Conditions: Influenza
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2364
Healthy volunteers: yes

Brief summary:
A Phase 2b Study to Determine the Efficacy of Candidate Influenza Vaccine MVA-NP+M1 in Adults aged 18 years and over. 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

Detailed description:
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 2200 participants in Season 1 and 2800-3800 participants in Season 2.

Arms:
arm 1: Vaccination administered: MVA-NP+M1 (IM injection, 0.5 ml, 1.5 x10\^8 pfu.) arm 2: Vaccination administered: Sodium Chloride (IM injection, 0.5 ml, 0.9%)

Interventions: intervention 1: MVA-NP+M1 intervention 2: Saline
Intervention descriptions: intervention 1: Trial Vaccine intervention 2: Sodium Chloride Placebo

Protocol document:
Prot_000.pdf: 


 
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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  


 
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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 


 
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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 


 
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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 


 
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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 
 
 
 


 
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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 
 
 
 


 
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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 
 
 


 
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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 
 
 


 
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Immunogenicity Laboratories 
 Veracity Biolabs 
1 Dalmore Drive 
Scoresby 3179  
Victoria  
Australia 
360biolabs Pty Ltd 
85 Commercial Road 
Melbourne 
Victoria 
Australia, 3004 


 
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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 
 
 
 
 


 
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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 


 
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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]. 


 
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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. 
 
 


 
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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. 


 
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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 


 
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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


 
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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. 
 
 
 


 
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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  
 
 


 
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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. 


 
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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).  


 
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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.  


 
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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 


 
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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 


 
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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 


 
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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. 


 
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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). 
 
 


 
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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.  


 
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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. 


 
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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  


 
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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 


 
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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 


 
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• 
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 
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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 
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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 


 
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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  
                                                 
 
 
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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 
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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). 


 
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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 


 
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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. 


 
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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.  
  
 


 
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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 


 
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• 
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 


 
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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 
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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. 


 
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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. 


 
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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 


 
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• 
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 


 
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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.  


 
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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. 
 
 


 
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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. 


 
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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. 
 
 


 
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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. 


 
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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 
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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 


 
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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. 
 
 


 
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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 


 
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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 


 
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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.  
 
 
 


 
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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. 
 
 


 
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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. 
 
 


 
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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.  


 
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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. 


 
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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. 
 
 


 
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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 
• 
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• 
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 


 
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• 
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.  
 
 


 
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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 
 
 


 
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Appendix 3 
Toxicity Table for Clinical and Laboratory Abnormalities 
 


 
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SAP_001.pdf: 
Vaccitech Ltd 
 
Protocol: FLU009 
Statistical Analysis Plan 
 
Final Version 2.0, 01Jan2020 
 
1 
 
 
  
 
  
STATISTICAL ANALYSIS PLAN 
PHASE 2B 
 
DATE OF PLAN: 
Final Version 2.0, 01Jan2020 
 
BASED ON: 
Protocol Final Version 3.0, dated 20May2019 
 
eCRF, dated 27Mar2019 
 
 
STUDY DRUG: 
MVA-NP+M1 
 
PROTOCOL NUMBER: 
FLU009 
 
STUDY TITLE: 
A Phase 2b Study to Determine the Efficacy of Candidate Influenza Vaccine 
MVA-NP+M1 in Adults aged 18 years and over 
 
SPONSOR: 
Vaccitech Ltd 
The Schrodinger Building 
Heatley Road 
The Oxford Science Park 
Oxford, OX4 4GE 
UK 
This study is being conducted in compliance with good clinical practice, 
including the archiving of essential documents. 


Vaccitech Ltd 
 
Protocol: FLU009 
Statistical Analysis Plan 
 
Final Version 2.0, 01Jan2020 
 
2 
 
 
  
 
SIGNATURE PAGE 
 
This document has been prepared and/or reviewed by: 
 
 
 
 
 
 
Jian Wu 
Statistician 
Clinical Network Services Pty Ltd 
 
Signature 
 
Date 
 
 
 
 
 
Lynda Bluck 
Project Operations Manager 
Clinical Network Services Pty Ltd 
 
Signature 
 
Date 
 
This document has been reviewed and accepted by: 
 
 
 
 
 
 
Kathryn Rutkowski 
Statistician 
Vaccitech Ltd 
 
Signature 
 
Date 
Electronically signed by: Lynda Bluck
Reason: I approve
Date: 2020-01-06 16:33:56+13:00
06/01/2020
Jian Wu
Electronically signed by: Jian Wu
Reason: I am the Author
Date: 2020-01-06 14:37:22+11:00
06/01/2020
Kathryn T. Rutkowski
Electronically signed by: Kathryn T. Rutkowski
Reason: I approve
Date: 2020-01-05 22:45:51-05:00
05/01/2020


Vaccitech Ltd 
 
Protocol: FLU009 
Statistical Analysis Plan 
 
Final Version 2.0, 01Jan2020 
 
3 
 
 
  
 
TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS.......................................................................................7 
2. 
SUMMARY OF UPDATES FROM SAP FINAL VERSION 1 
(21NOV2019) ...............................................................................................................9 
3. 
INTRODUCTION ......................................................................................................10 
4. 
STUDY OBJECTIVE(S) AND ENDPOINT(S) ........................................................11 
4.1. 
Study Objective(s) ......................................................................................................11 
4.1.1. 
Primary Objective .......................................................................................................11 
4.1.2. 
Secondary Objectives .................................................................................................11 
4.2. 
Study Endpoint(s) .......................................................................................................11 
4.2.1. 
Primary Endpoint ........................................................................................................11 
4.2.2. 
Secondary Endpoints ..................................................................................................11 
5. 
STUDY DESIGN .......................................................................................................12 
5.1. 
Design Information .....................................................................................................12 
5.2. 
Definition of Study Drugs ..........................................................................................13 
5.3. 
Sample Size Considerations .......................................................................................14 
5.3.1. 
Sample Size Justifications ..........................................................................................14 
5.3.2. 
Sample Size Re-estimation .........................................................................................14 
5.4. 
Randomization ............................................................................................................14 
6. 
PLANNED ANALYSES ............................................................................................16 
6.1. 
Interim Analyses .........................................................................................................16 
6.2. 
Final Analysis .............................................................................................................17 
7. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING ...............................................................................................................18 
7.1. 
General Summary Table and Individual Subject Data Listing Considerations ..........18 
7.2. 
General Post Text Summary Table and Individual Subject Data Listing 
Format Considerations ................................................................................................18 
7.3. 
Data Management .......................................................................................................19 
7.4. 
Data Presentation Conventions ...................................................................................19 
7.5. 
Analysis Populations ..................................................................................................20 
7.5.1. 
Safety Analysis Set .....................................................................................................20 
7.5.2. 
Efficacy Analysis Set ..................................................................................................20 
7.5.3. 
Per Protocol Analysis Set ...........................................................................................20 


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7.5.4. 
Immunology Analysis Set...........................................................................................21 
7.5.5. 
All Randomised Analysis Set .....................................................................................21 
7.6. 
Baseline Definition .....................................................................................................21 
7.7. 
General Derived and Transformed Data .....................................................................21 
7.7.1. 
Age ..............................................................................................................................21 
7.7.2. 
Study Day ...................................................................................................................21 
7.7.3. 
Change from Baseline .................................................................................................21 
7.7.4. 
Other Derivations ........................................................................................................22 
8. 
TREATMENT COMPARISONS ...............................................................................23 
8.1. 
Data Display Treatment and Other Sub-Group Descriptors .......................................23 
9. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES ...................................24 
9.1. 
Multicentre Studies .....................................................................................................24 
9.2. 
Other Strata and Covariates ........................................................................................24 
9.3. 
Examination of Subgroups .........................................................................................24 
9.4. 
Multiple Comparisons and Multiplicity......................................................................24 
9.5. 
Data Handling Conventions ........................................................................................25 
9.5.1. 
Premature Withdrawal and Missing Data ...................................................................25 
9.5.2. 
Handling of Dropouts .................................................................................................25 
9.5.3. 
Additional/Unscheduled Assessments ........................................................................25 
9.5.4. 
Assessment Windows .................................................................................................25 
9.6. 
Derived and Transformed Data ..................................................................................25 
10. 
STUDY POPULATION .............................................................................................26 
10.1. 
Disposition of Subjects ...............................................................................................26 
10.2. 
Protocol Deviations ....................................................................................................26 
10.3. 
Demographic and Baseline Characteristics ................................................................26 
10.4. 
Vaccine Administration ..............................................................................................27 
10.5. 
Prior and Concomitant Medications ...........................................................................27 
11. 
EFFICACY ANALYSES ...........................................................................................28 
12. 
SAFETY ANALYSES ...............................................................................................31 
12.1. 
Adverse Events ...........................................................................................................31 
12.2. 
Deaths and Serious Adverse Events ...........................................................................33 
12.3. 
Adverse Events Leading to Discontinuation of Investigational Product 
and/or Withdrawal from the Study .............................................................................33 


