the highly polymorphic 
surface proteins (haemagglutinin [HA/H], neuraminidase [NA/N]) of the influenza virus. 
Inactivated or live vaccines are made up of proteins from viruses or live viruses, respectively, 
covering four influenza virus strains (H1N1, H3N2 and two strains of influenza B). The 
composition of virus strains used in the production of vaccines is based on a prediction of 
strains likely to circulate in the population in the upcoming influenza season. As the circulating 
virus strains change, current vaccines need to be reformulated annually to match new strains 
arising through genetic drift in the surface proteins of these seasonal viruses. As these surface 
proteins to which vaccine-induced antibodies are targeted are highly polymorphic, there is little 
protection against strains of a new subtype and limited protection even across strains within 
the same subtype. Approximately one year in 20, vaccine efficacy is much lower than expected 
owing to antigenic drift away from the vaccine strain [5]. This need for constant redesign and 
remanufacture increases the vaccine cost, places limitations on supply [6] and critically delays 
vaccine production when new strains arise until the HA and NA sequences have been identified 
leaving large populations susceptible to infection and illness from the new strains. The efficacy 
of current vaccines is also limited in the face of antigenic mismatch between circulating strains 
and those in the vaccine and it is also substantially reduced in older adults. Vaccination in older 
adults, who are a major target group for vaccination, prevents laboratory-confirmed influenza 
in only 30 to 40% compared to 70 to 90% in young adults [7]. There is therefore a major 
demand for improved vaccination strategies that can provide protection against a broad 
spectrum of virus strains particularly for older groups.  
In situations where individuals are exposed to a newly arisen influenza virus strain against 
which they lack protective neutralising antibodies, cross-reactive T-cells against conserved 
internal antigens of influenza have been shown to be associated with limiting viral shedding, 
reduced duration of symptoms and minimising severity of symptomatic illness [8, 9]. A vaccine 
against influenza that induced protective T-cell responses against conserved internal antigens 
could therefore provide lasting immunity against not only human seasonal influenza, but also 
other subtypes currently found in avian species or swine which have the potential to cause a 
new pandemic. Since adults have been primed by prior exposure to influenza, a vaccine 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 13 OF 78 
expressing conserved internal antigens of influenza such as nucleoprotein (NP) and Matrix 1 
(M1) could be used to boost cross-reactive T-cell responses to protective levels, providing 
durable broad immunity to all subtypes of influenza A. 
The internal proteins of the influenza virus are more conserved compared to the external 
surface glycoproteins. There are two reasons for selecting NP and M1 as a target for T-cell 
inducing vaccines. First, there is very little polymorphism of NP and M1 between influenza A 
isolates. NP is 92% identical between H3N2 and H1N1 strains, and 91% identical between 
H3N2 and H5N1 strains. M1 is 95% identical between H3N2 and H1N1 strains, and 93% 
identical between H3N2 and H5N1 strains. This low level of variation appears to allow strong 
T-cell cross-reactivity. In the local population more than 70% of individuals generate a T-cell 
response to these two antigens [10]. Second, analysis of T-cell response to all the proteins of 
influenza have shown that the T-cell response to NP and M1 is the strongest and 80% of 
individuals have responses to these two proteins. Recent studies have also shown that T-cells 
specific to M1 and NP are associated with protecting individuals against influenza by limiting 
viral shedding, reduced duration of symptoms and minimising severity of symptomatic illness 
[8, 9]. 
Recombinant viral vectored vaccines have been used in humans to induce high frequencies of 
CD4+ and CD8+ T-cell responses to a wide range of antigens. One such recombinant viral 
vector is Modified Vaccinia Ankara (MVA) which has been used to generate strong T-cell 
responses to a wide range of antigens, including antigens from plasmodium, tuberculosis, 
hepatitis C, human immunodeficiency virus (HIV) and influenza. MVA-NP+M1 is a 
recombinant, replication-deficient MVA vector expressing the influenza antigens NP and M1 
as a fusion protein [11].  
MVA is an attractive candidate orthopox vaccine vector for safety and immunogenicity 
reasons. The successful worldwide eradication of smallpox using vaccination with vaccinia 
virus highlighted vaccinia as a candidate vaccine vector. Although millions of humans have 
been vaccinated with conventional replication-competent vaccinia virus, its small but definite 
risk to both researchers and future patients led to the development of several attenuated strains 
of vaccinia during smallpox eradication. MVA was originally derived from the vaccinia strain 
Ankara by over 500 serial passages in primary chicken embryo fibroblasts (CEF cells). MVA 
has six major genomic deletions compared to the parental Ankara genome and is severely 
compromised in its ability to replicate in mammalian cells. No replication has been documented 
in non-transformed mammalian cells. 
MVA has an excellent safety record. It was administered intradermally to approximately 
120,000 people during the smallpox eradication campaign [12]. MVA is currently in 
development as a vector for multiple diseases including HIV-1 [13, 14], tuberculosis [15], 
hepatitis C virus [16], influenza [11] and melanoma [17]. MVA vectored vaccines developed 
at the University of Oxford have been administered to over 4500 individuals including infants, 
young children, elderly adults, HIV-infected adults and children and patients with cancer in 
Europe and Africa without any safety concerns. Clinical studies have shown intramuscular 
administration, as compared to intradermal, to be associated with fewer and short-lived local 
adverse events and no reduction in immunogenicity [18]. 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 14 OF 78 
1.2 
Non-clinical Studies 
MVA NP+M1 has been shown to be immunogenic in BALB/c mice. Biodistribution studies 
were not conducted with MVA-NP+M1. Distribution studies in mice, however, showed no 
evidence of replication of the virus or presence of disseminated infection 1 week after 
intradermal and intramuscular injections using similar MVA vaccines (MVA85A, MVA 
ME-TRAP, MVA AMA1 and MVA MSP1). A distribution study was therefore not thought to 
be necessary for MVA-NP+M1. Previous toxicology studies in mice showed no evidence of 
systemic MVA-related toxicity after administration (either intradermal or intramuscular). A 
low level of local irritation at the vaccination site after intradermal administration is normally 
noted in these toxicology studies.  
Single and repeat dose toxicology studies were performed on BALB/c mice using the 
MVA-NP+M1 manufactured in CEF and revealed that repeated administration of 
MVA-NP+M1 had no effect on mortality, cage side observations or bodyweights. Mice gained 
weight and had normal food consumption during the study. Clinical observations, vaccination 
site reactogenicity, clinical chemistry, clinical haematology, gross necropsy, organ weights and 
histopathology indicated no overt toxicity related vaccine administration (see the Investigator’s 
Brochure). 
The MVA viral vector manufactured using the AGE1.CR.pIX® avian cell line has been 
previously used with a different insert for an Ebola preventive vaccine (MVA-EBOZ). A Good 
Laboratory Practice-compliant non-clinical toxicology study was conducted to evaluate the 
local and systemic toxicity of the MVA85A vaccine manufactured using the AGE1.CR.pIX® 
avian cell line. The MVA85A was used as a surrogate test article to support the use of a 
MVA-EBOZ vaccine produced in the AGE1.CR.pIX® avian cell line and to demonstrate the 
safety of the vaccine for the first in human study.  
1.3 
Clinical Experience with MVA-NP+M1 
Administration of the MVA-NP+M1 vaccine is supported by data from eight clinical studies, 
see Table 1-1. The first six studies used MVA-NP+M1 manufactured in CEF; a total of 
145 participants received MVA-NP+M1 in these studies. 
Two studies have since been conducted with the vaccine manufactured using the 
AGE1.CR.pIX® cell line. The first was a small Phase 1 bridging study (FLU008) to ensure the 
product was safe and elicited comparable or superior immune responses than those induced by 
the same vaccine made in CEF cells. This was followed by a Phase 2 study (FLU007) of elderly 
participants who either received the licensed quadrivalent influenza vaccine (QIV) followed 
by either placebo (N=430) or MVA-NP+M1 (N=430).  
Full details of the clinical experience with MVA-NP+M1 can be found in the Investigator’s 
Brochure. 
 
 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 15 OF 78 
Table 1-1 
Summary of MVA-NP+M1 Clinical Studies 
Study 
Phase 
Vaccine 
Purpose 
Age 
(years) 
Route 
Dose of  
MVA-NP+M1  
N 
MVA-NP+M1 manufactured in CEF  
FLU001  
1 
MVA-NP+M1 
Safety and 
immunogenicity of two 
routes of administration 
and dose effect 
18-50 
ID 
5 x 107 pfu 
12 
MVA-NP+M1 
18-50 
IM 
5 x 107 pfu 
8 
MVA-NP+M1 
18-50 
IM 
2.5 x 108 pfu 
8 
MVA-NP+M1 
50-59 
IM 
1.5 x 108 pfu 
10 
MVA-NP+M1 
60-69 
IM 
1.5 x 108 pfu 
10 
MVA-NP+M1 
70+ 
IM 
1.5 x 108 pfu 
10 
FLU002 
2a 
MVA-NP+M1 
Safety and efficacy of 
influenza challenge 
18-50 
IM 
1.5 x 108 pfu 
15 
FLU003  
1 
MVA-NP+M1 / 
Seasonal influenza vaccine 
Safety and 
immunogenicity when 
co-administered with 
seasonal vaccine 
50+ 
IM 
1.5 x 108 pfu 
9 
FLU004  
1 
ChAdOx1-NP+M1 /  
MVA-NP+M1 
Dose escalation to assess 
the boosting effect of 
MVA-NP+M1 after 
adenovirus prime 
18-50 
IM 
1.5 x 108 pfu 
3 
FLU005 
1 
ChAdOx1-NP+M1 /  
MVA-NP+M1 (8 weeks apart) 
Safety and 
immunogenicity of 
different prime-boost 
combinations of 
MVA-NP+M1 and 
adenovirus in different 
age groups 
18-50 
IM 
1.5 x 108 pfu 
12 
ChAdOx1-NP+M1 /  
MVA-NP+M1 (52 weeks apart) 
18-50 
IM 
1.5 x 108 pfu 
8 
MVA-NP+M1 /  
ChAdOx1-NP+M1 (8 weeks apart) 
18-50 
IM 
1.5 x 108 pfu 
13 
ChAdOx1-NP+M1 /  
MVA-NP+M1 (52 weeks apart) 
18-50 
IM 
1.5 x 108 pfu 
12 
ChAdOx1-NP+M1 /  
MVA-NP+M1 (8 weeks apart) 
>50+ 
IM 
1.5 x 108 pfu 
12 
FLU006  
1 
MVA-NP+M1 / 
Co-administered with seasonal 
influenza vaccine (Viroflu®) 
Safety and 
immunogenicity when 
co-administered with 
seasonal vaccine 
18-50 
IM 
1.5 x 108 pfu 
3[b] 
MVA-NP+M1 manufactured in AGE1.CR.pIX®  
FLU008 
1 
MVA-NP+M1 
Bridging study to assess 
safety and 
immunogenicity of 
MVA-NP+M1 
manufactured on new 
cell line 
18-50 
IM 
1.5 x 108 pfu 
6 
FLU007 
2 
MVA-NP+M1 / 
Co-administered with seasonal QIV 
Safety and efficacy in the 
elderly when 
co-administered with 
seasonal vaccine 
≥65 
IM 
1.5 x 108 pfu 
430 
Abbreviations: CEF=chicken embryo fibroblasts; ID=intradermal; IM=intramuscular; N=number of participants; pfu=plaque forming 
units; QIV=quadrivalent influenza vaccine 
[a] Simian adenovirus vectored vaccine ChAdOx1 NP+M1 
[b] FLU006 was stopped early due to futility as recruitment was slower than had been expected. 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 16 OF 78 
1.3.1 
Safety and Immunogenicity Summary 
The vaccine has been shown to have a good safety profile with no vaccine related serious 
adverse events (SAEs). A dose dependent increase in adverse events was observed, and a dose 
of 1.5 x108 plaque forming units (pfu) was found to be the optimal balance between 
immunogenicity and reactogenicity across age groups [11]. There was no apparent difference 
between the vaccine manufactured in CEF and using AGE1.CR.pIX®. The vaccine also had a 
good safety profile when co-administered with the standard seasonal influenza vaccine.  
Vaccination with MVA-NP+M1 results in a rapid increase in influenza-specific cross-reactive 
interferon gamma (IFN-γ)-secreting effector T-cells (determined by enzyme-linked 
immunosorbent spot (ELISpot) assay) across age groups which are maintained at protective 
levels over the course of a year [11]. In the older age groups, MVA-NP+M1 can boost 
pre-existing levels of influenza-specific T-cells and maintain them for up to at least 6 months 
post-vaccination [19]. The immunogenicity of MVA-NP+M1 in older adults (aged 50+) 
receiving a dose of 1.5 x108 pfu (Study FLU001) is shown in Figure 1-1. 
MVA-NP+M1 in combination with licensed inactivated influenza vaccine induced 
influenza-specific T-cells and in addition, increase the magnitude and breadth of the antibody 
response induced by the inactivated influenza vaccine [20].  
There was no statistically significant difference between T-cell responses when data from 
participants receiving MVA-NP+M1 manufactured using AGE1.CR.pIX® was compared with 
historical data from MVA-NP+M1 manufactured in CEF (FLU005), as shown in Figure 1-2. 
Figure 1-1 
Immunogenicity of MVA-NP+M1 in Older Adults (FLU001) 
 
