An Exploratory Study to Establish the Dose, Safety and Pathogenicity of a New Influenza A H3N2 Challenge Strain in Healthy Participants 18 to 55 Years of Age
Phase: NA
Conditions: Influenza A H3N2
Sponsor: Hvivo

 
 
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CLINICAL STUDY PROTOCOL 
AN EXPLORATORY STUDY TO ESTABLISH THE DOSE, 
SAFETY AND PATHOGENICITY OF A NEW INFLUENZA A 
H3N2 CHALLENGE STRAIN IN HEALTHY PARTICIPANTS 
18 TO 55 YEARS OF AGE 
TITLE PAGE 
Brief Title 
Dose, safety, and pathogenicity of a new influenza A 
H3N2 challenge strain 
Protocol Version and Date 
Final v4.0,  20 December 2024 
Sponsor 
hVIVO Services Limited 
40 Bank Street, Canary Wharf, London E14 5NR, UK 
hVIVO Study Number 
HRD-vCS-006 
Compound 
Not applicable 
IRAS ID 
341061 
 
Confidentiality and Protections Statement: 
This document contains confidential information of hVIVO. This document must not be 
disclosed to anyone other than the study staff and members of the Independent Ethics 
Committee/Institutional Review Board or Competent Authorities. The information in this 
document cannot be used for any purpose other than the conduct or evaluation of the clinical 
investigation without the prior written consent of hVIVO. 
Personal data included in the protocol is subject to the UK Data Protection Act considerations 
and protections. 
 

hVIVO 
Study Number: HRD-vCS-006 
Clinical Study Protocol 
Version: Final V4.0 20DEC2024 
 
 
 
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Sponsor Statement 
This protocol was subjected to critical review. The information it contains is consistent with 
current knowledge of the risks and benefits of the study intervention, and with the moral, 
ethical, and scientific principles governing clinical research as set out in the current Declaration 
of Helsinki and the principles of International Council for Harmonisation (ICH) Good Clinical 
Practice (GCP). 
 
Sponsor Signatory 
Name, title (typed or printed): 
Alex Mann, Senior Director, Clinical Science 
 
 
Signature and Date: 
 
 
 
 

hVIVO 
Study Number: HRD-vCS-006 
Clinical Study Protocol 
Version: Final V4.0 20DEC2024 
 
 
 
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Investigator Agreement 
I have read the protocol and agree to conduct the study in accordance with the approved 
protocol and any future amendments, the Declaration of Helsinki, the principles of ICH GCP, 
the current regulatory requirements as detailed in the Medicines for Human Use (Clinical Trial) 
Regulations (Statutory Instrument 2004/1031) and all subsequent amendments, the UK Data 
Protection Act 2018, any other applicable laws, and guidance. 
I agree to conduct the procedures described in this protocol according to these guidelines and 
to appropriately direct and assist the study staff under my control. 
 
Principal Investigator Signatory 
Name (typed or printed): 
Dr. Alexandre Lima 
 
 
Signature and Date: 
 
 
 
 
 
 
 
 
 
Note: In this protocol, the terms hVIVO and ‘investigator’ distinguish between the principal 
investigator’s (PI’s) responsibility, and actions required by the organization (hVIVO). The term 
‘investigator’ includes appropriately qualified persons to whom the PI has formally delegated 
his/her investigator roles and responsibilities. 
 
 

hVIVO 
Study Number: HRD-vCS-006 
Clinical Study Protocol 
Version: Final V4.0 20DEC2024 
 
 
 
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Study Staff Contact Information 
Contact 
Details 
Sponsor 
hVIVO Services Limited 
40 Bank Street, Canary Wharf, London E14 5NR, UK 
Sponsor’s representative  
Alex Mann 
hVIVO Services Limited 
40 Bank Street, Canary Wharf, London E14 5NR, 
UK 
Email: 
 
Principal Investigator and Clinical 
Study Facilities 
Dr. Alexandre Lima 
Phone: 
 
Email: 
 
hVIVO Services Limited 
21 Plumbers Row, London E1 1EQ, UK 
hVIVO Services Limited 
36 George Street, Manchester M1 4HA, UK 
hVIVO Services Limited 
40 Bank Street, Canary Wharf, London E14 5NR, 
UK 
Key Protocol Contributors 
Refer to the local study contact list document 
 
 
 
 

hVIVO 
Study Number: HRD-vCS-006 
Clinical Study Protocol 
Version: Final V4.0 20DEC2024 
 
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
PROTOCOL HISTORY  
Document  
Date  
Amendment Type  
Amendment 3 (Protocol v4.0) 
20-December-2024 
Substantial  
Amendment 2 (Protocol v3.0) 
31-October-2024 
Non-Substantial  
Amendment 1 (Protocol v2.0)  
01-August-2024 
Substantial  
Original Protocol (Protocol v1.0)  29-February-2024 
Not applicable  
 
Amendment 3 (Protocol v4.0) – 20 December 2024  
This amendment is substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.  
 