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12.4. 
Clinical Laboratory Evaluations .................................................................................33 
12.5. 
eDiary Data .................................................................................................................34 
12.6. 
Other Safety Measures ................................................................................................34 
13. 
IMMUNOGENICITY ANALYSES ..........................................................................35 
14. 
HEALTH OUTCOMES ANALYSES .......................................................................38 
15. 
CLINICAL PHARMACOLOGY DATA ANALYSES .............................................39 
16. 
BIOMARKER DATA ANALYSIS ...........................................................................40 
17. 
PHARMACOGENETIC DATA ANALYSES...........................................................41 
18. 
VIRAL GENOTYPING/PHENOTYPING ................................................................42 
19. 
REFERENCES ...........................................................................................................43 
20. 
ATTACHMENTS .......................................................................................................44 
20.1. 
Table of Contents for Data Display Specifications ....................................................44 
20.1.1. 
Planned Data Listings .................................................................................................44 
20.2. 
Planned Summary Tables ...........................................................................................46 


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LIST OF TABLES 
Table 1: 
List of Abbreviations ....................................................................................................7 
 


Vaccitech Ltd 
 
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Statistical Analysis Plan 
 
Final Version 2.0, 01Jan2020 
 
7 
 
 
  
 
1. 
LIST OF ABBREVIATIONS 
 
Table 1: 
List of Abbreviations 
Abbreviation 
Term 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
BMI 
Body Mass Index  
CI 
Confidence Interval 
CNS 
Clinical Network Services Pty Ltd 
CRF 
Case Report Form 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
DMC 
Data Monitoring Committee  
eCRF  
Electronic Case Report Form  
ELIspot 
IFN-γ Enzyme Linked Immunospot 
GMC 
Geometric Mean Concentration  
ICH 
International Conference on Harmonization 
ICS 
Intracellular Cytokine Staining 
ILI 
Influenza-like Illness 
ISR 
Injection Site Reactions 
MedDRA  
Medical Dictionary for Regulatory Activities  
MMRM 
Mixed Model for Repeated Measures 
NCS 
Not Clinically Significant 
PFU 
Plaque Forming Units 
PT 
Preferred Term 
QIV 
Quadrivalent Influenza Vaccines 
RR 
Relative Risk 
RT-PCR 
Reverse Transcription Polymerase Chain Reaction 
SAE  
Serious Adverse Event  
SAP 
Statistical Analysis Plan 


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Abbreviation 
Term 
SD  
Standard Deviation  
SFU 
Spot Forming Units 
SOC 
System Organ Class 
SOP  
Standard Operating Procedure  
TEAE  
Treatment Emergent Adverse Event  
VE 
Vaccine Efficacy 
WHO-DD 
World Health Organization Drug Dictionary 


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2. 
SUMMARY OF UPDATES FROM SAP FINAL VERSION 1 
(21NOV2019) 
 
• Futility analysis at interim analysis has been updated by following a non-binding 
conditional power approach.  
• Sample size re-estimation at interim analysis will be conducted as proposed by protocol. 
• Other editorial changes to clarify the text. 
 


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3. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) is an adjunct to the Vaccitech Ltd Protocol FLU009. This 
SAP outlines the FLU009 study and describes the methods for the analysis of the data arising 
from this clinical trial. This document is mainly based on the statistical section of the study 
protocol (Final Version 3.0, 20May2019). Therefore some sections are described briefly, and 
references are made to the related sections in the protocol. The analyses outlined in this 
document, if different from the protocol, will supersede those specified in the protocol. 
The structure and content of this SAP aim to provide sufficient detail to meet the requirements 
described by CNS Standard Operating Procedure CNSSOPBMT002_V001: Statistical Analysis 
Plan, and the International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH): Guidance on Statistical Principles in 
Clinical Trials. 
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 Quadrivalent Influenza Vaccines (QIV).  
 


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4. 
STUDY OBJECTIVE(S) AND ENDPOINT(S) 
4.1. 
Study Objective(s) 
4.1.1. 
Primary Objective 
The primary objective of the study is: 
• 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  
4.1.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• 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 
• To assess the immunogenicity of MVA-NP+M1 when given as an adjunct to licensed 
QIV in adults aged 18 years and over 
4.2. 
Study Endpoint(s) 
4.2.1. 
Primary Endpoint 
The primary endpoint of the study is: 
• Incidence rate of laboratory confirmed influenza using reverse transcription 
polymerase chain reaction (RT-PCR) on deep nasal/mid-turbinate swab samples 
4.2.2. 
Secondary Endpoints 
The secondary endpoints of the study are: 
• Incidence and severity of influenza-like illness (ILI) 
• Duration of ILI 
• Occurrence of solicited local and systemic reactogenicity signs and symptoms for 7 
days following vaccination 
• Occurrence of SAEs during the whole study duration 
• Frequency of influenza-specific T-cells measured by IFN-γ/granzyme B ELISpot 
• Geometric mean titre of influenza-specific neutralising antibodies 


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5. 
STUDY DESIGN 
5.1. 
Design Information 
As mentioned above, 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 will consist of a screening/vaccination visit and a follow-up period: 
• Screening/Vaccination visit: In this visit, potential participants will be identified for study 
eligibility. Following screening and confirmation of eligibility on Day 0, all participants 
will be randomised in a 1:1 ratio to receive MVA-NP+M1 or placebo, which will be 
administered by intramuscular injection.  
• Follow-up period: This period is from Day 1 to the end of the influenza season. In the 
follow-up period, participants will: 
➢ record oral temperature and any solicited adverse events for 7 days post-
vaccination  
➢ record unsolicited adverse events for 28 days post-vaccination 
➢ record 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.  
➢ receive two nasal swabs, within 72 and 96 hours of respiratory/ILI symptom 
onset, for laboratory to confirm influenza using RT-PCR  
The majority of participants will participate in the main cohort of the study. 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 for the main cohort, the immunogenicity 
cohort will attend three additional clinic visits on Days 7 (+3 days) and 28 (±7 days) and Week 
26 (±1 week) (approximate end of the influenza season).   
For both main and immunogenicity cohorts, to accommodate the timing of vaccination in the 
influenza season, slightly different follow-up procedures are outlined for: 
• 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: Not required to 
complete the eDiary in the period after Day 28 until 01 May, otherwise as normal. 


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• 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: required to complete the 
eDiary for the study period as normal. 
The treatment groups and number of study participants are as follows: 
 
 
Data Monitoring Committee 
The study will be subject to oversight by a Data Monitoring Committee (DMC). The DMC will 
review the study safety data and make recommendations concerning the continuation, 
modification, or termination of the study. According to protocol, a DMC will hold following 
meetings: 
• 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), 
• Perform unscheduled review of data if one of the study pausing or holding rules is met. 
 
This study is not a group sequential design, with no formal stopping rules set up for efficacy. The 
futility analysis is informal and is for information only. It should not impact the overall type I 
error control at the final analysis. 
 
5.2. 
Definition of Study Drugs 
MVA-NP+M1 is the investigational study vaccine. On day 0, each participant will receive a 
single dose of 
• 1.5 x 108 plaque forming units (pfu) MVA-NP+M1 or 
• 0.5 mL 0.9% saline placebo 
 


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5.3. 
Sample Size Considerations 
5.3.1. 
Sample Size Justifications 
Various disease incidence rates in the control arm, relative vaccine efficacy in the MVA-NP+M1 
arm, and alpha levels (two-sided) were assumed for the sample size calculation. Sample sizes 
based on various scenarios are provided as follows: 
 
All calculations assumed 80% power. Given this is a proof of concept study, an alpha of 0.1 
(two-sided test) was 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.  
5.3.2. 
Sample Size Re-estimation 
After the first influenza season, which will enrol approximately 2,200 participants, a sample size 
recalculation will be performed on the basis of the observed relative vaccine efficacy of MVA-
NP+M1 during the first influenza season, as well as the observed rates of influenza within each 
treatment group  
5.4. 
Randomization 
Eligible participants will be randomised to the study based on a randomisation schedule managed 
by IBM Clinical Development. The randomisation schedule will be prepared by an independent 
statistician not involved in the study. Participants will be randomised on Day 0 after informed 
consent has been provided and eligibility confirmed. 


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Participants in the main cohort will be stratified by age <65 years and ≥65 years 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.  
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. 
 