Weeks Post-vaccination  
Abbreviations: PBMC=peripheral blood mononuclear cells; SFU=spot forming units; W=weeks 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 17 OF 78 
Figure 1-2 
Area under the Curve Responses for Participants Vaccinated using 
MVA-NP+M1 (1.5 × 108 pfu) Manufactured on AGE1.CR.pIX® and 
Chicken Embryo Fibroblasts 
 
Abbreviations: AUC=area under the curve; CEF=chicken embryo fibroblasts 
Individual and median values are shown 
Comparison performed using the Mann-Whitney test on data from FLU008 compared to historical data from 
Coughlin et al. (FLU005) [21] 
1.3.2 
Efficacy Summary 
The efficacy of MVA-NP+M1 has been tested in two studies. In a small Phase 2a challenge 
study 
of 
MVA-NP+M1 
alone 
(FLU002), 
MVA-NP+M1 
vaccinated 
participants 
experimentally challenged with live influenza virus trended to less severe symptoms and 
shorter duration of viral shedding compared to unvaccinated controls [22]. A second Phase 2 
study (FLU007), collecting symptom endpoints is now unblinded and undergoing further 
analysis. 
1.4 
Rationale for Study 
Vaccination remains the most cost-effective strategy available to combat influenza. Current 
influenza vaccines work by inducing strain-specific antibodies against the highly polymorphic 
surface proteins of the influenza virus. The need for constant redesign and remanufacture 
increases the vaccine’s cost, places limitations on supply and critically delays vaccine 
production when new strains arise. There is therefore a major demand for improved vaccination 
strategies that can provide protection against a broad spectrum of virus strains.  
Previous studies have demonstrated the safety of MVA-NP+M1 across different age groups, 
including older adults and in combination with seasonal influenza vaccine; the immunogenicity 
of MVA-NP+M1 in older adults given alone and in combination with licensed inactivated 
seasonal influenza vaccine; and the effect of MVA-NP+M1 in limiting the severity of influenza 
illness in adults.  
This study will therefore investigate the immunogenicity and efficacy in terms of viral and 
symptom endpoints in a large number of healthy adults aged 18 and over when given as an 
A G E 1 .C R .p IX
C E F
0
2 0 0 0 0
4 0 0 0 0
6 0 0 0 0
8 0 0 0 0
A U C
n s
b

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 18 OF 78 
adjunct to standard QIV. This MVA-NP+M1, produced using the novel immortalised duck 
retinal cell line AGE1.CR.pIX®, also addresses the scalability issues of CEF manufactured 
vaccines. 
 
 
 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 19 OF 78 
2 
STUDY OBJECTIVES AND DESIGN 
2.1 
Objectives and Endpoints 
The study objectives and corresponding endpoints are provided below.  
Note: that licensed QIV refers to a standard adult dose of QIV (15 g per HA component) rather than a high dose 
QIV. 
Objectives 
Endpoints 
Primary 
To assess the effect of MVA-NP+M1 on the 
reduction of laboratory confirmed influenza 
when given as an adjunct to licensed QIV in 
adults. 
Primary 
Incidence rate of laboratory confirmed influenza 
using reverse transcription polymerase chain reaction 
(RT-PCR) on deep nasal/mid-turbinate swab samples. 
Secondary 
• 
To assess the impact of MVA-NP+M1 on 
incidence and severity of influenza-like 
symptoms in adults aged 18 years and 
over when given as an adjunct to licensed 
QIV  
Secondary 
• 
Incidence and severity of influenza-like illness 
(ILI) 
• 
Duration of ILI 
• 
To assess the safety of MVA-NP+M1 or 
placebo when given as an adjunct to 
licensed QIV in adults aged 18 years and 
over 
• 
Occurrence of solicited local and systemic 
reactogenicity signs and symptoms for 7 days 
following vaccination 
• 
Occurrence of SAEs during the whole study 
duration 
• 
To assess the immunogenicity 
of 
MVA-NP+M1 when given as an adjunct 
to licensed QIV in adults aged 18 years 
and over 
• 
Frequency 
of 
influenza-specific 
T-cells 
measured by IFN-γ/granzyme B ELISpot  
• 
Geometric mean titre of influenza-specific 
neutralising antibodies  
 
 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 20 OF 78 
2.2 
Design 
This is a Phase 2b, multicentre, randomised, single-blind study in up to 6000 adults to compare 
the efficacy, safety and immunogenicity of MVA-NP+M1 when given as an adjunct to a 
standard, licensed adult dose of QIV. The study will be conducted on an outpatient basis and 
will run over two consecutive influenza seasons. It is aimed to recruit approximately 2200 
participants in Season 1 and 2800-3800 participants in Season 2. The study design is shown in 
Figure 2-1. 
Figure 2-1 
Study Flow Diagram 
 
Abbreviations: AEs=adverse events; eDiary=electronic diary; ILI=influenza-like illness; SAE=serious adverse 
event 
The majority of participants will participate in the main cohort of the study. These participants 
will attend the clinic for a single screening/vaccination visit on Day 0 and will be followed up 
over the duration of the influenza season into which they are recruited. 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 21 OF 78 
Approximately 50 participants will participate in an immunogenicity cohort; it is anticipated 
this will be at one centre only. In addition to the visits and procedures outlined for the main 
cohort, these participants will attend for a further three clinic visits on Days 7(+3 days) and 
28 (±7 days) and Week 26 (±1 week) (approximate end of the influenza season). 
Following screening and confirmation of eligibility on Day 0, all participants will be 
randomised in a 1:1 ratio to the two treatment groups shown in Table 2-1. Participants in the 
immunogenicity cohort only will also have pre-vaccination safety laboratory and 
immunogenicity blood samples taken. 
Table 2-1 
Treatment Groups and Number of Participants 
 
Group 1 
Group 2 
Study treatments 
MVA-NP+M1 
Placebo 
Dose 
1.5 x 108 pfu 
None 
Volume 
0.5 mL 
0.5 mL 
Route of administration 
Intramuscular injection 
Intramuscular injection 
Vaccination days 
Day 0 
Day 0 
Number of participants; 
Main cohort 
Immunogenicity cohort 
2500-3000 
2475 
25 
2500-3000 
2475 
25 
Vaccinations (1.5 x 108 pfu MVA-NP+M1 or saline placebo) will be administered by 
intramuscular injection using the Z-track technique on Day 0. Participants will be observed for 
at least 30 minutes post-vaccination in case of immediate adverse events and to comply with 
GMO licence regulations. All participants will be provided with an oral thermometer, tape 
measure and electronic diary card (eDiary) and instructed how to complete the eDiary at home. 
Participants will record their oral temperature and any solicited adverse events for 7 days 
post-vaccination and unsolicited adverse events for 28 days post-vaccination. Participants will 
be asked to record whether or not they have a respiratory illness and / or ILI every week during 
the influenza season, starting on 01 May and ending on or before 15 October in line with 
official Australian influenza season. Respiratory illness or Influenza Like Illness (ILI) for this 
protocol that triggers a nasal swab collection (to maximize the likelihood of recovering virus 
positive samples) is defined as the presence of one or more of the following symptoms; fever 
or feverishness, cough, sore throat, congestion, chest pain, myalgia, and shortness of breath. 
Any episode with any one of these symptoms should undergo nasal sampling.  The ILI 
regulatory definition used in the statistical section is defined as either fever or feeling feverish 
AND either a cough or sore throat.   
Participants who are vaccinated early in the influenza season and complete the 28 day period 
for reporting unsolicited adverse events prior to 01 May will not be required to record any 
further data after Day 28 in the eDiary until this ILI reporting period starts. These participants 
will be telephoned ~7 days in advance of 01 May by way of reminder to start recording 
symptoms weekly. 
The actual influenza season start and end dates used for final analysis will be determined by 
the Australian surveillance network and will be specified in the statistical analysis plan (SAP).  

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 22 OF 78 
For every respiratory /ILI episode, patients will be asked to record the severity of their 
symptoms daily and any medications taken to treat the symptoms. If they experience such 
symptoms, they should attend the clinic on two occasions, the first within 72 hours of the onset 
of symptoms, for deep nasal/mid-turbinate swabs to be taken. Both swabs must be taken within 
96 hours of symptom onset. These will be analysed for laboratory-confirmed influenza using 
RT-PCR. 
Weekly reminders to complete their diary will be sent to each participant through the IBM 
system or through site appointment systems, depending on where they are enrolled, over the 
duration of the influenza season. The study team will also contact participants by telephone 
every 4 weeks (±1 week) over the duration of the influenza season to remind participants to 
complete the ILI assessment in their diary and to enquire if they have had any hospitalisations, 
other SAEs or adverse events of special interest (AESI) (and other unsolicited adverse events 
at the first contact only for the main cohort). 
Main Cohort: 
Follow-up procedures for the main cohort are outlined in Figure 2-2 (participants who are 
vaccinated early in the influenza season and have completed Day 28 assessments prior to the 
start of the ILI reporting period on 01 May) and Figure 2-3 (participants who are vaccinated 
later in the influenza season and have Day 28 just prior to, or after, the start of the ILI reporting 
period on 01 May). The study team will contact participants by telephone on Day 1 (+2 days) 
post-vaccination and Day 7 (+3 days) post-vaccination for safety follow-up. If the participant 
has persistent, vaccine-related Grade 3 adverse events during the first 4 weeks post-vaccination 
they may be asked to attend a further clinical assessment.  
At the end of the influenza season, all participants will be contacted by telephone to inform 
them of the end of the follow-up period and confirm all information has been collected.  

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 23 OF 78 
Figure 2-2 
Follow-up Procedures for the Main Cohort (Participants Vaccinated early 
in the Influenza Season) 
Applies to participants who have Day 28 prior to the start of the ILI reporting period on 01 May. Participants are 
not required to complete the eDiary in the period after Day 28 until 01 May  
Abbreviations: AE=adverse event; eDiary=electronic diary; ILI=influenza-like illness; SAE=serious adverse 
event 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 24 OF 78 
Figure 2-3 
Follow-up Procedures for the Main Cohort (Participants Vaccinated later 
in the Influenza Season) 
 
Abbreviations: AE=adverse event; eDiary=electronic diary; ILI=influenza-like illness; SAE=serious adverse 
event 
Immunogenicity Cohort: 
Follow-up procedures for the immunogenicity cohort are outlined in Figure 2-4 (participants 
who are vaccinated early in the influenza season and have completed Day 28 assessments prior 
to the start of the ILI reporting period on 01 May) and Figure 2-5 (participants who are 
vaccinated later in the influenza season and have Day 28 just prior to, or after, the start of the 
ILI reporting period on 01 May). 
The study team will contact participants by telephone on Day 1 (+2 days) post-vaccination for 
safety follow-up. Participants will attend the clinic for the following visits: 
• 
Day 7 (+3 days) for assessment of solicited and unsolicited adverse events and safety 
laboratory blood samples  
• 
Day 28 (±7 days) for assessment of unsolicited adverse events and safety laboratory and 
immunogenicity blood samples 
• 
Week 26 (±1 week) (end of the influenza season) for immunogenicity blood samples and 
to confirm all information has been collected 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 25 OF 78 
Figure 2-4 
Follow-up Procedures for the Immunogenicity Cohort (Participants 
Vaccinated early in the Influenza Season) 
 
Applies to participants who have Day 28 prior to the start of the ILI reporting period on 01 May. Participants are 
not required to complete the eDiary in the period after Day 28 until 01 May  
Abbreviations: AE=adverse event; eDiary=electronic diary; ILI=influenza-like illness; SAE=serious adverse 
event 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 26 OF 78 
Figure 2-5 
Follow-up Procedures for the Immunogenicity Cohort (Participants 
Vaccinated later in the Influenza Season) 
 
Abbreviations: AE=adverse event; eDiary=electronic diary; ILI=influenza-like illness; SAE=serious adverse 
event 
2.3 
Data Monitoring Committee and Study Pausing and Stopping Rules 
A data monitoring committee (DMC) will be appointed to review the study data and make 
recommendations concerning the continuation, modification, or termination of the study as 
detailed in Section 5.1.4.  
The following study pausing or holding rules will apply for the study: 
1. 
One or more study treatment-related SAE(s) or study treatment-related AESI occurs. 
OR 
2. 
Anaphylaxis or bronchospasm occur within 4 hours of vaccination, indicative of an 
immediate hypersensitivity reaction to vaccination. 
OR 
3. >10% of participants experience a Grade 3 or higher event judged related to study 
treatment, excluding local vaccination site reactions that decrease to <Grade 3 within 
24 hours. 
OR 
4. An adverse event pattern of concern occurs. 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 27 OF 78 
If the Principal Investigator, local Medical Monitor, or Sponsor pauses the study, the decision 
will be recorded in a memorandum to the study file and will trigger DMC review, see 
Section 5.1.4. 
The DMC may recommend resumption of enrolment with changes to the protocol if it judges 
that such changes will reduce safety risks. However, the final decision to resume study 
activities, amend the protocol, or terminate the study will be made by the Sponsor. The study 
site will be allowed to resume activities only upon receipt of written notification from the 
Sponsor. Decisions regarding pausing and resumption of the study will be communicated to 
the institutional review board (IRB)/independent ethics committee (IEC) by the Principal 
Investigator and to the applicable national regulatory authority by the Sponsor (or designee). 
 