Overall Rationale for the Amendment:  
The primary reason for this protocol amendment was toinclude Throat swabs – virology: 
qRTPCR, viral culture assessments twice daily within 1.2, Schedule of Events.  
 
 

hVIVO 
Study Number: HRD-vCS-006 
Clinical Study Protocol 
Version: Final V4.0 20DEC2024 
 
 
 
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TABLE OF CONTENTS 
Title Page ................................................................................................................................... 1 
Table of Contents ....................................................................................................................... 6 
List of Tables ............................................................................................................................. 9 
1. 
SYNOPSIS .................................................................................................................. 10 
1.1. 
Study Schematic: On-study Participant Progression ................................................. 21 
1.2. 
Schedule of Events .................................................................................................... 22 
2. 
INTRODUCTION...................................................................................................... 30 
2.1. 
Background ............................................................................................................... 30 
2.2. 
Study Rationale ......................................................................................................... 31 
2.3. 
Benefit/Risk Assessment ........................................................................................... 31 
2.3.1. 
Risk Assessment .................................................................................................... 31 
2.3.1.1. 
Vulnerable Persons ............................................................................................ 35 
2.3.1.2. 
Risk Associated With Coronavirus Disease 2019 Pandemic ............................ 35 
2.3.2. 
Benefit Assessment ................................................................................................ 35 
2.3.3. 
Overall Benefit/Risk Conclusion ........................................................................... 36 
3. 
OBJECTIVES AND ENDPOINTS .......................................................................... 37 
4. 
STUDY DESIGN ........................................................................................................ 43 
4.1. 
Overview of Study Design ........................................................................................ 43 
4.2. 
Scientific Rationale for Study Design ....................................................................... 44 
4.3. 
Justification for Dose ................................................................................................ 44 
4.4. 
End-of-Study Definition ............................................................................................ 44 
5. 
STUDY POPULATION ............................................................................................ 45 
5.1. 
Inclusion Criteria ....................................................................................................... 45 
5.2. 
Exclusion Criteria ...................................................................................................... 47 
5.3. 
Lifestyle Considerations ............................................................................................ 51 
5.3.1. 
Meals and Dietary Restrictions .............................................................................. 51 
5.3.2. 
Caffeine, Alcohol, and Tobacco ............................................................................ 51 
5.3.3. 
Activity .................................................................................................................. 51 
5.3.4. 
Other Restrictions .................................................................................................. 51 
5.4. 
Screen Failures .......................................................................................................... 51 
6. 
STUDY INTERVENTIONS AND CONCOMITANT THERAPY ....................... 53 
6.1. 
Study Intervention(s) Administered .......................................................................... 53 
6.2. 
Challenge Agent ........................................................................................................ 54 
6.2.1. 
Preparation/Handling ............................................................................................. 54 
6.2.2. 
Accountability/Storage .......................................................................................... 54 
6.3. 
Randomization and Blinding ..................................................................................... 55 
6.3.1. 
Randomization ....................................................................................................... 55 
6.3.2. 
Blinding.................................................................................................................. 55 
6.4. 
Study Intervention Compliance ................................................................................. 55 
6.5. 
Concomitant Therapy ................................................................................................ 56 
6.6. 
Dose Modification ..................................................................................................... 57 
6.7. 
Treatment of Overdose .............................................................................................. 58 
7. 
PARTICIPANT 
WITHDRAWAL 
/ 
DISCONTINUATION 
/ 
DISCONTINUATION OF STUDY INTERVENTION ......................................... 59 
7.1. 
Participant Withdrawal .............................................................................................. 59 

hVIVO 
Study Number: HRD-vCS-006 
Clinical Study Protocol 
Version: Final V4.0 20DEC2024 
 
 
 