 


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6. 
PLANNED ANALYSES 
6.1. 
Interim Analyses 
FLU009 was not designed as a group sequential trial. Therefore, no formal interim stopping 
boundaries for efficacy have been established. However, 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 review cumulative safety and efficacy data from the first influenza season. This 
review of safety and efficacy data will also  include a futility analysis, as well as a  sample size 
recalculation based on the observed relative vaccine efficacy in the MVA-NP+M1 vaccine 
group. Plans for the futility analysis and sample size recalculation will be established a priori 
(prior to any unblinding of study data) and are described below. . The study will not be stopped 
for efficacy at the interim analysis because no stopping rule was set up for this purpose. 
All unblinded-by-group summaries will be prepared for the DMC by an independent 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 charter. 
 
Futility Analysis 
The futility analysis will be conducted using a Conditional Power (CP) approach, with various 
assumptions of the final sample size to be recruited at the end of study. A final sample size of 
6000, 6500, 7000, or a final sample size based on sample size recalculation will be assumed for 
the purpose of conditional power calculation. 
Given the first influenza season resulted in a relatively high number of virologically-confirmed 
cases of influenza, investigators anticipate the second influenza season will be somewhat milder 
than the first. Therefore, various assumptions for vaccine effect in the next influenza season will 
be made under each of the final sample size assumptions. CP will be calculated for the following 
scenarios: 
a. CPT – Conditional power under the current trend (i.e., observed relative VE following 
season 1) 
b. CPD – Conditional power under the original design (i.e., influenza incidence for MVA-
NP+M1: 1.56%, and for placebo: 2.4%) 
c. CPN – Conditional power under the null hypothesis (i.e., influenza incidence for MVA-
NP+M1: 2.4%, and for placebo: 2.4%) 
d. CP80LB – Conditional power under the lower bound of the 80% CI of the current trend 


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e. CPHF – Conditional power under influenza case accrual in the second season being 
approximately half of that observed in the first influenza season (i.e., pooled influenza 
incidence during Season 2 is approximately 0.8%). Other influenza incidence rates in the 
second season for both groups could be assumed as well.  
The calculation of CP will follow the approach proposed by Jennison  and Turnbull (2000). CP is 
a predictive power, and is used as a non-binding guide to stop the study for futility. When the 
final decision of DMC is made, CP and the totality of data for efficacy and safety at IA need to 
be considered.  
Refer to the DMC charter for guidelines relating to the interpretation of these calculations and 
the resulting recommendations to the Sponsor. 
 
Sample Size Recalculation 
A sample size recalculation will be performed on the basis of the observed relative vaccine 
efficacy and the observed incidence rates of influenza within each treatment arm following the 
first influenza season. This calculation will be based on an alpha of 0.10 significance level (two-
sided test) and 80% power, and the results will be shared with the DMC at the time of the interim 
analysis. 
Refer to the DMC charter for guidelines relating to the interpretation of these calculations and 
the resulting recommendations to the Sponsor. 
 
6.2. 
Final Analysis 
The final analysis of the study will be conducted once all participants have completed the study, 
the clinical database has been locked, and randomisation has been unblinded. All planned 
analyses to be conducted at the final analysis will be included within the SAP, which will be 
finalized prior to database lock. 
 


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7. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING 
7.1. 
General Summary Table and Individual Subject Data Listing 
Considerations 
Summary tables and listings will be prepared according to ICH Guideline E3 (as appropriate for 
a phase II study).  
In general, summary tables will be organized with respect to the vaccination groups. The 
summary tables will clearly indicate the number of participants to which the data apply and 
unknown or not performed are distinguished from missing data. Summary tables for any 
concomitant medications will be coded according to the latest available version of World Health 
Organization Drug Dictionary (WHO-DDE). Adverse event preferred terms and body/organ 
systems and medical history conditions will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA®) dictionary version 20.1 (or higher). The WHO-DDE and MedDRA 
version numbers used for coding will be reported in the outputs. 
Listings will also be sorted by vaccination group, subject number and visit date/time. 
In general, missing data will not be imputed unless otherwise specified. Any imputed or derived 
data will be flagged in the individual participant data listings. Imputed data will not be 
incorporated into any raw or primary datasets. These data will be retained in derived analysis 
datasets. 
7.2. 
General Post Text Summary Table and Individual Subject Data 
Listing Format Considerations 
The tables, figures and listings will be numbered using a decimal system to reflect main levels of 
tables and listings (e.g., Table XX.YY.ZZ. …). 
1. The first level number will be consistent with the corresponding Clinical Study Report 
(CSR) appendix in which the tables or listings will appear. For example, the post text 
tables will appear in Appendix 14 (and will be numbered 14.XX.YY) and the individual 
participant data listings will appear in Appendix 16 (and will be numbered 16.XX.YY). 
The participant disposition table will be first in the first section of the report and will be 
numbered Table 14.1. The supportive participant data listing will be Listing 16.1. Any 
subset table will have the number Table 14.1.2, etc. 
2. Table numbering will follow ICH E3 for CSRs. Participant disposition, baseline 
characteristics and demography, and prior and concomitant medications tables should 
appear as the second level number (Table 14.1 series). Efficacy tables will occupy the 
next sub-level (Table 14.2 series). Safety tables will follow next (Table 14.3 series). 
Similar conventions will be applied to the participant data listings. 


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3. Each table and listing title will be complete, accurate and concise. The last line of the title 
will provide the analysis group being summarised (e.g., Safety Population, etc.). 
4. If possible, variables being summarised and statistics reported will appear in the left most 
column of a table. The next columns for vaccination groups should report the data from 
left to right for the vaccination group (MVA-NP+M1 and Placebo) respectively. 
7.3. 
Data Management 
All data will be recorded by the site in individual source documents. An electronic Case Report 
Form (eCRF) will be created by the data management group for recording of the required data in 
the study database. All eCRF information is to be filled in by site staff. If an item is not available 
or is not applicable, this fact should be indicated. Blank spaces should not be present unless 
otherwise directed.  
The study monitor will perform source data verification of data entered into the eCRF and raise 
queries for correction by the site. The data entered into the eCRF will be subject to data 
validation checks for consistency and completeness by the data management group. Data queries 
will then be generated and sent to the investigational site for response before the database is 
locked and released for statistical analysis. 
Data storage, data transfer and data cleaning will be conducted according to the relevant CNS 
Standard Operating Procedures (SOPs). 
7.4. 
Data Presentation Conventions 
Continuous safety variables (e.g., clinical laboratory values and vital signs) will be reported to 
the same precision as the source data. Derived variables will be reported using the same 
precision as the value(s) from which they were derived. For the reporting of descriptive statistics, 
the mean and median will be reported to 1 decimal place more than the source data; the 
minimum and the maximum values will be presented to the same precision as the source data and 
standard deviations (SD) will be reported to 2 decimal places more than the source data.  
For categorical/discrete variables, the frequency count and the percentage (of available data) for 
each class of the variable will be presented and will be displayed in the form XX (XX.X%) 
where the percentage is in the parentheses. When there is no data for a category, the result will 
be presented as 0. 
Date variables will be formatted as DDMMMYYYY for presentation. Time will be formatted in 
military time as HH:MM for presentation. 
Extra measurements (such as unscheduled or repeat assessments) will not generally be included 
in summary tables but will be included in participant listings. They may be used if a scheduled 
measurement is missing and the timing of the extra measurement is deemed suitable. They will 
be used in summary tables which are not ‘time specific’, for example, summaries of maximum 
post vaccination values. In the data listings and summary tables presented as part of the CSR, 


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scheduled assessments will be identified by the protocol specified nominal visit day and 
scheduled time point. 
The table, figures and listing shells as part of this SAP provide the expected layout and titles of 
the tables, figures and listings. Any changes to format, layout, titles, numbering, or any other 
minor deviation will not necessitate a revision to the SAP nor will it be considered a deviation 
from planned analyses. Only true differences in the analysis methods or data handling will 
necessitate such documentation. The appropriate listings supporting the tables will be included 
and are not specified in the individual sections throughout the document. 
Minor modifications may be necessary to the planned design of tables, listings and figures to 
accommodate data collected during the actual study conduct. Any major deviations from the 
final approved SAP (e.g., change in the population used, change from statistical 
method/assumption listed, transformation of data type [e.g., continuous data transformed to 
categorical], exclusion of planned analysis, etc.) or additional unplanned analyses will be 
documented (with justification) in the CSR. 
7.5. 
Analysis Populations 
Four different analysis populations will be defined: Safety Analysis Set, Efficacy Analysis Set 
Immunology Analysis Set, and All Randomised Analysis Set. Participant inclusion into each 
population will be determined after database lock and prior to the randomisation unblinding. 
7.5.1. 
Safety Analysis Set 
The Safety Analysis Set will consist of all randomised participants who received at least one 
vaccination (according to the vaccination actually received). The safety population will be used 
for all safety endpoint analysis. 
7.5.2. 
Efficacy Analysis Set 
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 Efficacy Analysis 
Set will be used for the analyses of demographics, baseline, prior and concomitant medications, 
and all efficacy endpoints. This is the main analysis population for efficacy endpoints. 
7.5.3. 
Per Protocol Analysis Set 
The Per Protocol Analysis Set will consist of all randomised participants who received the study 
vaccine, had follow-up for respiratory illness and/or influenza-like illness (ILI) during the 
influenza season, and did not have major protocol violation/deviation. The Per Protocol Analysis 
Set will be used for the analyses of all efficacy endpoints, and results based on Per Protocol 
Analysis Set will be used as supportive evidence to Efficacy Analysis Set. 
 