 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 28 OF 78 
3 
STUDY PROCEDURES 
3.1 
Schedule of Assessments 
A schedule of assessments is provided in Table 3-1 for the main cohort and Table 3-2 for the 
immunogenicity cohort. A list of evaluations by visit/call day is provided in Appendix 1. 
Table 3-1 
Schedule of Assessments (Main Cohort) 
 
Screening / 
Vaccination 
Follow-up  
Visit/Call Day 
D0[a] 
D1(+2) 
D7(+3) 
D28(±7) 
D29-EOS[b] 
Informed consent 
X 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
Medical history reviewed 
X 
 
 
 
 
Physical examination 
X 
 
 
 
 
Urine pregnancy test (women of childbearing potential) 
X 
 
 
 
 
Randomisation 
X 
 
 
 
 
Vaccination 
X[c] 
 
 
 
 
Post-vaccination observation period (30 mins) 
X 
 
 
 
 
eDiaries, tape measure and thermometers provided 
X 
 
 
 
 
Telephone contact  
 
X[d] 
X[d] 
X (4 weekly)[e] 
IBM/site appointment system reminder 
 
X(weekly)[f] 
eDiaries completed for local reactogenicity 
 
X (daily) 
 
 
eDiaries completed for systemic reactogenicity 
 
X (daily) 
 
 
eDiaries completed for unsolicited adverse events 
 
X (daily) 
 
eDiaries completed for ILI symptoms  
 
X (weekly 01 May to 15 October)[g] 
Nasal swabbing 
 
X (if required)[h] 
Abbreviations: D=day; eDiaries=electronic diaries; EOS=end of study; ILI=influenza-like illness; mins=minutes; SAE=serious 
adverse event 
Note: SAEs will be recorded for the duration of the study. 
[a]  Screening and Vaccination can occur on a separate day as long as QIV Vaccination is within the 28 day window  
[b] Participants will be followed up over the followed-up over the duration of the influenza season into which they are 
recruited. 
[c] MVA-NP+M1 or placebo by intramuscular injection. 
[d] To review adverse events. If the participant has persistent, vaccine-related Grade 3 adverse events during the first 4 weeks 
post-vaccination they may be asked to attend a further clinical assessment.  
[e] To remind participants to complete the ILI assessment in their diary and to enquire if they have had any hospitalisations 
or SAEs (plus other unsolicited adverse events at the first call only); final call performed at the end of the influenza 
season.  
[f] 
Reminders to be sent out weekly to complete the eDiary. Reminders will not be sent between Day 28 and the start of the ILI 
reporting period on 01 May for participants vaccinated early in the influenza season who have Day 28 assessments prior to 
the start of the ILI reporting period. 
[g] Assessment of ILI weekly. In the event of an episode, the severity of symptoms will be recorded daily and any 
medications taken to treat the symptoms. For participants vaccinated early in the influenza season and who have Day 28 
assessments prior to the start of the ILI reporting period, a telephone reminder will be sent 7 days prior to the 01 May. 
[h] If influenza symptoms are experienced, participants should attend the clinic on two occasions, the first within 72 hours of 
the onset of symptoms for deep nasal/mid-turbinate swabs to be taken. Both swabs must be taken within 96 hours of 
symptom onset.  

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 29 OF 78 
Table 3-2 
Schedule of Assessments (Immunogenicity Cohort) 
 
Screening 
Vaccination 
Follow-up 
Visit/Call Day
~<120 
0 
D1(+2d) 
D7(+3d) 
D28(±7d) 
W26(±1w) [a] 
Informed consent 
X    or 
X[b] 
 
 
 
 
Inclusion and exclusion criteria 
X    or 
X[b] 
 
 
 
 
Medical history taken/reviewed 
X    or 
X[b] 
 
 
 
 
Physical examination 
X    or  
X[b] 
 
(X) 
 
 
Urine pregnancy test (women of childbearing potential) 
 
X 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
Vaccination 
 
X[c] 
 
 
 
 
Post-vaccination observation period (30 mins) 
 
X 
 
(X) 
 
 
eDiaries, tape measure and thermometers provided 
 
X 
 
 
 
 
Telephone contact 
 
 
X[d] 
 
X (4 weekly)[e] 
IBM/site appointment system reminder 
 
 
X (weekly)[f] 
In clinic assessment of local reactogenicity 
 
 
 
X 
 
 
In clinic assessment of systemic reactogenicity 
 
 
 
X 
 
 
In clinic assessment of unsolicited adverse events 
 
 
 
X 
X 
 
eDiaries completed for local reactogenicity 
 
 
X (daily) 
 
 
eDiaries completed for systemic reactogenicity 
 
 
X (daily) 
 
 
eDiaries completed for unsolicited adverse events 
 
X 
X (daily) 
 
eDiaries completed for ILI symptoms 
 
 
X (weekly 15 May to 15 October)[g] 
Nasal swabbing 
 
 
X (if required)[h] 
Haematology/biochemistry (mL) 
 
12 
 
12 
12 
 
Exploratory immunology (mL) 
 
50 
 
 
50 
50 
Blood volume per visit (mL) 
 
62 
 
12 
62 
50 
Cumulative blood volume (excluding repeats) (mL) 
 
62 
62 
74 
136 
186 
Abbreviations: D/d=day; eDiaries=electronic diaries; ILI=influenza-like illness; mins=minutes; SAE=serious adverse event; W/w=week; 
(X)=Performed if considered necessary 
Note: SAEs will be recorded for the duration of the study. 
[a] 
Participants will be followed up over the duration of the influenza season into which they are recruited. A final clinic visit will be 
performed at the end of the influenza season. 
[b] Participants recruited through general advertising may have consent taken and a separate screening visit up to 120 days before 
vaccination. Participants recruited through their local healthcare provider will have screening procedures on Day 0 (as for the main 
cohort). 
[c] MVA-NP+M1 or placebo by intramuscular injection. 
[d] To review adverse events.  
[e] To remind participants to complete the ILI assessment in their diary and to enquire if they have had any hospitalisations or SAEs; final 
assessment performed at the end of the influenza season at the ~Day 182 in-clinic assessment. 
[f] Reminders to be sent out weekly to complete the eDiary. Reminders will not be sent between Day 28 and the start of the ILI reporting 
period on 15 May for participants vaccinated early in the influenza season who have Day 28 assessments prior to the start of the ILI 
reporting period. 
[g] Assessment of ILI weekly. In the event of an episode, the severity of symptoms will be recorded daily and any medications taken to 
treat the symptoms. For participants vaccinated early in the influenza season and who have Day 28 assessments prior to the start of the 
ILI reporting period, a telephone reminder will be sent 7 days prior to the 15 May. 
[h] If influenza symptoms are experienced, participants will attend the clinic on two occasions, the first within 72 hours of the onset of 
symptoms for deep nasal/mid-turbinate swabs to be taken. Both swabs must be taken within 96 hours of symptom onset. 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 30 OF 78 
3.2 
Participant Selection 
3.2.1 
Recruitment and Informed Consent 
Potential participants for the main cohort of the study will be identified by their local healthcare 
provider’s practice (either directly or through database searches) or through study specific 
advertising. The practice will send study specific information to potentially eligible participants 
with an invitation to take part in the study. Interested participants with suitable existing medical 
history will be invited to participate in the study.  
Other methods may also be used to recruit participants for the immunology cohort, such as 
advertising or referrals. All recruitment materials must be approved by the Sponsor and 
IRB/IEC.  
Only patients who plan to receive a licensed QIV vaccine on the day of or in the 28 days before 
randomisation will be eligible. 
Informed consent for the study will be obtained before any protocol specific procedures are 
performed as detailed in Section 8.3. Participants participating in the immunogenicity cohort 
will be asked to consent to have blood samples collected for laboratory safety tests and 
immunology assessments. Blood tests will not be a condition of participation in the main study 
and any participants initially recruited to the immunogenicity cohort who then does not wish 
to have blood tests will be offered participation in the main study without blood tests. 
3.2.2 
Assignment of Participant Identification Number 
After informed consent is obtained, participants will be screened to assess eligibility for the 
study. For identification purposes, each participant for whom informed consent has been 
obtained will be assigned a unique 7-digit participant identification number (PID) by the site 
staff. The PID consists of three digits to represent site number assigned by the Sponsor, 
followed by a 4-digit number assigned by the site. (For example, if the clinical study site 
number is 120, the first participant to be screened would receive the number 120-0001, where 
all except “-0001” were pre-assigned by the Sponsor.) This participant identification number 
will be used throughout the study. 
Eligibility for entry into the study will be based on the inclusion and exclusion criteria 
described in Section 3.2.3. The Investigator must document confirmation of eligibility prior to 
randomisation. For participants determined to be ineligible for the study, the reason for 
screening failure will be captured on the screening log and reported in the Monitoring Visit 
Reports. 
3.2.3 
Eligibility Criteria 
All participants will be assessed for eligibility against the following inclusion and exclusion 
criteria: 
3.2.3.1 
Inclusion Criteria 
Participants must meet all of the following criteria at the time of randomisation: 
1. 
Healthy male or female adults aged 18 years and over  