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7.2. 
Participant Discontinuation ....................................................................................... 59 
7.2.1. 
Temporary Discontinuation/Temporary Delay in Enrollment ............................... 60 
7.3. 
Lost to Follow-up ...................................................................................................... 60 
7.4. 
Participant Replacement Strategy ............................................................................. 60 
7.5. 
Stopping Rules .......................................................................................................... 61 
7.6. 
Potential Adaptations to Operational Design ............................................................ 62 
8. 
STUDY ASSESSMENTS AND PROCEDURES .................................................... 65 
8.1. 
Demographics and Baseline Characteristics ............................................................. 65 
8.1.1. 
Demographics ........................................................................................................ 65 
8.1.2. 
Height, Body Weight, and Body Mass Index ........................................................ 65 
8.1.3. 
Medical and Medication History ........................................................................... 65 
8.1.4. 
Challenge Agent Serology Samples....................................................................... 66 
8.1.5. 
Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder (GAD-7) 
Questionnaire ......................................................................................................... 66 
8.2. 
Respiratory Samples .................................................................................................. 66 
8.2.1. 
Nasal Wick ............................................................................................................. 66 
8.2.2. 
Nasopharyngeal Swab ............................................................................................ 66 
8.2.2.1. 
Throat swab ....................................................................................................... 66 
8.2.2.2. 
Respiratory Pathogen Screen ............................................................................. 67 
8.2.2.3. 
Influenza Discharge Test ................................................................................... 67 
8.2.3. 
Breath respiratory sampling ................................................................................... 67 
8.3. 
Pathogenicity Assessments ....................................................................................... 67 
8.3.1. 
Participant Diary Cards .......................................................................................... 67 
8.3.2. 
Nasal Discharge Collection from Paper Tissues .................................................... 69 
8.3.3. 
Viral Load Assessment .......................................................................................... 69 
8.3.4. 
Exploratory Assessments ....................................................................................... 69 
8.4. 
Safety Assessments ................................................................................................... 70 
8.4.1. 
Complete Physical Examination ............................................................................ 70 
8.4.2. 
Directed Physical Examination .............................................................................. 70 
8.4.3. 
Vital Signs .............................................................................................................. 70 
8.4.4. 
Tympanic Temperature .......................................................................................... 71 
8.4.5. 
Electrocardiogram .................................................................................................. 71 
8.4.6. 
Clinical Safety Laboratory Assessments ............................................................... 71 
8.4.6.1. 
Urinalysis ........................................................................................................... 71 
8.4.6.2. 
Drugs of Misuse and Cotinine ........................................................................... 72 
8.4.6.3. 
Alcohol Breath Testing ..................................................................................... 72 
8.4.6.4. 
Safety Blood Assessments and Analysis ........................................................... 72 
8.4.7. 
Pregnancy Tests and Follicle-stimulating Hormone .............................................. 72 
8.4.8. 
Lung Function ........................................................................................................ 72 
8.5. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting ................... 73 
8.5.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information .................................................................................................. 73 
8.5.2. 
Method of Detecting Adverse Events/Serious Adverse Events ............................. 73 
8.5.3. 
Follow-up of Adverse Events/Serious Adverse Events ......................................... 73 
8.5.4. 
Regulatory Reporting Requirements for Serious Adverse Events ......................... 74 
8.5.5. 
Pregnancy ............................................................................................................... 74 
8.6. 
Pharmacokinetics ...................................................................................................... 74 
8.7. 
Pharmacodynamics.................................................................................................... 74 
8.8. 
Immunogenicity Assessments ................................................................................... 74 
8.9. 
Genetics ..................................................................................................................... 74 

hVIVO 
Study Number: HRD-vCS-006 
Clinical Study Protocol 
Version: Final V4.0 20DEC2024 
 
 
 