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7.5.4. 
Immunology Analysis Set 
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. 
The Immunology Analysis Set will be used for the analysis of all immunogenicity endpoints. 
7.5.5. 
All Randomised Analysis Set 
The All Randomised Analysis Set will consist of all randomised participants regardless of 
whether the participant received the study vaccine or not. The All Randomised Analysis Set will 
be used for the analysis of participant disposition. 
7.6. 
Baseline Definition 
Baseline will be defined as the last available, non-missing observation prior to the vaccination, 
unless specifically mentioned otherwise. 
In general, Unknown, Not Done, Not Applicable and other classifications of missing data will 
not be considered when calculating baseline observations. However, valid categorical 
observations will be considered for baseline calculations. In addition, non-missing results from 
unscheduled assessments prior to the vaccination may also be considered in the calculation of 
baseline observations. 
7.7. 
General Derived and Transformed Data 
7.7.1. 
Age 
Age, in completed years, at screening will be defined as: 
Age (years) = integer value ((Date Signed Informed Consent – Date of Birth + 1) / 365.25) 
7.7.2. 
Study Day 
Study day will be calculated using the vaccination date as the reference date. If the date of 
interest occurs on or after the vaccination date, then study day will be calculated as (date of 
interest – date of vaccination). If the date of interest occurs prior to the vaccination date, then 
study day will be calculated as (date of interest – date of vaccination). The day of vaccination 
will be identified as Study Day 0 in data analysis according to protocol. In CDISC standard, 
however this is Study Day 1, which will not be followed.  
Data listings will present study days in addition to assessment dates, where applicable.  
7.7.3. 
Change from Baseline 
Actual change from baseline will be calculated as (post-baseline result – baseline result). 


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Percent change from baseline will be calculated as (actual change from baseline/baseline result)* 
100. 
7.7.4. 
Other Derivations 
Body Mass Index (kg/m2, to one decimal place) = Body Weight (kg) / (Height2 (m)). 
Treatment emergent adverse events (TEAEs) will be defined as AEs which commence on or 
after the time of start of vaccination. AEs without an onset date or time will be defined as 
treatment emergent except if an incomplete date (e.g., month and year) clearly indicates that the 
event started prior to start of vaccination or if the AE stop date indicates that the event started 
and/or stopped prior to start of vaccination. 
Duration of AE (in hours, to one decimal place) = (AE Resolution Date/Time) - (AE Onset Date/ 
Time). 


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8. 
TREATMENT COMPARISONS 
8.1. 
Data Display Treatment and Other Sub-Group Descriptors 
For data listings, Main and Immunogenicity cohorts will be listed separately for clarity. For the 
summary tables of efficacy and safety analyses, where applicable, data from both cohorts will be 
pooled together for the summary. 
The following labels for vaccination groups will be used on all listings, in the following order: 
• MVA-NP+M1/Main 
• Placebo/Main 
• MVA-NP+M1/Immunogenicity 
• Placebo/ Immunogenicity 
The following labels for vaccination groups will be used on all tabulations and plots, in the 
following order: 
• MVA-NP+M1 
• Placebo 
. 
 
 
 


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9. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
The listings, figures and summary tables for the disposition, safety, efficacy and immunogenicity 
data will be the responsibility of the study Biostatistician at CNS. 
The currently supported version (9.4 or higher) of SAS software will be used to perform all data 
analyses. The actual SAS version used will be presented in the Clinical Study Report. 
All data in the database will be presented in the data listings. Unless otherwise stated, all listings 
will be sorted by vaccination group, participant number and assessment date/time. 
Unless otherwise stated, continuous variables will be summarised using descriptive statistics 
including number of non-missing observations, mean, standard deviation (SD), median, 
minimum and maximum values. Categorical variables will be summarised with frequency counts 
and percentages. The population size (N for sample size and n for available data) and the 
percentage (of available data) for each class of the variable will be presented. Percentages will be 
rounded to one decimal place, with the denominator being the number of participants in the 
relevant population, unless otherwise stated. 
Only data from nominal protocol scheduled visits will be included in the summary tables. Data 
from unscheduled visits will not be included in the summary tables but will be included in the 
figures and listings. 
All statistical tests, if conducted, will be two-sided and statistical significance will be determined 
at the 0.05 level, unless otherwise stated. 
9.1. 
Multicentre Studies 
Vaccine efficacy by study sites will be assessed separately as a subgroup analysis. 
9.2. 
Other Strata and Covariates 
Not applicable for this study. 
9.3. 
Examination of Subgroups 
Vaccine efficacy for age<65 years and age ≥65 years will be assessed separately as subgroup 
analysis. 
9.4. 
Multiple Comparisons and Multiplicity 
No multiplicity adjustment will be performed unless otherwise stated. 


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9.5. 
Data Handling Conventions 
9.5.1. 
Premature Withdrawal and Missing Data 
For participants who are withdrawn from the study prior to study completion, all data compiled 
up to the point of discontinuation will be used for analysis. All withdrawals will be included in 
all analyses up to the time of withdrawal. 
There will be no imputation for missing data, unless otherwise stated. Adverse events with 
missing or partial dates will be handled such that in the absence of contradictory information an 
AE is treatment emergent. 
9.5.2. 
Handling of Dropouts 
All data collected prior to drop out will be listed and included in data summaries. 
9.5.3. 
Additional/Unscheduled Assessments  
Extra measurements (such as unscheduled or repeat assessments) will not generally be included 
in summary tables but will be included in participant listings. They may be used if a scheduled 
measurement is missing and the timing of the extra measurement is deemed suitable. They will 
be used in summary tables which are not ‘time specific’; for example, summaries of maximum 
post dosing values. 
The original data will always be presented in the listings.  
9.5.4. 
Assessment Windows 
No derived visit windows will be applied to assessments. All assessments will be included in the 
listings. Protocol specified nominal visit names will be used for the analyses. For vaccine 
efficacy, all clinical events happened during the influenza season, starting on 01 May and ending 
on or before 15 October in line with official Australian influenza season, will be included for the 
analysis. 
9.6. 
Derived and Transformed Data 
The required endpoints and variables will be derived by the Statistical Programmers at CNS 
using the derivations specified in Section 7.7 of this SAP. 


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10. 
STUDY POPULATION 
All disposition analyses will be conducted on the All Randomised Analysis Set. Baseline and 
demographic analyses will be conducted on the Efficacy Analysis Set. All summaries will be 
presented by vaccination group and overall. 
10.1. 
Disposition of Subjects 
A disposition listing will present date of informed consent, randomization, study completion or 
withdrawal, the reason for withdrawal, if applicable, and whether included in each analysis 
population, for each participant. 
A listing of whether or not all inclusion and exclusion criteria were met and if not, which criteria 
were not met, by participant, will also be presented. 
The following will be summarised, by vaccination group and for all participants: 
• The number of participants randomised overall and by study site 
• The number of participants followed during the influenza season overall and by study 
site 
• Number of participants completed the study 
• Number of participants withdrawn and primary reason for withdrawal 
• Number of participants in each analysis population 
10.2. 
Protocol Deviations 
Participant data will be examined for evidence of protocol deviations in order to assess how well 
the protocol was followed. These will be assessed prior to the unblinding of the study. 
Participants with major protocol deviations may be summarised if these CRF data are available. 
The sponsor will review all protocol deviations that are recorded and will identify those that are 
deemed to be major protocol deviations. 
All protocol deviations will be detailed in listings. 
10.3. 
Demographic and Baseline Characteristics 
All baseline and demographic data recorded at Screening/Vaccination visit and prior to the 
vaccination will be listed. 
Participant demographic and baseline variables (age, sex, childbearing potential, post 
menopausal status, ethnicity, race, height, body weight, BMI and body temperature) will be 
summarised by vaccination group.  
Medical history at Screening/Vaccination visit will be listed only. 