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 31 OF 78 
2. 
Receipt of a standard-dose licensed influenza QIV vaccine on the day of, or within 
28 days prior to, randomisation 
3. 
A female participant is eligible for this study if she is not pregnant or breast feeding and 
one of the following: 
a. 
Of non-childbearing potential (i.e. women who have had a hysterectomy or tubal 
ligation or are postmenopausal, as defined by no menses in greater than or equal to 
1 year) 
b. 
Of childbearing potential but agrees to practice effective contraception 8 weeks 
post-vaccination and has a negative urine pregnancy test pre-vaccination. 
Acceptable methods of contraception include one or more of the following:  
i. 
Male partner who is sterile prior to the female participant’s entry into the 
study and is the sole sexual partner for the female participant  
ii. 
Implants of levonorgestrel 
iii. 
Injectable progestogen 
iv. 
An intrauterine device with a documented failure rate of <1% 
v. 
Oral contraceptives 
vi. 
Double barrier methods including diaphragm or condom  
vii. 
Abstinence as long as it is line with the usual and preferred lifestyle of the 
participant 
4. 
Participant is willing and has capacity to provide written informed consent for 
participation in the study (in the Investigator’s opinion) 
5. 
Able and willing (in the Investigator’s opinion) to comply with all study requirements 
6. 
Willing to allow the Investigators to discuss the participant’s medical history with their 
healthcare provider 
7. 
Present and able to visit the clinic in the event of an influenza symptom episode during 
the influenza season 
3.2.3.2 
Exclusion Criteria 
Participants must have none of the following at the time of randomisation: 
1. 
Any other significant disease, disorder or finding (including blood test results), which, in 
the opinion of the Investigator, would either put the participant at risk because of 
participation in the study, or may influence the result of the study 
2. 
Receipt of any investigational product within 6 months prior to study, or prior 
participation in a clinical study of any Influenza vaccine and agreement not to participate 
in another clinical study for the duration of study follow-up 
3. 
Prior receipt of an investigational vaccine likely to impact on interpretation of the study 
data 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 32 OF 78 
4. 
Active infection with HIV, Hepatitis B or Hepatitis C (from patient history or medical 
records) 
5. 
History of severe allergic reactions (e.g. anaphylaxis)  
6. 
History of auto-immune disease e.g. Guillain-Barré syndrome. Those with mild 
autoimmune-related diseases such as well-controlled diabetes, well-controlled thyroid 
disease or mild arthritic diseases can be enrolled.  
7. 
Not willing to comply with study procedures 
8. 
Immunosuppressed or taking immunosuppressive medications. Subjects with diseases 
that require immunosuppressive medication such as anti-TNF compounds, high dose 
glucocorticoids or daily glucocorticoids likely to suppress the adrenal axis should not be 
enrolled.  
9. 
Use of warfarin or other blood thinning medications. Subjects on anticoagulants that may 
result in significant hematoma or bleeding at the injection site (e.g. thrombin inhibitors, 
fractionated heparin etc.) should be excluded but those on platelet inhibitors such as 
aspirin or clopidogrel can be enrolled.   
10. 
Tattoos or birthmarks at the vaccination site 
11. 
Participant bruises easily, has haematoma or keloid scarring 
12. 
Receipt of a licenced inactivated vaccine (e.g. pneumococcal vaccine) within 2 weeks 
prior to vaccination 
13. 
Receipt of an off licensed live vaccine (e.g. herpes zoster vaccine) within 4 weeks prior 
to vaccination 
3.2.4 
Screening/Baseline Assessments 
Participants enrolled in the main cohort will be screened for eligibility and vaccinated on 
Day 0. However, vaccination can be performed on a different day to screening as long as QIV 
vaccination falls within the required 28-day window.  
Participants enrolled in the immunogenicity cohort may have a separate screening visit up to 
120 days before Day 0. 
The following will be performed at screening: 
• 
Collection of baseline information 
- 
Demographic information including age, ethnicity, gender 
- 
Height, weight 
- 
Medical history, including any allergies 
- 
Prior medications (recent [within the last 4 weeks] and currently ongoing) 
- 
Any co-morbidities 
• 
Physical examination  
• 
Description (brand) and timing of QIV received by the patient 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 33 OF 78 
• 
Urine pregnancy test sensitive to 25IU human chorionic gonadotrophin (pre-vaccination 
on Day 0 in women of childbearing potential) 
Results and findings that make the participant ineligible will be discussed with the participant 
and they will be referred for follow-up care with their healthcare provider if necessary. 
Participants will not be vaccinated, or will have vaccination deferred in the event of the 
following;  
• 
Acute disease at the time of vaccination. Acute disease is defined as the presence of a 
moderate or severe illness with or without fever. All vaccines can be administered to 
persons with a minor illness such as diarrhoea, mild upper respiratory infection with or 
without low-grade febrile illness, i.e. temperature of ≤37.5°C/99.5°F 
• 
Temperature of >37.5°C (99.5°F) at the time of vaccination 
3.3 
Study Randomisation 
Eligible participants will be randomised to the study based on a randomly-generated sequence 
of numbers (randomisation schedule) managed by IBM Clinical Development. The 
randomisation schedule will be prepared by a statistician who will not be involved in the 
study’s statistical analyses. Participants will be randomised on Day 0 after informed consent 
has been provided and eligibility confirmed.  
Participants in the main cohort will be stratified by age <65 years and ≥65 years of age at the 
time of randomisation. Investigators will aim to enrol approximately 70% of participants in the 
<65 years old strata. 
Participants recruited into the immunogenicity cohort will be randomised separately from the 
main cohort with no stratification. 
All participants will be randomised in a 1:1 ratio to one of two treatment groups: 
Group 1: 1.5 x 108 pfu MVA-NP+M1  
Group 2: 0.5 mL 0.9% -saline placebo  
Discontinued participants will not be replaced. 
3.4 
Investigational Product Administration 
Vaccination will take place after consent and screening/baseline assessments have been 
completed and the participant has been randomised. All participants will receive either 
MVA-NP+M1 or placebo, according to randomisation as described in Section 3.3. Details of 
the study treatments are provided in Section 4. 
All investigational vaccine administrations will be made into the deltoid muscle by 
intramuscular injection using a suitable sterile needle and syringe and employing the Z-track 
technique. The skin and subcutaneous tissues will be pulled and held to one side before the 
needle is inserted deep into the muscle tissue in the identified vaccination site. The vaccine is 
injected slowly, followed by a 10 second delay, at which time the needle is removed and the 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 34 OF 78 
tissues are quickly permitted to resume their normal position. This provides a Z-shaped track, 
which makes it difficult for the injected vaccine to seep back into subcutaneous tissues. 
If MVA-NP+M1 or placebo are given on the same day as the QIV the two vaccines must not 
be given to the same deltoid muscle. 
All vaccinations will be made by a suitably qualified health professional. A second study team 
member will be present to account for each vaccination given. 
The suitably qualified healthcare professional will wear gloves, eye protection and an apron or 
laboratory coat/gown during the procedure. The vaccination site will be covered with an 
occlusive sterile dressing to minimise dissemination of the recombinant virus into the 
environment. This should absorb any virus that may leak out through the needle track. The 
sterile dressing will be removed 30 minutes after vaccination. The dressing will be discarded 
as genetically modified organism (GMO) waste.  
Allergic reactions to vaccination are possible, therefore, appropriate drugs and medical 
equipment to treat acute anaphylactic reactions must be immediately available and a medically 
qualified study team member trained to recognise and treat anaphylaxis must be present in the 
clinic during the entire vaccination procedure and post-vaccination observation period. 
3.5 
Participant Follow-up and Contact 
3.5.1 
Follow-up over Influenza Season 
All participants who are assigned a participant identification number and receive study vaccine 
will be followed up over the duration of the influenza season to which they are recruited, unless 
they withdraw consent, are lost to follow-up (see Section 3.5.2) or the study is terminated early. 
Participants will be followed up twice over the first week on Day 1 (+2 days) by telephone call 
and on Day 7 (+3 days) by either telephone call (main cohort) or in-clinic visit 
(immunogenicity cohort). Weekly reminders to complete their diary will be sent to each 
participant through the IBM system or through site appointment systems, depending on where 
they are enrolled, over the duration of the influenza season. The study team will also contact 
participants by telephone every 4 weeks (±1 week) over the duration of the influenza season to 
remind them to complete the ILI assessment in their diary and to enquire if they have had any 
hospitalisations or SAEs (plus other unsolicited adverse events at the first call only for the main 
cohort). Three attempts will be made for each follow-up phone call made during the study, if 
the participant cannot be contacted at any of these occasions this will be recorded and attempts 
will be made again at the next scheduled call.  
Participants will receive a digital thermometer to record their temperature over the first 7 days 
post-vaccination and an eDiary to be used during the follow-up period. The eDiary is a 
web-based tool to: 
1. 
Directly collect solicited adverse events over the first 7 days post-vaccination and 
influenza symptoms and medications over the duration of the influenza season (between 
01 May and 15 October). These data will be integrated into the clinical database and 
directly used for analysis 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 35 OF 78 
2. 
Record unsolicited adverse events (all adverse events up to Day 28; hospitalisations and 
other SAEs only thereafter) and concomitant medications to enable the site staff to 
engage in a conversation with the participant during the scheduled telephone calls during 
the follow-up period. The eDiary will be considered source documentation for these data 
and relevant information should be collected and recorded on the unsolicited adverse 
event and concomitant medication electronic case report forms (eCRFs) 
Participants will be trained in the use of the eDiary and will receive an instruction manual to 
take home. 
3.5.2 
Loss to Follow-up 
If the study site’s team members are unable to establish contact with a participant who either 
misses a scheduled study visit or fails to complete the eDiary, the study site must make every 
possible effort to re-establish contact and document such efforts. If contact is re-established, 
then the participant will resume participation in the study. 
If contact with the participant cannot be re-established by the end of the influenza season, then 
a determination of “lost to follow-up” should be made.  
3.6 
Study Evaluations 
3.6.1 
Efficacy Evaluations 
Participants will be asked to record in the eDiary whether or not they have respiratory 
symptoms indicating potential influenza every week during the influenza season. These 
symptoms include fever or feverishness, cough, sore throat, congestion, chest pain, myalgia, 
and shortness of breath. The regulatory definition of ILI is defined as feeling feverish or having 
a fever (temperature ≥37.8 C) and at least one of the following symptoms: a cough, and/or 
sore throat. For every respiratory episode, participants will be asked to record the severity of 
their symptoms daily and any medications taken to treat the symptoms.  
If they experience any influenza symptom(s), participants should attend the clinic on two 
occasions, the first as soon as possible and at least within 72 hours of the onset of symptoms 
for deep nasal/mid-turbinate swabs to be taken. Both swabs must be taken within 96 hours of 
symptom onset.  
Swabs will be taken with a flexible aluminium or plastic fine-shafted swab with a polyester, 
Dacron, or rayon tip. For deep nasal swabs the swab will be inserted into the nostril and back 
into the nasopharynx and will be slowly withdrawn with a rotating motion. For Mid-Turbinate 
swabs the swab is inserted in to the nostril to the point of resistance at the turbinate’s and slowly 
withdrawn in a rotating motion. Both methods should result in a well-coated swab.  The tip of 
the swab will be transferred into a vial containing transport media labelled with the 
participant’s details.  
Four swabs will be collected (one from each nostril at two visits within 96 hours) at each 
occurrence of any influenza symptom. However, if the participant experiences extreme 
discomfort during the first swab visit then there can be exceptions made in returning for the 
second swab. It will always be preferable to collect swabs at two timepoints, however, if it 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 36 OF 78 
becomes evident that the collection of swabs is detrimental to influenza symptom reporting 
and participants returning later in the season for swabbing then the collection a single swab 
can take precedence to ensure participants continue to report influenza symptoms.  
These will be analysed at the study central laboratory for laboratory-confirmed influenza using 
RT-PCR. 
3.6.2 
Immunogenicity Laboratory Evaluations 
Samples for immunogenicity analysis will only be taken from participants in the 
immunogenicity cohort. At each scheduled timepoint, a 50 mL blood sample will be taken and 
handled according to the Laboratory Manual. 
Assessment of immune response to MVA-NP+M1 will be performed based on the percentage 
of CD4+ and CD8+ T-cells that produce any of the cytokines or functional markers or a 
combination of these simultaneously following stimulation with peptide pools derived from 
and representing the entire amino acid sequence of the mycNP+M1 encoded in the vaccine. 
Response will be measured using the ex vivo IFN-/Granzyme B ELISpot assay. The immune 
response will also be assessed by flow cytometry in the multi-colour intracellular cytokine 
staining (ICS) assay.  
The antibody assays will include microneutralisation and hemagglutination inhibition titres 
using standard methodologies for the four strains that are in the licensed vaccine. 
3.6.3 
Safety Evaluations 
3.6.3.1 
Adverse Events 
3.6.3.1.1 Solicited Adverse Events 
Solicited adverse events are events the participant is specifically asked about. These adverse 
events are commonly observed soon after receipt of vaccines and relate to local and systemic 
signs and symptoms. Solicited adverse events will be collected for 7 days post-vaccination1. 
These will be recorded daily in the eDiary for all participants. Participants in the 
immunogenicity cohort will also have an in-clinic assessment on Day 7 (+3 days). Solicited 
adverse events will also be reviewed during the telephone calls on Day 1 (+2 days) (all 
participants) and Day 7 (+3 days) (main cohort only). 
For this study, solicited adverse events to be collected include:  
• 
Vaccination site reactions: pain, induration, warmth, erythema (redness) 
• 
Systemic adverse events: feverishness, chills, myalgia, fatigue, headache, nausea, 
arthralgia, malaise  
                                                 
 
 