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10.4. 
Vaccine Administration  
All vaccine administration data will be listed based on available data reported from CRF. 
10.5. 
Prior and Concomitant Medications 
The start dates of non-investigational medications will be used to assign medications into 
different categories. 
• Prior medication: Any medication which started and ended before the time of vaccine 
administration. If the start date of the medication is not complete or missing, it will be 
treated as prior medication. 
• Concomitant medication: Any medication which ended on or after the time of vaccine 
administration or still ongoing at the final visit or at the premature study withdrawal. 
Medications will be classified as a prior medication or a concomitant medication. There is no 
overlapping between these two. If a medication has a missing or partial missing start/end date or 
time and it cannot be determined whether it ended before or after the time of vaccine 
administration, it will be considered as prior medication. 
Prior and concomitant medications will be coded by WHO-DDE latest available version. Data 
will be summarised by Anatomical Therapeutic Chemical (ATC) system (Level 2) and drug 
preferred name. The summary tables will show the number and percentage of participants taking 
each medication by ATC Level 2 and preferred name. 
For the summaries of prior and concomitant medications, participants who take the same 
medication (in terms of the ATC Level 2 and preferred name) more than once will only be 
counted once for that medication. 
In the summary tables, prior medication and concomitant medications will be presented by 
decreasing frequency of total medications overall within each ATC class and then similarly by 
decreasing frequency of total medications overall within each preferred name. In cases of ATC 
classes or preferred names with equal frequencies, medications will be sorted alphabetically. 
Prior medication and concomitant medications will be listed and summarised, separately, by 
vaccination group. 


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11. 
EFFICACY ANALYSES 
The primary efficacy endpoint is the incidence rate of laboratory confirmed influenza using 
reverse transcription polymerase chain reaction (RT-PCR) on deep nasal/mid-turbinate swab 
samples. The secondary efficacy endpoints are: 
• Incidence and severity of influenza-like illness (ILI) 
• Duration of ILI 
All efficacy analyses will be conducted on the Efficacy and Per Protocol Analysis Sets, and all 
efficacy data will be listed. Efficacy data will be analysed separately for overall participants, age 
<65 years and age ≥65 years, and by study site.  
 
Incidence rate of laboratory confirmed influenza using RT-PCR 
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. If participants experience any influenza 
symptom(s), participants should attend the clinic on two occasions, the first as soon as possible 
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. Participants with laboratory confirmed 
influenza using RT-PCR will be defined as the influenza positive cases, otherwise they will be 
defined as influenza negative cases. Some participants might have confirmed RT-PCR data from 
hospital or general practitioner visits within the influenza season. These data, if available, will be 
included in the analysis.  
The incidence rate of laboratory confirmed influenza using RT-PCR will be estimated for each 
vaccine group. The 95% CI for the incidence rate will be estimated by mid-p exact method. The 
90% CI and 85% CI will be estimated as well based on the same method. The difference in 
incidence rate between vaccine groups will be compared by Fisher’s exact method. 
Vaccine efficacy (VE) will be estimated as: 
VE (%) =100*(1-RR), where RR is the relative risk of confirmed influenza between MVA-
NP+M1 and placebo. The RR and its 95% CI (90% CI and 85% CI as well) will be estimated 
from a log binomial regression model. The log-binomial model might be less numerically stable 
than the logistic model or might fail to converge. For comparison purpose, the RR and its 95% 
CI (90% CI and 85% CI as well) will also be estimated from a Poisson regression with robust 
variance, which provides adequate correction for overestimation of standard error when binomial 
data are applied to Poisson regression. 


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The RR can also be approximated based on the hazard ratio between MVA-NP+M1 and placebo. 
Survival analysis will be used for the analysis of time to confirmed influenza as well. The time to 
confirmed influenza is defined as the duration (days) from vaccination to first confirmed 
influenza using RT-PCR during the influenza season. For the calculation of time to the first 
confirmed influenza, the time of  the first confirmed influenza swab will be used for the 
calculation (end date). Participants without confirmed influenza throughout the entire influenza 
season will be censored at the last day recorded with the ILI dairy. 
The survival function will be summarized for 25th percentile, median, and 75th percentile and 
their 95% CIs. The plot of Kaplan-Meier estimates for the two vaccine groups will be presented. 
The hazard (chance) of confirmed influenza will be compared between MVA-NP+M1 and 
placebo by a Cox regression. The hazard ratio and its 95% CI (90% CI and 85% CI as well) will 
be estimated.     
 
Incidence and severity of influenza-like illness (ILI) 
ILI is defined as feeling feverish or having a fever (feeling feverish or having a fever 
(temperature ≥37.8 C)) and at least one of the following symptoms: cough, sore throat. ILI 
positive cases will be derived from daily ILI diary.  
Similar analysis methods, as above for the incidence of laboratory confirmed influenza, will be 
used to estimate ILI incidence rate and 95% CI for each vaccine group. Rate difference between 
MVA-NP+M1 and placebo will be compared by Fisher’s exact method. The relative risk and its 
95% CI will be estimated from a log-binomial model and a Poisson regression model with robust 
variance. 
The following symptoms will be recorded on daily ILI diary   
• Feeling hot  
• Temperature (use direct reading for AUC calculation) 
• Cough 
• Sore throat 
• Blocked nose 
• Chest pain 
• Muscle aches 
• Shortness of breath 
with their severities (score) recorded as 
• Not Present (0) 


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• Mild (1) 
• Moderate (2) 
• Severe (3) 
For each symptom, the severity score as above will be used to calculate the area under the curve 
(AUC), along with the calendar day, for the entire influenza season (01 May to 15 October) by 
following trapezoidal rule. All the ILI diary records during the influenza season will be used for 
the analysis. If ‘Have you experienced any Influenza Like Symptoms today?’ is answered as 
‘No’, then all the above symptoms will be treated as ‘Not Present (0)’ and body temperature 
treated as 37°C for AUC calculation purpose. Participants could be followed for varying days in 
the influenza season, therefore the AUC will be time weighted to 168 days: 
Time weighted AUC=((raw AUC [time in days])/(number of days used for analysis)) * 168 
The nonparametric comparison method of Wilcoxon rank-sum test (also named as Mann-
Whitney U test) will be used to compare the time weighted AUC between MVA-NP+M1 and 
placebo. The time weighted AUC will also be logarithm transformed, and the logarithm 
transformed time weighted AUC will be compared between MVA-NP+M1 and placebo by using 
an Analysis of Variance (ANOVA) model. The estimated least squares means from ANOVA 
will be anti-log transformed to obtain the geometric mean, and the geometric mean ratio of the 
time weighted AUC and its 95% CI will also be estimated between MVA-NP+M1 and placebo.   
Duration of ILI 
ILI duration analysis is only applicable for ILI positive participants. The duration of ILI is 
defined as the duration (days) from the first day ILI criteria met (as defined above) until the first 
day afterwards ILI criteria not met (event, ILI recovery). ILI positive participants with ILI 
criteria met throughout the entire influenza season will be censored at the last day recorded with 
the ILI dairy.  
Survival analysis will be used for the analysis of duration of ILI. The survival function for 
duration of ILI will be estimated by the Kaplan-Meier method. The survival function will be 
summarized for 25th percentile, median, and 75th percentile and their 95% CIs. The plot of 
Kaplan-Meier estimates for the two vaccine groups will be presented. The hazard (chance) of ILI 
recovery (ILI criteria not met) will be compared between MVA-NP+M1 and placebo by a Cox 
regression. The hazard ratio and its 95% CI will be estimated.     


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12. 
SAFETY ANALYSES 
All safety analyses will be conducted on the Safety Analysis Set. 
All safety summaries will be provided by vaccination group. Data for AEs, SAEs, clinical 
laboratory parameters, and physical examinations will be presented by participant listings 
(including assessments of abnormality and clinical significance, where applicable). Summaries 
will be prepared for key variables (detailed below) by protocol specified time-point (where 
applicable). 
No inferential statistical testing will be performed for safety variables. 
12.1. 
Adverse Events 
Adverse events include unsolicited adverse events and solicited adverse events. Unsolicited 
adverse events are events meeting the criteria for adverse events apart from those the participant 
is specifically asked about. 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. The solicited local injection site reactions (ISR) 
include pain, induration, warmth, and erythema (redness). The solicited systemic reactions 
include feverishness, chills, myalgia, fatigue, headache, nausea, arthralgia, and malaise. 
These solicited AEs are sourced from ‘7 Day Diary’ CRF pages.  
Unsolicited non-serious adverse events will be collected for 28 days post-vaccination. 
Hospitalisations, other serious adverse events and or adverse events of special interest will be 
collected for the duration of the influenza season. Solicited adverse events, including solicited 
local injection site reactions (ISR) and solicited systemic reactions, will be collected for 7 days 
post-vaccination. These will be recorded daily in the eDiary for all participants. 
Adverse events will be coded using MedDRA® (latest available version). Adverse events will be 
grouped by system organ class (SOC) and preferred term (PT), and summarised by actual 
vaccination group at time of onset of the AE. The summary tables will present the frequency and 
percentage of total participants and number of events, by system organ class and by preferred 
term. For the summaries of AEs, participants who experience the same AE (in terms of the 
MedDRA PT) more than once will only be counted once for that event in the number of 
participants, but all occurrences of the same event will be counted in the number of events. 
All AE summaries will be restricted to TEAEs only. Treatment emergent events are defined as 
AEs which commence on or after the time of vaccine administration through to the end of the 
study. AEs without an onset date or time will be defined as treatment emergent except if an 
incomplete date (e.g., month and year) clearly indicates that the event started prior to start of 
vaccine administration or if the AE stop date indicates that the event started and/or stopped prior 
to start of vaccine administration. 


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For any AEs with a missing or unknown severity, relationship to vaccination or outcome, a 
worst-case scenario will be implemented. Any AEs with a missing or unknown severity will be 
considered as severe in the summary tables. Similarly, any AEs with a missing or unknown 
relationship to vaccination will be considered related to vaccine in the summary tables. Further, 
any AEs with a missing or unknown outcome will be considered as fatal in the summary tables. 
Incidence of AEs as well as the duration, severity, relationship to vaccination, outcome and 
action taken will be listed for each participant. In addition, listings of solicited local injection site 
reactions (ISR) and solicited systemic reactions, AEs leading to discontinuation of the study, 
SAEs and deaths, will be provided if applicable.  
The following AE summaries will be provided: 
• Overall summary of TEAEs 
➢ Any solicited local injection site reaction  
➢ Any severe solicited local injection site reaction  
➢ Any solicited systemic reaction 
➢ Any severe solicited systemic reaction 
➢ Any TEAE 
➢ Any severe TEAE 
➢ Any TEAE considered as related to vaccination (evaluated by the investigator as 
related to vaccination) 
➢ Any serious TEAE 
➢ Any TEAE leading to vaccine withdrawal 
➢ Any TEAE leading to discontinuation from study 
➢ Any TEAE leading to death 
• Solicited local injection site reactions (ISR)  
• Solicited local injection site reactions (ISR) by severity  
• Solicited systemic reactions  
• Solicited systemic reactions by severity  
• TEAEs overall by SOC and PT 
• TEAEs overall  by severity and by SOC and PT 
• TEAEs overall  by relationship to vaccine and by SOC and PT 
• Treatment-related TEAEs overall by severity and by SOC and PT 


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• Serious TEAEs overall by SOC and PT  
• TEAEs overall leading to discontinuation from study by SOC and PT 
• TEAEs overall leading to death 
In the summary tables, AEs will be presented by decreasing frequency of total events overall 
within each SOC and then similarly by decreasing frequency of total events overall within each 
PT. SOCs or PTs with equal frequencies will be sorted alphabetically. 
12.2. 
Deaths and Serious Adverse Events 
Incidence of SAE’s as well as the duration, severity, relationship to vaccination, outcome and 
action taken will be listed for each participant and summarised by vaccination group with 
frequency counts by SOC and PT. 
Deaths, if any, will be listed with primary cause of death. 
12.3. 
Adverse Events Leading to Discontinuation of Investigational 
Product and/or Withdrawal from the Study 
Incidence of AE’s leading to vaccine withdrawal or discontinuation from study, as well as the 
duration, severity, relationship to vaccination, outcome and action taken will be listed for each 
participant and summarised by vaccination group with frequency counts by SOC and PT. 
12.4. 
Clinical Laboratory Evaluations 
Laboratory safety tests will be performed for participants in the immunogenicity cohort only at 
pre-vaccination Day 0, Day 7 and Day 28. 
All individual clinical laboratory results (haematology and biochemistry) will be presented in 
data listings. Values outside the laboratory reference range will be flagged (low-L, high-H). 
Actual values and actual change from baseline for clinical laboratory data will be summarised at 
each protocol scheduled time point, by vaccination group. Box plots will be generated as well to 
present the observed and change from baseline values for each laboratory parameter. Frequency 
tabulations of the number of normal and abnormal (low and high) records, as well as the number 
of clinically significant (CS) and not clinically significant (NCS) (if data available) will also be 
summarised at each protocol scheduled time point, by vaccination group. Shift table of 
laboratory data from baseline to protocol defined post dosing visits will be summarised as well.     
Haematology data to be collected are: full blood count, haemoglobin, haematocrit, erythrocytes, 
mean cell volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin 
concentration, leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils and 
platelets. 


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Biochemistry data to be collected are: sodium, potassium, urea, creatinine, albumin and liver 
function tests (alanine transaminase, alkaline phosphatase and bilirubin). 
12.5. 
eDiary Data 
eDiary is used to 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). Unsolicited adverse events (all adverse events up to Day 28; hospitalisations 
and other SAEs only thereafter) and concomitant medications will also be collected through the 
eDiary. All participant diary data will be presented in data listings. 
Diary reported ISRs will be summarised at each protocol scheduled time point, by vaccination 
group, using descriptive statistics. ISR by severity will be summarised as well. If a participant 
reported multiple injection sites at one scheduled time point, then any positive finding from any 
injection sites will be used for the frequency summary. The maximum redness (mm) and 
maximum skin thickening (mm) of all injection sites will be used for the summary analysis. 
12.6. 
Other Safety Measures 
All pregnancy test data and physical examination data will be listed. 


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13. 
IMMUNOGENICITY ANALYSES 
Samples for immunogenicity analysis will only be taken from participants in the 
immunogenicity cohort at Day 0, Day 28 and Week 26. Immunological and immunogenicity 
parameters include: 
• IFN-γ and GzmB enzyme linked immunospot (ELIspot) assay  
• Immune response determined by Intracellular Cytokine Staining (ICS) assay  
All immunogenicity analyses will be conducted on the Immunology Analysis Set. All 
Immunological and immunogenicity data will be listed.  
In ELIspot, adjusted Spot Forming Units (SFU) per million (106) PBMCs (peripheral blood 
mononuclear cells) after background (dimethyl sulfoxide, DMSO) subtraction will be counted. 
For ICS assay, DMSO-subtracted cytokine response, as well as DMSO cytokine response will be 
collected. The cytokine response will be counted as the percentage CD4+ and CD8+ T cell 
response. The actual parameters depend on the final data reported from laboratory.   
 
ELISpot Assay 
ELISpot results will be evaluated in various ways to comprehensively understand the nature of 
cell-mediated immune responses following vaccination with MVA-NP+M1: 
• Descriptive summaries (univariate statistics) of response magnitudes 
• Assessing responder status 
• Evaluating magnitude of immune response with baseline response as a covariate 
With PBMC samples being evaluated using a double-color enzymatic (DCE) ELISpot assay, the 
analyses described below will be performed on both interferon-gamma (IFN-γ) and granzyme-B 
(GzmB) responses, with IFN-γ responses being the primary focus. 
 
Descriptive Summaries 
Univariate statistics (n, mean, SD, median, Q1, Q3, min, max) at each timepoint and changes 
from baseline, including 95% CI for the median based on order statistics, will be summarized for 
NP- and M1-specific DMSO-subtracted responses, Total (NP+M1) DMSO-subtracted responses, 
and DMSO (negative control) responses. Descriptive statistics for each stimulation antigen (NP, 
M1, NP+M1, and DMSO) will be calculated according to the average number of SFU per 
million PBMCs across all applicable wells. If the ELIspot data are reported in the unit of 250,000 
PBMCc/well, the number for SFU needs to be converted to the unit of per million (106) PBMCs 
by multiplying 4. 


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Dot plots of participant-level, NP-specific DMSO-subtracted responses, M1-specific DMSO-
subtracted responses, Total (NP+M1) DMSO-subtracted responses, and DMSO responses will be 
displayed graphically by timepoint. Results associated with a positive responder (definition in 
below section), a non-responder, and an unevaluable responder will be denoted by different 
symbols. Median responses and their associated 95% CI will also be plotted by study visit. 
 