1 In the event that they persist longer than 7 days then an adverse event will be recorded 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 37 OF 78 
Participants will be asked to record the presence of these symptoms and grade the severity as 
described in Section 5.3.1. Oral temperature will be measured using the thermometer provided 
and the diameter of induration will be measured with the tape measure provided.  
3.6.3.1.2 Unsolicited Adverse Events 
Unsolicited adverse events are other events meeting the criteria for adverse events (see 
Section 5.2) apart from those the participant is specifically asked about. Unsolicited 
non-serious adverse events will be collected for 28 days post-vaccination. Hospitalisations, 
other SAEs and AESI will be collected for the duration of the influenza season. 
Participants will collect unsolicited adverse events in the eDiary and these will be reviewed 
during telephone calls with the participant and relevant information (event term, start and end 
date, severity, causality, outcome and seriousness) collected and entered into the eCRF as 
described in Section 5.2, Section 5.3.2, Section 5.4 and Section 5.5.  
3.6.3.2 
Laboratory Safety Tests 
Laboratory safety tests will be performed for participants in the immunogenicity cohort only. 
5 mL blood samples will be taken for haematology and biochemistry pre-vaccination on Day 0 
and on Days 7 (+3 days) and 28 (±7 days). Results from laboratory safety tests obtained on the 
study must be reviewed by the Investigator (or a designee who is a medically qualified study 
team member) and managed in accordance with the study site procedures. The clinical 
significance of all results outside of the normal range will be determined by the Investigator 
and may be reported as an adverse event at the discretion of the Investigator. Additional 
laboratory safety tests may be performed if the Investigator deems them to be necessary to fully 
evaluate an adverse event. In the event that the Investigator elects to order 
non-protocol-specified laboratory tests, the Investigator must record the rationale for the tests 
and a determination of clinical significance of the result in the source documents. The 
Investigator must keep the local Medical Monitor informed of adverse events of clinical 
significance. 
Abnormal results and findings will be discussed as applicable with the participant, and the 
participant will be referred for follow-up with their healthcare provider if necessary. 
3.6.3.2.1 Haematology 
For each assessment, a sample of venous blood will be collected in a tube containing 
ethylenediaminetetraacetic acid (EDTA) according to local laboratory procedures.  
The following will be measured: full blood count: haemoglobin, haematocrit, erythrocytes, 
mean cell volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin 
concentration, leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils and 
platelets. 
3.6.3.2.2 Biochemistry 
For each assessment, a sample of venous blood will be collected in a heparinised tube according 
to local laboratory procedures. 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 38 OF 78 
The following will be measured: sodium, potassium, urea, creatinine, albumin and liver 
function tests (alanine transaminase, alkaline phosphatase and bilirubin). 
3.6.3.3 
Physical Examination 
A skin, respiratory, cardiovascular, abdominal and lymphatic system examination will be 
performed at screening for all participants. A symptom-directed exam will be repeated, if 
required on Day 7 (+3 days) for participants in the immunogenicity cohort only. Results will 
be recorded as normal, abnormal and not clinically significant or abnormal and clinically 
significant. 
3.6.3.4 
Concomitant Medications 
Concomitant medication includes prescription and non-prescription drugs or other treatments, 
and any vaccines other than the study vaccine.  
Recently used and ongoing medications will be reviewed and recorded during screening. 
Concomitant medications used by participants post-vaccination will coincide with the 
collection period of adverse events. All medications taken will be recorded in the eDiary and 
will be discussed with the participant at the scheduled telephone calls during the study. All 
medications taken in the first 28 days will be recorded in the eCRF. Thereafter, only the 
following will be recorded: 
• 
All medications taken to treat SAEs 
• 
All new vaccinations 
• 
All antibiotic use 
• 
Any new medication to treat respiratory illness 
The name of the medication, treatment start and stop dates (or ‘ongoing’), and indication must 
be recorded on the concomitant medication eCRF. The indication recorded on the concomitant 
medication eCRF must correspond to a medical term/diagnosis recorded on the adverse event 
eCRF, or to a pre-existing condition noted in the participant’s medical history, or be noted as 
prophylaxis, e.g. dietary supplement. 
4 
STUDY TREATMENTS 
Detailed instructions on the receipt, storage, accountability, preparation and disposal of the 
study treatments can be found in the Pharmacy Manual. A study vaccine manager will be 
responsible for the study treatments and must be a designated study team member, such as the 
study pharmacist. A Delegation of Authority Log will be maintained by the study site and will 
identify the individual(s) authorised to prepare and administer the study vaccine. 
4.1 
Description of Study Treatments 
Participants will receive either the study vaccine, MVA-NP+M1, or placebo, according to 
randomisation). 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 39 OF 78 
4.1.1 
MVA-NP+M1 
Participants randomised to Group 1 will receive MVA-NP+M1, a MVA virus recombinant, 
replication-deficient, vector expressing the conserved influenza antigens NP and M1 as a fusion 
protein.  
MVA-NP+M1 is manufactured under Good Manufacturing Practice conditions. It is provided 
in polymer vials as a liquid for injection. It will be certified by a Qualified Person, labelled and 
sent to PCI Pharma Services distribution centre in Australia for storage and distribution to 
clinical sites. 
Each vial of MVA-NP+M1 contains 700 µL volume in formulation buffer containing 10% 
sucrose, 0.1% pluronic acid, 25 mM TRIS to a target final concentration of 1.2 x 109 tissue 
culture infectious dose (TCID50)/mL. On the vaccination day, MVA-NP+M1 will be allowed 
to reach room temperature and administered within 1 hour of removal from the fridge. 
The dose of MVA-NP+M1 to be used in this study will be 1.5 x 108 pfu (4.3 x 108 TCID50), 
based on previous Phase 1 and Phase 2a clinical studies which have shown the vaccine is well 
tolerated and immunogenic at this dose, see Section 1.2. In FLU001, participants up to the age 
of 85 years received doses of 1.5 x108 pfu and 2.5 x 108 pfu MVA-NP+M1 in FLU001 and the 
former was shown to be less reactogenic and better tolerated.  
4.1.2 
Placebo 
Participants randomised to Group 2 will receive a placebo injection of 0.9% saline (sourced by 
Fisher Clinical Services) instead of MVA-NP+M1. Each vial of saline will only be used for a 
single participant. 
4.2 
Blinding 
This study is single blind.  
The participant will be blinded to which study vaccine (MVA-NP+M1 or placebo) they are 
administered. The Investigator and all study staff acting to determine or record safety, as well 
as all laboratory staff will also remain blinded (“observer blind”). The pharmacist and any 
study staff administering the study vaccine will not be blinded. The volume and site of 
vaccination will be the same for both Group 1 and Group 2. Identical syringes and needles will 
be used for preparation and administration of each study vaccine. Study vaccine will be 
prepared out of sight of the participant. 
4.3 
Receipt and Storage 
MVA-NP+M1 will be shipped to a distribution centre in the study region. It will then be 
shipped to the study sites at 2oC to 8oC with a continuous temperature-monitoring device.  
Upon receipt, the pharmacist or study vaccine manager must immediately inspect all vials for 
damage. Any damage or discrepancies from the packing list must be documented and promptly 
discussed with the Sponsor and the Study Monitor to determine the appropriate action. The 
temperature monitors should be downloaded according to the accompanying instructions in the 
shipment. Temperature records must be sent to the Local Sponsor and the site will receive 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 40 OF 78 
written confirmation that the vials are clinically released before they are used. If the 
temperature monitor has been out of range then the shipment should be placed into quarantine 
and the Sponsor and Study Monitor contacted immediately to determine whether the study 
vaccine may be used. 
Vials of MVA-NP+M1 in the outer carton (to protect from light) must be stored between 
2 and 8oC in a continuously monitored refrigerator. The vials of saline placebo will be stored 
at room temperature. 
All study treatments must be kept in a secured location with no access for unauthorised 
personnel. 
At the start of the study, a sufficient number of MVA-NP+M1 and placebo vials will be shipped 
to each study site to vaccinate approximately 20% of the planned participants based on 
recruitment projections. Further study vaccine supplies may be requested following the re-
supply process in the Vaccine Management Manual. 
4.4 
Accountability 
The pharmacist or study vaccine manager is required to maintain accurate accountability 
records for the study vaccine. Instructions and forms to be completed and kept for 
accountability will be provided to the pharmacist or study vaccine manager. If the pharmacist 
or study vaccine manager wishes to use site-specific accountability forms, these must be 
reviewed and approved in advance by the Sponsor. Upon completion of the study, all 
accountability records will be copied and the copies returned to the Sponsor or its designee. 
The originals must be maintained at the study site with the rest of the study records. 
The number of vials of MVA-NP+M1 and placebo received and dispensed must be recorded 
on a participant by participant basis, including the applicable batch number. At the end of the 
study, all MVA-NP+M1 will be returned to the local country depot for destruction. 
The brand of QIV used by each participant must also be documented. 
4.5 
Preparation 
MVA-NP+M1 will be allowed to reach room temperature before use. It will be kept at room 
temperature after removal from the refrigerator and administered within 1 hour. 
0.9% Saline placebo will be stored at room temperature. 
0.5 mL volume of MVA-NP+M1 or 0.9% Saline placebo will be withdrawn from the 
vial/ampoule using a sterile needle and syringe prior to use according to the procedure in the 
Pharmacy Manual. 
4.6 
Disposal of Unused Investigational Product 
MVA-NP+M1 will be returned to the local country depot for destruction. 0.9% Saline placebo 
will be destroyed locally according to the sites own policy. This destruction will be recorded 
with an original copy kept at site and a copy send to the Sponsor Trial Master File. 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 41 OF 78 
4.7 
Compliance 
Vaccine administration will take place at the study site and will be performed by a suitably 
qualified healthcare professional. The precise date and time of vaccination shall be documented 
in the eCRF. The study will be monitored by a Study Monitor approved by the Sponsor. During 
these visits, all procedures will be monitored for compliance with the protocol. Source 
documents will be reviewed and compared with the data entries in the eCRFs to ensure 
consistency.  
  