Responder Status 
To determine a participant’s responder status at a given timepoint, ELISpot responses will be 
evaluated using the Permutation-based Resampling (PR) method (Hudgens et al., 2004). This 
approach can only provide statistically significant results when there is an adequate number of 
permuted outcomes. Therefore, in instances where results from only one negative control well 
(instead of two as planned) are available, responder status cannot be determined.  
A step-down permutation algorithm (Westfall and Young, 1993) is used by PR method to control 
the family wise error rate (FWER) when significant SFU difference between antigen and 
background is tested in order to identify responders. Briefly in a single step permutation, SFU for 
NP and M1 will be compared with SFU for DMSO (background) by using a t-test, and an actual 
unadjusted p-value will be calculated for each antigen (NP and M1). Then a permutation sample 
(re-randomisation sample) across all samples (NP, M1, and DMSO) will be formed. A pseudo p-
value will be calculated for each antigen in the same way as above based on the permutation 
sample. The minimal p-value of the pseudo p-values (p-values for NP vs DMSO and for M1 vs 
DMSO) will be taken as the minimal pseudo p-value. The permutation will be conducted for 
20,000 times. For each antigen, the permutation adjusted p-value is then computed as the 
proportion of times that the actual unadjusted p-value is greater than or equal to the minimal 
pseudo p-values. The above procedures are further adjusted by the step-down method to 
calculate the step-down permutation adjusted p-value to improve testing power while 
maintaining strong control of type I error. A participant is regarded as a responder for an antigen 
if the step-down permutation adjusted p-value is <0.05. The multiplicity adjustment by the step-
down permutation algorithm is only used to control the type I error when the responder is 
identified for one endpoint at one timepoint. The multiplicity between endpoint (IFN-γ and 
GzmB) and between visits (Day 28 and Week 26) is not further adjusted.  PR method is not 
applicable for Total (NP+M1) response because the assumptions of permutation test such as 
exchangeability and subset pivotality might not meet when samples are added and permuted with 
the original data (NP, M1 and DMSO).  
For each timepoint, the proportion of participants within each treatment group who have a 
positive responder status will be compared using Fisher’s Exact Test. Response rate 
(responder/non-responder) will be summarised at each protocol scheduled time point, by 
vaccination group, using frequency tabulations. Response rates will be calculated based on the 
number of participants with available data. The 95% CI for the response rate will be estimated by 


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mid-p exact method. A relative risk of response and its 95% CI will also be estimated between 
MVA-NP+M1 and placebo by a log binomial regression model. 
 
ANCOVA 
Many participants are expected to have baseline immune responses resulting from prior exposure 
to influenza. Therefore, a positive responder status at a post-baseline timepoint will not 
necessarily indicate the immune response came from vaccination with MVA-NP+M1; these 
immune responses will also need to be assessed in relation to the associated baseline response. 
Day 28 and Week 26 ELISpot results (background subtracted NP, M1 and NP+M1) will each be 
analyzed independently using an ANCOVA model with treatment, Total (NP+M1) baseline 
ELISpot response (background subtracted), and treatment by baseline response interaction. 
 
ICS Assay 
The data and analysis for ICS assay will be exploratory. Depending on the ICS data available 
and final analysis decision, ICS assay might be analyzed in the same way as ELIspot assay. The 
final analysis of ICS assay might not happen at the same time for ELIsopt assay. 
  


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14. 
HEALTH OUTCOMES ANALYSES 
Not applicable for this study. 


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15. 
CLINICAL PHARMACOLOGY DATA ANALYSES 
Not applicable for this study. 


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16. 
BIOMARKER DATA ANALYSIS 
Not applicable for this study. 


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17. 
PHARMACOGENETIC DATA ANALYSES 
Not applicable for this study. 


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18. 
VIRAL GENOTYPING/PHENOTYPING 
Not applicable for this study. 


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19. 
REFERENCES 
• FLU009 Protocol: A Phase 2b Study to Determine the Efficacy of Candidate Influenza 
Vaccine MVA-NP+M1 in Adults aged 18 years and over. 20 May 2019; Version 3.0 
• Hudgens, M.G., Self, S.G., Chiu, Y.L., Russell, N.D., Horton, H., McElrath, M.J., 2004. 
Statistical Considerations for the Design and Analysis of the ELISpot Assay in HIV-1 
Vaccine Trials. J. Immunol. Methods 288 (1–2), 19 (May). 
 
• Jennison, C., and Turnbull, B.W. 2000. Group Sequential Methods with Applications to 
Clinical Trials. Chapman & Hall/CRC. New York. 


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20. 
ATTACHMENTS 
20.1. 
Table of Contents for Data Display Specifications 
20.1.1. 
Planned Data Listings 
The following listings are planned to be generated for the study (Note: Numbering is indicative 
only and may be updated based on CSR requirements): 
Listing Number 
Listing Title 
Population 
IA Outputs 
16.2.1 Disposition 
 
 
Listing 16.2.1.1 
Study Enrolment and 
Completion/ Discontinuation 
All Randomised 
 
 
Listing 16.2.1.2 
Visit Dates and Study Days 
All Randomised 
 
 
Listing 16.2.1.3 
Randomisation 
All Randomised 
 
16.2.2 Protocol Deviations 
 
 
Listing 16.2.2 
Protocol Deviations 
Efficacy 
Y 
16.2.3 Subjects Excluded from Analyses 
 
 
Listing 16.2.3 
Population Assignment and 
Reason for Exclusion 
All Randomised 
 
16.2.4 Demographic and Other Baseline Data 
 
 
Listing 16.2.4.1 
Demographics  
Efficacy 
 
Listing 16.2.4.2 
Eligibility 
Efficacy 
 
 
Listing 16.2.4.3 
Medical History 
Efficacy 
 
 
Listing 16.2.4.4.1 
Prior Medications 
Efficacy 
 
 
Listing 16.2.4.4.2 
Concomitant Medications  
Efficacy 
 
16.2.5 Vaccine Administration Data 
 
 
 
Listing 16.2.5 
Vaccine Administration 
Efficacy 
 
16.2.6 Efficacy and Immunogenicity Data  
 
 
 
Listing 16.2.6.1 
Nasal Swab Visit and Test 
Efficacy 
Y 


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Listing Number 
Listing Title 
Population 
IA Outputs 
Result 
 
Listing 16.2.6.2 
Daily Influenza-like Illness 
(ILI) Diary 
Efficacy 
Y 
 
Listing 16.2.6.3 
Intracellular Cytokine Staining 
(ICS) Assays 
Immunology 
Y 
 
Listing 16.2.6.4 
Enzyme Linked Immunospot 
(ELIspot) Assays 
Immunology 
Y 
16.2.7 Adverse Event Data 
 
 
 
Listing 16.2.7.1 
Adverse Events 
Safety 
 
 
Listing 16.2.7.2 
Solicited Local Injection Site 
Reactions (ISR) 
Safety 
 
 
Listing 16.2.7.3 
Solicited Systemic Reactions 
Safety 
 
 
Listing 16.2.7.4 
Serious Adverse Events 
Safety 
Y 
 
Listing 16.2.7.5 
Adverse Events Leading to 
Study Discontinuation  
Safety 
Y 
 
Listing 16.2.7.6 
Deaths 
Safety 
Y 
 
Listing 16.2.7.7 
Post-vaccination 28 Days Diary 
Safety 
 
16.2.8 Laboratory Data 
 
 
 
Listing 16.2.8.1 
Haematology 
Immunology 
 
 
Listing 16.2.8.2 
Biochemistry 
Immunology 
 
16.4 Other Safety Data 
 
 
 
Listing 16.4.1 
Pregnancy Test  
Safety 
 
 
Listing 16.4.2 
Physical Examination 
Safety 
 
 
Listing 16.4.3 
Comments  
Safety 
 
 
Listing 16.4.4 
Telephone Call  
Safety 
 


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20.2. 
Planned Summary Tables 
The following tables are planned to be generated for the study (Note: Numbering is indicative 
only and may be updated based on CSR requirements). Sample size re-calculation will be 
provided at IA if needed.  
Table Number 
Table Title 
Population 
IA Outputs 
14.1 Subject Data Summaries 
 
 
Table 14.1.1 
Study Participation and 
Disposition 
All 
Randomised 
Y 
 
Table 14.1.2 
Demographics 
Efficacy 
Y 
Table 14.1.3.1 
Prior Medications 
Efficacy 
 
 
Table 14.1.3.2 
Concomitant Medications 
Efficacy 
 
14.2 Efficacy and Immunogenicity Data Summaries 
 
 
 
Table 14.2.1.1.1 
Incidence of Laboratory 
Confirmed Influenza using RT-
PCR: Overall 
Efficacy 
Y 
 
Table 14.2.1.1.2 
Incidence of Laboratory 
Confirmed Influenza using RT-
PCR: Overall 
PP 
 
 
Table 14.2.1.1.3 
Survival Analysis of Time to 
Confirmed Influenza using RT-
PCR: Overall 
Efficacy 
Y 
 
Table 14.2.1.1.4 
Survival Analysis of Time to 
Confirmed Influenza using RT-
PCR: Overall 
PP 
 