 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 42 OF 78 
5 
SAFETY 
5.1 
Responsibilities for Ensuring the Safety of Study Participants 
The national Regulatory Authority, the study Sponsor, the Institution through which the 
research is performed and all members of the Principal Investigator’s study site team share 
responsibility for ensuring that participants in this study are exposed to the least possible risk 
of adverse events that may result from participation in this protocol.  
5.1.1 
Principal Investigator 
The Principal Investigator has a personal responsibility to closely monitor study participants 
and an inherent authority to take whatever measures necessary to ensure their safety. The 
Principal Investigator has the authority to terminate, suspend or require changes to a clinical 
study for safety concerns and may delay an individual’s study vaccine administration or pause 
study vaccine administration in the whole study if they have some suspicion that the study 
vaccine might place a participant at significant risk. The Principal Investigator determines 
severity and causality for each adverse event.  
Responsibilities of the Principal Investigator may be assigned to a designee who is a medically 
qualified team member, however the accountability for the specific task remains with the 
Principal Investigator. 
5.1.2 
Study Sponsor 
The Sponsor also has an institutional responsibility to ensure participant safety. This 
responsibility is vested in the local Medical Monitor and a DMC. 
5.1.3 
Local Medical Monitor 
The local Medical Monitor is the Sponsor’s representative and is a credentialed physician or 
surgeon in their country of residence with the necessary expertise to act in such capacity. The 
local Medical Monitor reviews the safety of the product for protocols in a specific region and, 
in conjunction with the Sponsor, determines expectedness of study treatment-related SAEs. 
The local Medical Monitor, in consultation with the Sponsor, may assess the causality for 
adverse events and may upgrade the causality determined by the Principal Investigator.  
5.1.4 
Data Monitoring Committee 
A DMC will be appointed to review the study data and make recommendations concerning the 
continuation, modification, or termination of the study. The DMC will perform the following: 
• 
Scheduled evaluation of study conduct and progress and review of the cumulative safety 
and efficacy data. Scheduled meetings will take place as follows: 
- 
Kick off meeting before the first participant is enrolled 
- 
A meeting at the end of the first influenza season to review safety and efficacy data 
and perform a futility analysis (with re-powering if required), see Section 7.7.1 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 43 OF 78 
• 
Perform unscheduled review of data if one of the study pausing or holding rules is met, 
see Section 2.3 
There will be a minimum of three appropriately qualified committee members of whom one 
will be the designated chair. The DMC will operate in accordance with the study-specific 
charter, which will be agreed prior to the start of enrolment.   
The chair of the DMC may be contacted for advice and independent review by the Investigator 
or Sponsor in any other situation where the Investigator or Sponsor feels independent advice 
or review is important. 
The DMC will be convened if any of the pausing or holding rules is met. The DMC will be 
notified within 24 hours of the Investigators’ being aware of any study treatment-related SAEs. 
The DMC has the power to place the study on hold if deemed necessary.  
If, following review of data by the DMC, a recommendation to resume study enrolment and 
vaccine administration is made, the DMC will record their judgment in a memorandum to the 
study file and notify the Sponsor. The DMC memorandum will be forwarded to the local 
Medical Monitor and Principal Investigators.  
5.1.5 
Institutional Review Boards and Ethics Committees 
The IRB/IEC has institutional responsibility for the safety of participants in clinical studies. 
The IRB/IEC has the authority to terminate, suspend or require changes to a clinical study. 
5.1.6 
National Regulatory Authority 
Since the national regulatory authority receives all expedited safety reports for the study it also 
has the authority to terminate, suspend or require changes to a clinical study. 
5.2 
Definition of Adverse Event 
Adverse event means any untoward medical occurrence associated with the use of an 
investigational product in humans, whether or not considered product-related. An adverse event 
(also referred to as an adverse experience) can be any unfavourable and unintended sign (e.g. an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
investigational product and does not imply any judgment about causality. An adverse event can 
arise with any use of the investigational product (e.g. off-label use, use in combination with 
another product) and with any route of administration, formulation, or dose, including an 
overdose. 
Medical conditions that exist prior to administration of the study vaccine (pre-existing 
conditions) will be recorded in the participant’s medical history to establish baseline. 
Day-to-day fluctuations in pre-existing conditions that do not represent a clinically significant 
change in the participant’s status will not necessarily be reported as adverse events. 
Any adverse change from the participant’s baseline condition (determined from screening 
evaluations conducted to confirm study eligibility) that occurs following the administration of 
the study vaccine will be considered an adverse event. This includes the occurrence of a new 
adverse event or the worsening of a baseline condition, whether or not considered related to 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 44 OF 78 
the study vaccine. Intermittent conditions such as headaches in adults or irritability in infants 
may be present on study Day 0 but may represent an adverse event if the intensity or duration 
of the event is worse than usual following receipt of study vaccine. Adverse events include but 
are not limited to: adverse changes from baseline that represent increases in severity, adverse 
changes in the general condition of the participant, signs and symptoms noted by the 
participant, concomitant disease with onset or increased severity after study vaccine 
administration, and clinically significant changes in laboratory safety parameters occurring 
after study vaccine administration. 
The reporting period for all adverse events is specified in Section 3.6.3.1. Solicited adverse 
events will be reported using pre-defined terms. Unsolicited adverse events will be reported 
using a recognised medical term or diagnosis that accurately reflects the event. Adverse event 
evaluations will be reviewed by the Principal Investigator or by a designated medically 
qualified practitioner. Adverse event information is to be completed by members of the study 
team designated in writing by the Principal Investigator. The onset and resolution dates of the 
event and action taken in response to the event will be documented.  
5.3 
Assessing Severity 
The safety concepts of severity and seriousness are distinct concepts (see also Section 5.5). 
Severity refers to a degree of clinical manifestation. Seriousness refers to defined outcomes 
from an adverse event. A severe adverse event is not always serious and a serious adverse event 
is not always severe.  
5.3.1 
Solicited Adverse Events 
With the exception of the Day 7 (+3 days) in-clinic assessment for participants in the 
immunogenicity cohort, the severity of solicited adverse events will be made by the participant. 
Severity will be assigned using the definitions in Appendix 3. 
5.3.2 
Unsolicited Adverse Events 
For all unsolicited adverse events, the Principal Investigator is responsible for assessing the 
severity of the event and the causal relationship of the event to the study vaccine. 
The severity of all adverse events, including clinical findings and abnormal laboratory values, 
will be classified using the definitions in Appendix 3, or for those events without a 
classification in the toxicity table as one of the following grades:  
• 
Mild: Events are generally regarded as noticeable but have no impact on normal 
activities; they may or may not require over-the-counter treatment managed by the 
participant 
• 
Moderate: Events generally have some impact on an individual’s normal activities and 
may require general symptomatic medical intervention by a healthcare professional or by 
the participant 
• 
Severe: Events may be incapacitating, leading to suspension of normal daily activities, 
and would generally require more immediate medical evaluation and intervention by a 
healthcare professional 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 45 OF 78 
All Severe adverse events will be notified to the Medical Monitor to be assessed on life 
threatening severity (as per Appendix 3). If the Medical Monitor deems the event to be of such 
severity then this can be upgraded at their discretion to a grade 4 in the eCRF.  
A change in severity of an adverse event will not be recorded as a new adverse event. Only the 
highest severity level that occurs during the entire period of the adverse event will be recorded 
on the eCRF with the onset and resolution dates encompassing the entire duration of the event.  
5.4 
Assessing Causal Relationship (Relatedness) 
Solicited adverse events of vaccination site reactions will be considered causally related to 
study treatment. 
For all other adverse events, the Investigator and the Sponsor (the local Medical Monitor) will 
determine a causal relationship to the study vaccine. A number of factors will be considered 
in making this assessment, including: 1) the temporal relationship of the event to the 
administration of the study vaccine 2) whether an alternative aetiology has been identified and 
3) biological plausibility.  
Causality of all adverse events should be assessed by the Investigator using the following 
question: 
“Is there a reasonable possibility that the adverse event may have been caused by the study 
vaccine?” 
• 
YES (related): There is a reasonable possibility that the study vaccine contributed to the 
adverse event 
• 
NO (not related): There is no reasonable possibility that the adverse event is causally 
related to the administration of the study vaccine. There are other, more likely causes 
and administration of the study vaccine is not suspected to have contributed to the 
adverse event 
The Principal Investigator and the local Medical Monitor both determine causality. It is 
expected that communication and consultation may occur in the assessment of the causality of 
adverse events. 
Every effort should be made by the Investigator to determine the existence of any pre-existing 
conditions (e.g. headache in adults or rashes in infants on study Day 0 with onset prior to study 
vaccination) that must be taken into consideration when assessing causal relationship of an 
adverse event. Pre-existing conditions should be recorded in the eCRF as baseline history and 
substantiated by appropriate source documentation. Intermittent conditions such as headaches 
in adults or irritability in infants may not be present on study Day 0 but may represent an 
adverse event if the intensity or duration of the event is worse than usual following study 
vaccine. 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 46 OF 78 
5.5 
Assessing "Seriousness" and Serious Adverse Events 
Seriousness refers to the outcome of an adverse event. Seriousness is determined by both the 
Principal Investigator and the local Medical Monitor. If either Principal Investigator or local 
Medical Monitor determines an event to be serious, it will be classified as such. If any of the 
following outcomes are present then the adverse event is serious: 
• 
It results in death (i.e. the adverse event caused or led to the fatality). Serious does not 
describe an event which hypothetically might have caused death if it were more severe 
• 
It was immediately life-threatening (i.e. the adverse event placed the participant at 
immediate risk of dying. It does not refer to an event which hypothetically may have led 
to death if it were more severe) 
• 
It required inpatient hospitalisation or prolonged hospitalisation beyond the expected 
length of stay. Hospitalisations for scheduled treatments and elective medical/surgical 
procedures related to a pre-existing condition that did not increase in severity or 
frequency following receipt of study vaccine, are not serious by this criterion. 
Hospitalisation is defined as a hospital admission or an emergency room visit for a period 
greater than 24 hours 
• 
It resulted in a persistent or significant disability/incapacity (i.e. substantial reduction 
of the participant’s ability to carry out activities of daily living) 
• 
It resulted in a congenital anomaly or birth defect (i.e. an adverse finding in a child or 
foetus of a participant exposed to the study vaccine prior to conception or during 
pregnancy) 
• 
Other medically important conditions that may not result in death, threaten life or 
require hospitalisation (i.e. the adverse event does not meet any of the above serious 
criteria) may be considered an SAE when, based on appropriate medical judgment, they 
may jeopardise the participant and require medical or surgical intervention to prevent 
one of the serious outcomes listed in these criteria (e.g. allergic bronchospasm requiring 
intensive treatment in an emergency room or at home; blood dyscrasias or convulsions 
that do not result in hospitalisation, or the development of drug dependency or drug 
abuse) 
An SAE is an adverse event meeting the outcome criteria for seriousness regardless of 
relationship to the study vaccine. 
5.6 
Definition of Adverse Reaction 
An adverse reaction is an adverse event judged to be related to study vaccine. 
5.7 
Assessing Expectedness of Adverse Events 
Expected adverse events are adverse events consistent with the applicable product information 
provided by the Sponsor (the Investigator’s Brochure for an investigational product). The 
Sponsor, in conjunction with the local Medical Monitor, determines expectedness of related 
SAEs. 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 47 OF 78 
5.8 
Definition of Suspected Unexpected Serious Adverse Reaction  
When an adverse event is judged to be related to study vaccine and is judged to be both serious 
and unexpected, and is in a participant who received active vaccine, it is a suspected unexpected 
serious adverse reaction (SUSAR) and is subject to expedited reporting. 
5.9 
Definition of an Adverse Event of Special Interest 
AESI for this study are listed in Appendix 2Appendix 2. AESI should be recorded and 
reported using the same procedures as for SAEs. They should therefore be recorded over the 
duration of the influenza season to which the participant is recruited and reported to the 
Sponsor according to the process in Section 5.10. 
5.10 
Reporting of Serious Adverse Events 
5.10.1 
Reporting to the Sponsor  
All SAEs, which include SUSARs, are reported to the Sponsor for the entire study period. 
SUSARs are reported even after the study is over, if the Sponsor, local Medical Monitor or 
Principal Investigator becomes aware of them. The study site will be provided with specific 
reporting procedures including the SAE paper form and any supplemental reporting forms to 
be used. SAEs will be reported on the SAE paper form and the AE eCRF using a recognised 
medical term or diagnosis that accurately reflects the event. 
SAEs will be assessed for severity, causal relationship to the study vaccine, and expectedness 
by the Investigator and the local Medical Monitor according to their roles (as described in 
Section 5.1.1 and Section 5.1.3). The onset and resolution dates of the event and medical care 
taken in response to the event will be documented. If the event has not resolved by the end of 
the influenza season the participant is enrolled into, it will be documented as “ongoing” on the 
eCRF, however, follow-up of the SAE must continue until resolved or the condition has 
stabilised. Information recorded on the eCRF must be substantiated in the source documents. 
The SAE form for that event must be completed by the Principal Investigator, within one 
business day of the study site becoming aware of the event. The SAE form should be completed 
with all information known at the time. and scanned and emailed to safety@clinical.net.au. 
Fatal or life-threatening SAEs that the Investigator suspects are related to the study vaccine 
should be telephoned to the local Medical Monitor immediately upon the Investigator’s 
awareness of the event. If the local Medical Monitor is required by the protocol or chooses to 
suspend enrolment s/he shall immediately create a written memorandum for record to the study 
file and telephonically notify the Sponsor of this act. 
Contact information for all safety personnel are contained in the Team Contact List, which will 
be stored at the study site in the Site Regulatory Binder and maintained by the study Sponsor. 
Investigators must not wait to collect additional information to fully document the event before 
notifying the local Medical Monitor of an SAE. The initial notification should include the 
following (at minimum):  
• 
Protocol number and name and contact number of the Investigator 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 48 OF 78 
• 
Participant identification number (and initials and date of birth, if available) 
• 
Date participant received investigational product 
• 
SAE(s) and date of event onset 
• 
Current status of participant  
The Sponsor will notify the DMC of all SUSARs within 24 hours of becoming aware of an 
event and will provide all follow-up information in a timely manner. 
5.10.2 
Expedited Reporting  
SUSARs are subject to expedited reporting. The process will be further described in the Study 
Specific Safety Management Plan.  
The Sponsor has authorised the CRO to execute its responsibilities for expedited safety report 
submission to the appropriate regulatory authorities within specific time periods of being 
notified of the event (within 7 or 15 calendar days depending the character of the SUSAR); 
therefore, it is important that the Investigator submit additional information requested as soon 
as it becomes available. 
5.11 
Other Events Requiring Immediate Reporting 
The Investigator must report the following events to the Sponsor within 24 hours of becoming 
aware of the event:   
• 
Withdrawal of consent during the study for safety reasons 
• 
Protocol deviation affecting the safety of a participant or involving the vaccination 
process 
• 
Adverse event thought to be an allergic reaction to the study vaccine 
• 
Any event that, in the opinion of the Investigator, precludes further administration of the 
study vaccine  
• 
Pregnancy 
5.12 
Adverse Event Treatment, Follow-up, and Outcome 
Treatment of any adverse events will be determined by the Investigator using his/her best 
medical judgment and according to current clinical practice guidelines. All applied measures 
as well as follow-up will be recorded in the appropriate eCRF. 
The Investigator will continue follow-up on adverse events, including laboratory abnormalities 
and solicited adverse events, until the event has resolved, is otherwise satisfactorily explained, 
or the participant completes the study. The resolution date will be recorded on the eCRF as the 
last date on which the participant experienced the adverse event. If an adverse event resolution 
date is uncertain the Principal Investigator should estimate the completion date based on 
medical judgment and interview of the participant. Approximate dates of resolution from phone 
or other communications may be taken as adverse event resolution dates. Some examples of 
estimation of adverse event resolution are: 1) an asymptomatic laboratory abnormality on one 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 49 OF 78 
visit that has not been followed-up between visits but has resolved by the next visit may be 
assumed to have resolved by the midpoint of the inter-visit interval; 2) A resolved adverse 
event that was treated may be assumed to have been resolved by the end of treatment.  
Adverse events that are still present at the end of the study should be recorded as ongoing.  
Information recorded on the eCRF must be substantiated in the source documents. If an adverse 
event evolves into a condition that becomes “serious,” it will be designated as serious on the 
adverse event eCRF and a supplemental SAE Report form will be completed. 
Follow-up for SAEs must continue until resolution and the outcome reported to the Sponsor, 
even if this extends beyond the SAE reporting period (the end of the influenza season into 
which the participant is enrolled). 
For analysis purposes, the outcome for SAEs will be determined on or before the end of the 
second influenza season. 
Outcome of all adverse events will be classified as one of the following: 
• 
Resolved  
• 
Resolved with sequelae 
• 
Ongoing 
• 
Death 
If at any time after completion of the SAE reporting period the Investigator becomes aware of 
a serious adverse event that is suspected by the Investigator to be related to the study vaccine, 
the event must be reported to the Sponsor. 
5.13 
Follow-up of Participants Who Become Pregnant  
If a participant becomes pregnant during the study, she should be encouraged to continue in 
the study for safety follow-up. Follow-up should continue for pregnancy outcome including 
premature terminations, and data are to be included in the safety reports.  
The Investigator must notify the local Medical Monitor of the pregnancy immediately (even if 
already known to have resulted in spontaneous or elective abortion) by scanning and emailing, 
or faxing, the Pregnancy Notification Form to the local Medical Monitor. At a minimum, the 
estimated date of conception, the estimated due date, and the date the participant received the 
study vaccine should be provided.   
If a participant becomes pregnant, she will not have any interventions done as normally 
mandated by the protocol (applies only to participants in the immunogenicity cohort). The 
participant will undergo all other evaluations according to Table 3-1 or Table 3-2. 
The health status of the mother and child, the date of delivery, and the child’s sex, birth weight 
and multiparity should be reported to the local Medical Monitor after delivery, using a 
Pregnancy Notification Form. If delivery occurs before the end of the influenza season, the 
participant should continue to be followed for SAEs until this time unless withdrawal of 
consent has occurred. If delivery occurs after the end of the influenza season, the Investigator 
should attempt to maintain contact with the participant to obtain information after delivery.  

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 50 OF 78 
Pregnancy will not be recorded as an adverse event. If the pregnancy results in a miscarriage 
or a planned termination, the event (spontaneous abortion or elective abortion) will be reported 
as an adverse event or SAE per the Investigator's judgment (e.g. if it was a medically important 
or life-threatening event that meets the definition of an SAE).  
A congenital anomaly or birth defect (i.e. an adverse finding in a child or foetus of a participant 
exposed to the study vaccine before conception or during pregnancy) must be reported as a 
SAE. 
If it is determined after completion of the study that a participant became pregnant during the 
study, the participant should notify the Investigator. The pregnancy must be reported to the 
local Medical Monitor and the status of the mother and child after delivery will be obtained 
and reported, when possible. 
 
 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 51 OF 78 
6 
DATA COLLECTION, MONITORING AN RECORD RETENTION 
6.1 
Source Documentation 
Source documents are defined as the results of original observations and activities of a clinical 
investigation, including medical notes. The Investigator must permit the Study Monitor, the 
IEC/IRB, the Sponsor’s auditors and representatives from regulatory authorities direct access 
to all source documents for confirmation of the accuracy and reliability of data contained within 
the eCRFs (source document verification). Participant confidentiality will be protected at all 
times. 
Source documentation includes, but is not limited to, the following and will be identified in a 
source data location log: 
• 
Screening/enrolment log 
• 
Medical notes - which should be updated after each visit  
• 
Informed consent form 
• 
Laboratory reports (for the immunology cohort) 
• 
Visit dates  
• 
Study vaccine accountability forms 
6.2 
Data Management 
Data recorded on source documents will be entered on eCRFs using an electronic data capture 
system approved by the Sponsor. Data collection must be completed for each participant who 
signs an informed consent form and receives at least one vaccination. 
eCRFs should be completed in accordance with instructions. The Investigator is responsible 
for maintaining adequate and accurate medical records from which accurate information will 
be transcribed directly into the eCRFs using a secure internet connection. The eCRFs should 
be filled out completely by the Investigator or designee as stated on the delegation of 
responsibilities form. The eCRF system will be Food and Drug Administration Code of Federal 
Regulations 21 Part 11 compliant. 
The eCRFs must be reviewed, signed and dated by the Investigator when complete. 
Data entered into the eCRF will be validated as defined in the data validation plan. Validation 
includes, but is not limited to, validity checks (e.g. range checks), consistency checks and 
customised checks (logical checks between variables to ensure that study data are accurately 
reported) for eCRF data and external data. A majority of edit checks will be triggered during 
data entry and will therefore facilitate efficient ‘point of entry’ data cleaning.  
Data management personnel will perform both manual eCRF review and review of additional 
electronic edit checks to ensure that the data are complete, consistent and reasonable. The 
electronic edit checks will run continually throughout the course of the study and the issues 
will be reviewed manually online to determine what action needs to be taken. 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 52 OF 78 
Manual queries may be added to the system by clinical data management or Study Monitor. 
Clinical Data Managers and Study Monitors are able to remotely and proactively monitor the 
patient eCRFs to improve data quality. 
External immunogenicity data will be transferred electronically to the CRO. Discrepancies will 
be queried to the site and/or the laboratory until the electronic data and the database are 
reconciled.  
All updates to queried data will be made by authorised study site personnel only and all 
modifications to the database will be recorded in an audit trail. Once all the queries have been 
resolved, eCRFs will be locked by password protection. Any changes to locked eCRFs will be 
approved by the Investigator. 
Once the full set of eCRFs has been completed and locked, the Sponsor will authorise database 
lock and all electronic data will be sent to the designated statistician for analysis. Subsequent 
changes to the database will then only be made only by written agreement of the Sponsor. 
Unsolicited adverse events and medical history terms will be coded from the verbatim 
description (Investigator term) using the Medical Dictionary for Regulatory Activities 
(MedDRA). Medications will be coded according to the World Health Organization drug code. 
The clinical database (in SAS® format) will be transferred to the Sponsor at the end of the 
study.  
6.3 
Monitoring 
The study will be monitored in accordance with the principles of International Council on 
Harmonisation Good Clinical Practice (ICH GCP) by a Study Monitor approved by the 
Sponsor. During these visits, all procedures will be monitored for compliance with the protocol. 
Source documents will be reviewed and compared with the data entries in the eCRFs to ensure 
consistency. The frequency of monitoring visits will be determined, in part, by the rate of 
participant recruitment. 
The monitoring visits also provide the Sponsor with the opportunity to ensure that timely 
patient accrual and the other Investigator’s obligations and all applicable requirements are 
being fulfilled. 
6.4 
Record Retention 
All study records (source documents, signed informed consent forms, IRB/IEC correspondence 
and approval letters, study treatment management records) will be kept secured for a minimum 
of 2 years following the marketing of the investigational product. Additional storage will be 
according to the guidance of the applicable national regulatory authority or authorities. The 
Investigator will ensure that study records are not disposed of or removed from the study site 
without prior notification and approval from the Sponsor or its designee. 
 
 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 53 OF 78 
7 
STATISTICAL CONSIDERATIONS 
The planned statistical analyses for this study are outlined below. A more detailed SAP 
(including plans for any interim analysis, futility analysis, subgroup analysis, and sensitivity 
analysis) and including methods for imputing missing data, where applicable, will be created 
and finalised prior to database lock for preparation of the final study report (see Section 7.7.2). 
7.1 
Participant Analysis Sets 
• 
The Safety Analysis Set will consist of all randomised participants who received at least 
one vaccination (according to the vaccination actually received) 
• 
The Efficacy Analysis Set will consist of all randomised participants who received the 
study vaccine according to the randomised treatment group (i.e. intent-to-treat) 
• 
The Immunology Analysis Set will consist of all randomised participants according to 
their randomised treatment group who received the study vaccine, provided the 
pre-vaccination and at least one post-vaccination blood sample evaluable for 
immunological analysis and did not have any major protocol deviations that would 
impact on the results of the immunological analysis 
7.2 
Disposition, Demographics and Protocol Compliance 
All data will be listed. Summaries will be provided for the Safety Analysis Set, unless stated 
otherwise. 
Participant disposition (participants screened, screen failed [with reason], randomised, 
vaccinated and completed or withdrawn [with reason]) will be summarised by treatment group. 
Demographic parameters (age, sex, and race/ethnicity) and other baseline characteristics will 
be summarised by treatment group for all participants in the Safety Analysis Set. Medical 
history will be summarised by system organ class (SOC) and preferred term. 
Protocol deviations recorded during monitoring will be centrally collated, categorised 
according to deviation type and assigned as major or minor. Summaries will be generated by 
category. 
7.3 
Efficacy Analyses 
Efficacy analyses will be performed on the Efficacy Analysis Set. The primary endpoint, the 
incidence rate of laboratory confirmed influenza using RT-PCR on nasal swab samples, will 
be compared between vaccine groups using Fisher’s Exact Test. Secondary efficacy endpoints 
assessing the incidence and severity of influenza-like symptoms will be performed by 
comparing the incidence of ILI (using the regulatory definition of ILI defined as feeling 
feverish or having a fever (temperature ≥37.8 C) and at least one of the following symptoms: 
a cough, and/or sore throat) by Fisher’s test exact and symptom severity as an area-under-the-
curve (AUC) using a Mann-Whitney U Test. 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 54 OF 78 
7.4 
Immunogenicity and Other Immunology Analyses 
Immunogenicity data will be summarised for all time points as collected and as available for 
the Immunogenicity Analysis Set. Data will be transformed as appropriate prior to analysis, 
and all transformation processes will be clearly described in the SAP. 
7.4.1 
Immune Response Determined by Intracellular Cytokine Staining Assay 
Dimethyl sulfoxide (DMSO)-subtracted cytokine response, as well as DMSO cytokine 
response (to better understand the distribution of background noise in the assay) will be used 
to summarise percentage CD4+ and CD8+ T cell response by treatment group and stimulation 
antigen. Summaries will include the assessment of response at all pre- and post-vaccination 
immunogenicity time points, as well as change from pre-vaccination to each post-vaccination 
time point, by treatment group.  
The number (percentage) of participants designated as a responder according to the SAP will 
be summarised at each time point for ICS, and across all available time points compared to 
baseline cytokine expression, for all vaccinated participants by treatment group. 
7.4.2 
ELISpot Assay 
Median DMSO-subtracted antigen response will be used to summarise responses. Summaries 
will include the assessment of response at all pre- and post-vaccination immunogenicity time 
points, as well as change from pre-vaccination to each post-vaccination time point.  
The number (percentage) of participants designated as a responder according to the SAP will 
be summarised at each time point, and across all available time points, for all vaccinated 
participants by treatment group. 
7.5 
Safety Analyses 
Safety analyses will be performed using the Safety Analysis Set.  
7.5.1 
Adverse Events 
The number (percentage) of participants with unsolicited adverse events post-vaccination will 
be summarised by MedDRA system organ class and preferred term. Additional summaries will 
present the number (percentage) of participants with adverse events by severity and by 
relationship to investigational product; each participant will be counted once per preferred term 
at the greatest severity or most related state recorded for that term.  
Separate summaries of the number (percentage) of participants with solicited adverse events 
will also be presented. Solicited adverse events will also be summarised by severity; each 
participant will be counted once per term at the greatest severity and most related state recorded 
for that term. 
Separate listings will be provided for participants with SAEs and for participants with AESI 
and adverse events leading to discontinuation. SAEs may also be summarised by system organ 
class and preferred term. 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 55 OF 78 
7.5.2 
Injection Site Reactions 
The number (percentage) of participants recording vaccination site reactions in the eDiary in 
the first 7 days post-vaccination will be summarised by treatment group, timepoint 
post-vaccination and severity. 
7.5.3 
Clinical Laboratory Parameters 
The number (percentage) of participants with post-vaccination clinical laboratory values as 
newly abnormal following study vaccination and meeting toxicity mild criteria (Grade 1) or 
above as specified in the Toxicity Table (Appendix 3) summarised using shift tables at each 
post-vaccination timepoint and overall. Newly abnormal results will be separately listed with 
the normal range and baseline value.  
7.6 
Sample Size Considerations 
Sample size calculations based on various incidence rates in the control arm, relative vaccine 
efficacies for those in the MVA-NP+M1 arm, and alpha levels (two-sided) are provided in 
Table 7-1.  
Table 7-1 
Sample Size Calculations (80% power, two-sided alpha levels) 
Rate of Influenza 
in Control Arm 
Relative Vaccine 
Efficacy 
Total Sample Size Required  
α=0.10 
α=0.15 
α=0.20 
2% 
30% 
11478 
9658 
8360 
35% 
8188 
6890 
5964 
40% 
6082 
5118 
4430 
50% 
3652 
3074 
2660 
3% 
30% 
7586 
6382 
5524 
35% 
5412 
4554 
3,942 
40% 
4022 
3384 
2930 
50% 
2416 
2034 
1760 
4% 
30% 
5640 
4746 
4108 
35% 
4026 
3386 
2932 
40% 
2992 
2516 
2178 
50% 
1798 
1512 
1310 
All calculations assume 80% power and given this is a proof of concept study an alpha of 0.1 
is chosen for powering analyses. Based on the projected range of incidence rates in the control 
arm, a total sample size of approximately 5000 to 6000 participants over two influenza seasons 
is expected to provide approximately 80% power to detect a meaningful vaccine efficacy 
(approximately 35%) in the MVA-NP+M1 arm.  
After the first influenza season, which will enrol approximately 2,200 participants, a sample 
size recalculation may be performed on the basis of the observed relative vaccine efficacy of 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 56 OF 78 
MVI-NP+M1 during the first influenza season. This will be described in more detail in the 
SAP.  
7.7 
Plan for Statistical Summaries and Analyses 
7.7.1 
Preliminary Data Reviews 
The DMC will review cumulative safety and efficacy data from the first influenza season. This 
review of safety and efficacy data may include a formal futility analysis, as well as a potential 
sample size recalculation based on the observed relative vaccine efficacy in the MVA-NP+M1 
vaccine group. Any plans for a potential futility analysis and/or sample size recalculation will 
be established a priori (prior to any unblinding of study data) and will be clearly described 
within the SAP and DMC Charter. 
All unblinded-by-group summaries will be prepared for the DMC by an unblinded statistician 
not associated with the study conduct or development of the SAP for the final analysis. All 
procedures associated with this review, including objectives, data handling, and elements to be 
included for review will be documented in the DMC minutes. 
7.7.2 
Final Study Report 
The final study report will include all available efficacy, immunogenicity (including 
exploratory analyses) and safety data; clinical assessments; and concomitant medications from 
the duration of the study.  
Modifications or additions to the analyses described in Section 7.2 to Section 7.5 will be 
included in the SAP. Any decisions to deviate from the planned analyses described in the 
protocol and in the statistical analysis plan will be described in detail in the final study report. 
7.8 
Computer Methods 
Statistical analyses will be performed using SAS® version 9.4 or later under a Windows 
operating system. 
 
 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 57 OF 78 
8 
ETHICS 
8.1 
Regulatory Considerations 
The study will be conducted according to the ethical principles set forth in the Declaration of 
Helsinki, ICH GCP, and local regulatory requirements as applicable. The study site(s) should 
have recruitment and retention guidelines appropriate for different age groups (e.g., infants, 
adolescents, adults). 
The protocol and informed consent form will be reviewed and approved by an IRB/IEC prior 
to any protocol-specified procedures being conducted. The Investigator is responsible for 
ensuring that the protocol is reviewed by an IRB/IEC with the appropriate composition (per 
clinical study site guidelines). The Investigator will inform the IRB/IEC as to the progress of 
the study at applicable intervals as defined by IRB/IEC policy. 
There are potential known and unknown risks associated with vaccination. With any vaccine, 
including licensed ones, there is a rare risk of anaphylaxis which can be fatal. Participants will 
therefore be observed in the clinic for at least 10 minutes post-vaccination. Vaccination may 
also cause Guillain-Barré syndrome causing severe weakness, which may also be fatal.  
Intramuscular injection of influenza vaccines frequently causes the local and systemic signs 
and symptoms that are being collected as adverse events. These will be solicited from the 
participant to ensure they are nor occurring more frequently or are more severe than expected. 
With any new treatment there is always a possibility of an unexpected adverse events. Pausing 
and holding rules have been defined for the study (see Section 2.3) and the DMC will perform 
a review of safety data if one of these is met. There are also routinely scheduled reviews of 
safety and efficacy data throughout the study. 
To maintain confidentiality, participant identification numbers will be used to identify 
laboratory samples, source documents, eCRF, study reports etc. All study records will be 
maintained in a secured location. Clinical information will not be released without written 
permission from the participant except as necessary for monitoring or auditing of the study by 
the Sponsor or its designee or applicable regulatory authorities. 
After the study has been unblinded, the participant should be informed by the Investigator 
whether they received MVA-NP+M1 or placebo.  
8.2 
Institutional Review Board or Independent Ethics Committee 
All the documents the IRB/IEC may need to fulfil its responsibilities, such as the protocol, 
protocol amendments, informed consent form, information concerning participant recruitment, 
payment or compensation procedures, etc. will be submitted to the IRB/IEC by the Investigator. 
The IRB’s/IEC’s written, unconditional approval of the appropriate version of the study 
protocol and the informed consent form will be in the possession of the Investigator/study site 
staff prior to the conduct of any protocol-specified procedures.  
Modifications to the protocol may not be implemented without prior written IRB/IEC approval 
except when necessary to eliminate immediate hazards to the participants or when the 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 58 OF 78 
modification involves only logistical or administrative aspects of the study. Such logistical or 
administrative modifications will be submitted to the IRB/IEC in writing by the Investigator, 
and a copy of the correspondence to verify the submission will be maintained. 
The Investigator must inform the IRB/IEC of modifications to the informed consent form or 
any other documents previously submitted for review/approval and any new information that 
may adversely affect the safety of the participants or the conduct of the study, provide an annual 
update and/or request for re-approval, and advise the IRB/IEC when the study has been 
completed.  
Any study site-generated documents or forms to be provided to the participant 
(e.g.  information cards, letters from the Investigator), and all forms of study advertising (flyers, 
brochures, print advertisements, radio or television scripts, etc.) must be approved by the 
Sponsor or its designee prior to the study site submitting them to the IRB/IEC. Approval from 
the IRB/IEC must be obtained prior to providing the documents or forms to the participant. 
8.3 
Informed Consent 
Written, informed consent will be obtained prior to any protocol-specified procedures being 
conducted. The written consent document will embody the elements of informed consent as 
described in the Declaration of Helsinki and will also comply with local regulations. Informed 
consent will be documented in writing on a version-controlled consent form approved by the 
IRB/IEC.  
The informed consent process will be conducted in a private space, whether at the study site, 
at home, or at another location, to maintain confidentiality. The consent process will be 
conducted in the participant’s language of choice. All relevant information should be provided 
in both oral and written form in a way that is understandable to the participant. Ample time and 
opportunity must be given for the participant to inquire about details of the study. The potential 
participant should be encouraged to take the informed consent form home to discuss with 
family and friends before deciding whether or not to participate in the study. 
An assessment of a participant’s understanding of the key study concepts (e.g. procedures, 
risks) should be conducted prior to signing the consent form.  
The Investigator or the Investigator’s qualified designee will explain the nature of the study 
and inform the participant that participation is voluntary and that the participant can leave the 
study at any time, without penalty or loss of benefits to which they are otherwise entitled. The 
participant must be informed about the study’s purpose including why the participant was 
selected to participate, study goals, expected benefits and risks, potential risks, and that some 
potential risks are unforeseeable. The participant must be provided with a description of the 
procedures and the estimated duration of time required for participation in the study, as well as 
alternative interventions or courses of treatment, if applicable.  
The participant must receive an explanation as to whether any compensation and any medical 
treatments are available if injury occurs and, if so, what they are, where further information 
may be obtained, and who to contact in the event of a study-related injury. Participants must 
be told who to contact for answers to any questions related to the study. The extent of the 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 59 OF 78 
confidentiality of participant records must be defined and the participant must be informed that 
applicable data protection legislation applies. 
The participant must be informed that the Study Monitor(s), auditor(s), IRB/IEC members, and 
the applicable regulatory authorities will be granted direct access to the participant’s original 
study medical records for verification of protocol-specified procedures and/or data, without 
violating the confidentiality of the participant to the extent permitted by the applicable laws 
and regulations. The participant must be informed that his/her signature on the informed 
consent form indicates that he/she has decided to participate in the study, having read and 
discussed the information presented.  
Modifications made by the Investigator to an informed consent form templates provided to the 
Investigator by the Sponsor or its designee will be reviewed and approved by the Sponsor or 
its designee prior to being submitted to the IRB/IEC.  
The original, signed informed consent form for each participant will be maintained by the 
Investigator as part of the participant’s study records. A copy of the signed informed consent 
form will be provided to each participant/. 
Informed consent is an ongoing process. At every clinic visit it will be verbally reconfirmed 
that the participant is voluntarily consenting to the study and understands the significant aspects 
of the study (e.g. purpose, risks, duration). 
Participants in the immunogenicity cohort only will be asked to consent to have blood samples 
collected in addition to the procedures for the main cohort. Blood tests will not be a condition 
of participation in the main study and all participants initially recruited to the immunology 
cohort who then do not wish to have blood tests will be offered participation in the main study 
without blood tests.  
 