 
Figure 14.2.1.1.5 
Kaplan-Meier Plot of Time to 
Confirmed Influenza using RT-
PCR: Overall 
Efficacy 
Y 
 
Figure 14.2.1.1.6 
Kaplan-Meier Plot of Time to 
Confirmed Influenza using RT-
PCR: Overall 
PP 
 
 
Table 14.2.1.2.1 
Incidence of Laboratory 
Confirmed Influenza using RT-
Efficacy 
Y 


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Table Number 
Table Title 
Population 
IA Outputs 
PCR: Age<65 Years and Age ≥65 
Years 
 
Table 14.2.1.2.2 
Incidence of Laboratory 
Confirmed Influenza using RT-
PCR: by Study Site 
Efficacy 
Y 
 
Table 14.2.1.2.3 
Survival Analysis of Time to 
Confirmed Influenza using RT-
PCR: Age<65 Years and Age ≥65 
Years 
Efficacy 
Y 
 
Table 14.2.1.2.4 
Survival Analysis of Time to 
Confirmed Influenza using RT-
PCR: by Study Site 
Efficacy 
Y 
 
Figure 14.2.1.2.5 
Kaplan-Meier Plot of Time to 
Confirmed Influenza using RT-
PCR: Age<65 Years and Age ≥65 
Years 
Efficacy 
Y 
 
Figure 14.2.1.2.6 
Kaplan-Meier Plot of Time to 
Confirmed Influenza using RT-
PCR: by Study Site 
Efficacy 
Y 
 
Table 14.2.2.1.1 
Incidence of Influenza-like 
Illness (ILI): Overall 
Efficacy 
Y 
 
Table 14.2.2.1.2 
Incidence of Influenza-like 
Illness (ILI): Overall 
PP 
 
 
Table 14.2.2.2.1 
Incidence of Influenza-like 
Illness (ILI):  Age<65 Years and 
Age ≥65 Years 
Efficacy 
Y 
 
Table 14.2.2.2.2 
Incidence of Influenza-like 
Illness (ILI):  by Study Site 
Efficacy 
Y 
Table 14.2.3.1.1 
Time Weight Area Under the 
Curve (AUC) for Symptoms of 
Influenza-like Illness (ILI): 
Overall 
Efficacy 
Y 
 
Table 14.2.3.1.2 
Time Weight Area Under the 
Curve (AUC) for Symptoms of 
Influenza-like Illness (ILI): 
PP 
 


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Protocol: FLU009 
Statistical Analysis Plan 
 
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Table Number 
Table Title 
Population 
IA Outputs 
Overall 
 
Table 14.2.3.2.1 
Time Weight Area Under the 
Curve (AUC) for Symptoms of 
Influenza-like Illness (ILI): 
Age<65 Years and Age ≥65 
Years 
Efficacy 
Y 
 
Table 14.2.3.2.2 
Time Weight Area Under the 
Curve (AUC) for Symptoms of 
Influenza-like Illness (ILI): by 
Study Site 
Efficacy 
Y 
Table 14.2.4.1.1 
Survival Analysis of Duration of 
Influenza-like Illness (ILI): 
Overall 
Efficacy 
Y 
 
Table 14.2.4.1.2 
Survival Analysis of Duration of 
Influenza-like Illness (ILI): 
Overall 
PP 
 
 
Table 14.2.4.2.1 
Survival Analysis of Duration of 
Influenza-like Illness (ILI) ): 
Age<65 Years and Age ≥65 
Years 
Efficacy 
Y 
 
Table 14.2.4.2.2 
Survival Analysis of Duration of 
Influenza-like Illness (ILI) ): by 
Study Site 
Efficacy 
Y 
Figure 14.2.5.1.1 
Kaplan-Meier Plot of Duration of 
Influenza-like Illness (ILI): 
Overall 
Efficacy 
Y 
 
Figure 14.2.5.1.2 
Kaplan-Meier Plot of Duration of 
Influenza-like Illness (ILI): 
Overall 
PP 
 
Figure 14.2.5.2.1 
Kaplan-Meier Plot of Duration of 
Influenza-like Illness (ILI): 
Age<65 Years and Age ≥65 
Years 
Efficacy 
Y 
 
Figure 14.2.5.2.2 
Kaplan-Meier Plot of Duration of 
Influenza-like Illness (ILI): by 
Efficacy 
Y 


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Table Number 
Table Title 
Population 
IA Outputs 
Study Site 
Table 14.2.6.1 
Intracellular Cytokine Staining 
(ICS) Assay: Response Level and 
Change from Baseline 
Immunology  
Table 14.2.6.2 
Intracellular Cytokine Staining 
(ICS) Assay: Responder Analysis  
Immunology  
 
Table 14.2.6.3 
Intracellular Cytokine Staining 
(ICS) Assay: ANCOVA Analysis  
Immunology  
 
Figure 14.2.6.4 
Dot Plot of Intracellular Cytokine 
Staining (ICS) Assay: Individual 
Immunology  
 
Figure 14.2.6.5 
Median of Intracellular Cytokine 
Staining (ICS) Assay by Study 
Visit 
Immunology  
 
Table 14.2.7.1 
Enzyme Linked Immunospot 
(ELIspot) Assay: Response Level 
and Change from Baseline 
Immunology  
 
Table 14.2.7.2 
Enzyme Linked Immunospot 
(ELIspot) Assay: Responder 
Analysis  
Immunology  
 
Table 14.2.7.3 
Enzyme Linked Immunospot 
(ELIspot) Assay: ANCOVA 
Analysis  
Immunology  
 
Figure 14.2.7.4 
Dot Plot of Enzyme Linked 
Immunospot (ELIspot) Assay: 
Individual  
Immunology  
 
Figure 14.2.7.5 
Median of Enzyme Linked 
Immunospot (ELIspot) Assay by 
Study Visit  
Immunology  
14.3.1 Safety Data Summaries 
 
 
 
Table 14.3.1.1 
Overall Summary of Treatment 
Emergent Adverse Events 
Safety 
Y 
 
Table 14.3.1.2.1 
Solicited Local Injection Site 
Safety 
Y 


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Table Number 
Table Title 
Population 
IA Outputs 
Reactions (IRS)  
 
Table 14.3.1.2.2 
Solicited Local Injection Site 
Reactions (IRS) by Severity 
Safety 
Y 
 
Table 14.3.1.3.1 
Solicited Systemic Reactions 
Safety 
Y 
 
Table 14.3.1.3.2 
Solicited Systemic Reactions by 
Severity 
Safety 
Y 
 
Table 14.3.1.4 
Treatment Emergent Adverse 
Events 
Safety 
Y 
 
Table 14.3.1.5 
Treatment Emergent Adverse 
Events by Severity 
Safety 
Y 
 
Table 14.3.1.6 
Treatment Emergent Adverse 
Events by Relationship to 
Vaccine 
Safety 
Y 
 
Table 14.3.1.7 
Treatment Related Treatment 
Emergent Adverse Events by 
Severity 
Safety 
Y 
 
Table 14.3.1.8 
Serious Treatment Emergent 
Adverse Events  
Safety 
Y 
 
Table 14.3.1.9 
Treatment Emergent Adverse 
Events Leading to 
Discontinuation from Study 
Safety 
Y 
 
Table 14.3.1.10 
Treatment Emergent Adverse 
Events Leading to Death 
Safety 
Y 
14.3.4 Clinical Laboratory Data 
 
 
 
Table 14.3.4.1.1 
Haematology 
Immunology  
 
Table 14.3.4.1.2 
Haematology Abnormalities 
Immunology  
 
Table 14.3.4.1.3 
Shift Table of Haematology 
Immunology Y 
 
Figure 14.3.4.1.4 
Boxplot of  Haematology 
(Observed and Change from 
Baseline) 
Immunology Y 


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Table Number 
Table Title 
Population 
IA Outputs 
 
Table 14.3.4.2.1 
Biochemistry 
Immunology  
 
Table 14.3.4.2.2 
Biochemistry Abnormalities 
Immunology  
 
Table 14.3.4.2.3 
Shift Table of Biochemistry 
Immunology Y 
 
Figure 14.3.4.2.4 
Boxplot of  Biochemistry 
(Observed and Change from 
Baseline) 
Immunology Y 
14.3.5 Other Safety Summaries 
 
 
 
Table 14.3.5.1 
Diary Data – Injection Site 
Reactions (ISR) 
Safety 
 
14.3.6 Other Summaries 
 
 
 
Table 14.3.6.1 
Conditional Power at Interim 
Analysis 
NA 
Y 
 
Table 14.3.6.2 
Sample Size Re-estimation at 
Interim Analysis 
NA 
Y