 
 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 60 OF 78 
9 
STUDY COMPLETION 
The end of the study is defined as the date of database lock. 
The Investigator will notify the IRB/IEC when the study has been completed. 
 
 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 61 OF 78 
10 
PUBLICATION 
The final study report will be made available to the Principal Investigator for purposes of 
publications. The Principal Investigator and study staff must send all manuscripts, abstracts, 
and presentations using data from this study to the Sponsor for review prior to their submission. 
The Sponsor reserves the right to delete any part or parts of such materials deemed to be 
confidential or proprietary. 
 
 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 62 OF 78 
11 
CHANGES IN THE PROTOCOL 
The protocol may not be modified without written approval from the Sponsor. All changes to 
the protocol must be submitted to the IRB/IEC and must be approved by the IRB/IEC prior to 
their implementation except when necessary to eliminate immediate hazards to the participants 
or when the modification involves only logistical or administrative aspects of the study.  

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 63 OF 78 
12 
REFERENCES 
1. 
WHO, Influenza fact sheet No. 211. 2014. 
2. 
Molinari, N.A., et al., The annual impact of seasonal influenza in the US: measuring 
disease burden and costs. Vaccine, 2007. 25(27): p. 5086-96. 
3. 
Dawood, F.S., et al., Estimated global mortality associated with the first 12 months of 
2009 pandemic influenza A H1N1 virus circulation: a modelling study. Lancet Infect Dis, 
2012. 12(9): p. 687-95. 
4. 
Babakir-Mina, M., et al., Influenza virus A (H5N1): a pandemic risk? New Microbiol, 
2007. 30(2): p. 65-78. 
5. 
Kilbourne, E.D., et al., The total influenza vaccine failure of 1947 revisited: major 
intrasubtypic antigenic change can explain failure of vaccine in a post-World War II 
epidemic. Proc Natl Acad Sci U S A, 2002. 99(16): p. 10748-52. 
6. 
Bardenheier, B.H., et al., Influenza vaccine supply, 2005-2006: did we come up short? 
BMC Health Serv Res, 2007. 7: p. 66. 
7. 
Hannoun, C., F. Megas, and J. Piercy, Immunogenicity and protective efficacy of 
influenza vaccination. Virus Res, 2004. 103(1-2): p. 133-8. 
8. 
Hayward, A.C., et al., Natural T Cell Mediated Protection Against Seasonal and 
Pandemic Influenza: Results of the Flu Watch Cohort Study. American Journal of 
Respiratory and Critical Care Medicine, 2015. 
9. 
Sridhar, S., et al., Cellular immune correlates of protection against symptomatic 
pandemic influenza. Nat Med, 2013. 19(10): p. 1305-12. 
10. 
Lee, L.Y., et al., Memory T cells established by seasonal human influenza A infection 
cross-react with avian influenza A (H5N1) in healthy individuals. J Clin Invest, 2008. 
118(10): p. 3478-90. 
11. 
Berthoud, T.K., et al., Potent CD8+ T-cell immunogenicity in humans of a novel 
heterosubtypic influenza A vaccine, MVA-NP+M1. Clin Infect Dis, 2011. 52(1): p. 1-7. 
12. 
Hochstein-Mintzel, V., et al., [An attenuated strain of vaccinia virus (MVA). Successful 
intramuscular immunization against vaccinia and variola (author's transl)]. Zentralbl 
Bakteriol Orig A, 1975. 230(3): p. 283-97. 
13. 
Goepfert, P.A., et al., Phase 1 safety and immunogenicity testing of DNA and 
recombinant modified vaccinia Ankara vaccines expressing HIV-1 virus-like particles. J 
Infect Dis, 2011. 203(5): p. 610-9. 
14. 
Howles, S., et al., Vaccination with a modified vaccinia virus Ankara (MVA)-vectored 
HIV-1 immunogen induces modest vector-specific T cell responses in human subjects. 
Vaccine, 2010. 28(45): p. 7306-12. 
15. 
Scriba, T.J., et al., Modified vaccinia Ankara-expressing Ag85A, a novel tuberculosis 
vaccine, is safe in adolescents and children, and induces polyfunctional CD4+ T cells. 
Eur J Immunol, 2010. 40(1): p. 279-90. 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 64 OF 78 
16. 
Swadling, L., et al., A human vaccine strategy based on chimpanzee adenoviral and MVA 
vectors that primes, boosts, and sustains functional HCV-specific T cell memory. Sci 
Transl Med, 2014. 6(261): p. 261ra153. 
17. 
Dangoor, A., et al., Clinical and immunological responses in metastatic melanoma 
patients vaccinated with a high-dose poly-epitope vaccine. Cancer Immunol 
Immunother, 2010. 59(6): p. 863-73. 
18. 
O'Hara, G.A., et al., Clinical assessment of a recombinant simian adenovirus ChAd63: a 
potent new vaccine vector. J Infect Dis, 2012. 205(5): p. 772-81. 
19. 
Antrobus, R.D., et al., A T cell-inducing influenza vaccine for the elderly: safety and 
immunogenicity of MVA-NP+M1 in adults aged over 50 years. PLoS One, 2012. 7(10): 
p. e48322. 
20. 
Antrobus, R.D., et al., Coadministration of seasonal influenza vaccine and MVA-NP+M1 
simultaneously achieves potent humoral and cell-mediated responses. Mol Ther, 2014. 
22(1): p. 233-8. 
21. 
Coughlan, L., et al., Heterologous Two-Dose Vaccination with Simian Adenovirus and 
Poxvirus Vectors Elicits Long-Lasting Cellular Immunity to Influenza Virus A in Healthy 
Adults. EBioMedicine, 2018. 29: p. 146-154. 
22. 
Lillie, P.J., et al., Preliminary assessment of the efficacy of a T-cell-based influenza 
vaccine, MVA-NP+M1, in humans. Clin Infect Dis, 2012. 55(1): p. 19-25. 
 
 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 65 OF 78 
APPENDICES 
Appendix 1 
Detailed Description of Study Visits 
Written informed consent must be obtained before any screening procedures are performed. 
The following will be performed: 
Screening Visit(s): Day 0 for the main cohort, may be up to -120 days for participants in 
the immunology cohort recruited through general advertising 
1. 
Verify eligibility criteria 
2. 
Review of medical history 
3. 
Physical examination 
Vaccination: Day 0 
1. 
Verify eligibility criteria (if screening done prior to Day 0) 
2. 
Urine pregnancy test pre-vaccination (women of childbearing potential) 
3. 
Randomisation to study vaccine (MVA-NP+M1 or placebo) 
4. 
Take pre-vaccination safety laboratory blood sample (immunology cohort only) 
5. 
Take pre-vaccination immunology blood sample (immunology cohort only) 
6. 
Vaccinate participant with study vaccine  
7. 
Cover the vaccination site with a sterile dressing for 30 minutes, then remove and dispose 
as GMO waste. 
8. 
Observe participant for at least 30 minutes; record any immediate adverse events 
9. 
Provide eDiary, tape measure and thermometer 
10. 
Instruct participant to: 
• 
Take their oral temperature (for the next 7 days) 
• 
Assess other solicited adverse events (for the next 7 days)  
• 
Assess unsolicited adverse events (for the next 28 days) 
• 
Assess influenza symptoms over the duration of the influenza season between 01 May 
and 15 October. Assessments should be made weekly unless symptoms are 
experienced then the severity of symptoms should be recorded daily plus any 
medications to treat symptoms 
• 
Arrange to attend the clinic in the event of any influenza symptom(s) 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 66 OF 78 
• 
Inform the study site of any hospitalisations, other SAEs or AESI over the duration of 
the influenza season 
11. 
Discharge participant 
Follow-up: Day 1 until the end of the influenza season into which the participant is 
recruited 
In the event of any influenza symptom(s), participants should attend the clinic on two occasions, 
the first within 72 hours of the onset of symptoms for deep nasal/mid-turbinate swabs to be taken. 
Both swabs must be taken within 96 hours of symptom onset. 
Days 1-28 
1. 
Weekly reminders through the IBM system or through site appointment systems, to complete 
eDiary2 
2. 
Day 1 (+2 days): Telephone participant to assess adverse events 
3. 
Day 7 (+3 days):  
• 
Main cohort: Telephone participant to assess adverse events 
• 
Immunology cohort: In clinic visit 
- 
Perform physical examination (if considered necessary) 
- 
Assessment of solicited adverse events 
- 
Assessment of unsolicited adverse events 
- 
Take safety laboratory blood sample 
4. Day 28 (±7 days):  
• 
Immunology cohort: In clinic visit 
- 
Assessment of unsolicited adverse events 
- 
Take safety laboratory blood sample 
- 
Take immunogenicity blood sample 
Follow-up Day 29-End of Influenza Season 
1. 
4 weekly (±1 week) telephone call to: 
                                                 
 
 
2 For participants vaccinated early in the influenza season and having Day 28 assessments before the start of the ILI 
reporting period on 15 May, these reminders will not be required after Day 28 and before 15 May 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 67 OF 78 
• 
Remind participant to assess influenza symptom weekly and record any symptoms 
daily in the eDiary (between 01 May and 15 October) 
• 
Review whether there have been any hospitalisations, other SAEs or AESI and record 
these in the eCRF 
2. 
Week 26 (±1 week): 
• 
Immunology cohort: In-clinic visit 
- 
Take immunogenicity blood sample  
• 
Notify participant of end of follow-up and perform final review.  
 
 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 68 OF 78 
Appendix 2 
Adverse Events of Special Interest 
Adverse events of special interest represent a subset of adverse events that include autoimmune 
diseases and other systemic disorders of interest which could potentially have an autoimmune 
aetiology. Adverse events of special interest are listed below. The Principal Investigator should 
use clinical and scientific judgment in deciding whether other adverse events (i.e., events not listed 
here) could have an autoimmune origin and should therefore be reported as adverse events of 
special interest. 
• 
Bell's Palsy 
• 
Guillain Barré Syndrome 
• 
Myocarditis 
• 
Stevens-Johnson Syndrome 
 
 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 69 OF 78 
Appendix 3 
Toxicity Table for Clinical and Laboratory Abnormalities 
 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 70 OF 78 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 71 OF 78 
 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 72 OF 78 
 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 73 OF 78 
 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 74 OF 78 
 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 75 OF 78 
 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 76 OF 78 
 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 77 OF 78 
 

 
MVA-NP+M1 
 
Protocol FLU009  
 
CONFIDENTIAL 
20 May 2019; Version 3.0 
 
FORM CVC009-001 (1) 
CONFIDENTIAL 
PAGE 78 OF 78