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8.10. 
Biomarkers ................................................................................................................ 74 
9. 
STATISTICAL CONSIDERATIONS ..................................................................... 75 
9.1. 
Statistical Hypotheses ............................................................................................... 75 
9.2. 
Sample Size Determination ....................................................................................... 75 
9.3. 
Analysis Sets ............................................................................................................. 75 
9.4. 
Statistical Analysis .................................................................................................... 76 
9.4.1. 
Statistical Analysis Plan ......................................................................................... 76 
9.4.2. 
General Considerations .......................................................................................... 76 
9.4.2.1. 
Descriptive Statistics ......................................................................................... 76 
9.4.2.2. 
Inferential Statistics and Significance Testing .................................................. 77 
9.4.3. 
Planned Analysis .................................................................................................... 77 
9.4.3.1. 
Participant Accountability ................................................................................. 77 
9.4.3.2. 
Protocol Deviations ........................................................................................... 77 
9.4.3.3. 
Demographic and Baseline Characteristics ....................................................... 77 
9.4.3.4. 
Compliance to Challenge Agent ........................................................................ 77 
9.4.4. 
Primary Pathogenicity Analysis ............................................................................. 77 
9.4.5. 
Secondary Pathogenicity Analysis ......................................................................... 78 
9.4.6. 
Exploratory Analysis ............................................................................................. 78 
9.4.7. 
Safety Analysis ...................................................................................................... 78 
9.5. 
Interim Analysis ........................................................................................................ 79 
9.6. 
Data Monitoring Committee ..................................................................................... 79 
10. 
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL 
CONSIDERATIONS ................................................................................................. 80 
10.1. 
Appendix 1: Ethical and Study Oversight Considerations ........................................ 80 
10.1.1. Ethical Considerations ........................................................................................... 80 
10.1.2. Financial Disclosure............................................................................................... 80 
10.1.3. Confidentiality ....................................................................................................... 80 
10.1.4. Informed Consent Process ..................................................................................... 81 
10.1.5. Data Protection....................................................................................................... 82 
10.1.6. Committee(s) Structure .......................................................................................... 82 
10.1.7. Dissemination of Clinical Study Data.................................................................... 82 
10.1.8. Data Quality Assurance ......................................................................................... 82 
10.1.9. Source Documents ................................................................................................. 83 
10.1.10. Study Discontinuation ............................................................................................ 83 
10.1.11. Publication Policy .................................................................................................. 83 
10.2. 
Appendix 2: Clinical Laboratory Tests ..................................................................... 84 
10.3. 
Appendix 3: Adverse Events – Definitions and Procedures for Recording, Evaluating, 
Follow-up and Reporting .......................................................................................... 86 
10.3.1. Adverse Event ........................................................................................................ 86 
10.3.2. Serious Adverse Event ........................................................................................... 87 
10.3.3. Recording, Assessment, and Follow-up of Adverse Events/Serious Adverse Events
................................................................................................................................ 88 
10.3.3.1. Adverse Event/Serious Adverse Event Recording ............................................ 88 
10.3.3.2. Assessment ........................................................................................................ 89 
10.3.3.3. Assessment of Intensity ..................................................................................... 91 
10.3.3.4. Frequency .......................................................................................................... 91 
10.3.3.5. Assessment of Causality .................................................................................... 91 
10.3.3.6. Action Taken ..................................................................................................... 93 
10.3.3.7. Outcome ............................................................................................................ 93 

hVIVO 
Study Number: HRD-vCS-006 
Clinical Study Protocol 
Version: Final V4.0 20DEC2024 
 
 
 
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10.3.3.8. Follow-up .......................................................................................................... 93 
10.3.4. Reporting of Serious Adverse Events .................................................................... 94 
10.3.5. Adverse Reactions to Non-investigational Medicinal Products ............................ 95 
10.3.6. Post-study Adverse Events and Serious Adverse Events ...................................... 95 
10.3.7. Pregnancy ............................................................................................................... 95 
10.4. 
Appendix 4: Normal Ranges ..................................................................................... 97 
10.5. 
Appendix 5: Genetics ................................................................................................ 98 
10.6. 
Appendix 6: Abbreviations ....................................................................................... 99 
10.7. 
Appendix 7: Definitions .......................................................................................... 101 
10.7.1. General ................................................................................................................. 101 
10.7.2. Study Definition of Infection and Illness ............................................................. 102 
10.8. 
Appendix 8: Protocol Amendment History ............................................................. 104 
11. 
REFERENCES ......................................................................................................... 105 
 
LIST OF TABLES 
Table 6-1: 
Study Interventions ............................................................................................ 53 
Table 6-2: 
Prohibited Medication (Healthy Participants) ................................................... 56 
Table 6-3: 
Permitted Medication ........................................................................................ 57 
Table 7-1: 
Study Stopping Rules ........................................................................................ 61 
Table 7-2: 
Adaptive Features .............................................................................................. 63 
Table 9-1: 
Analysis Sets ..................................................................................................... 75 
Table 9-2: 
Methods for Analysis of Secondary Pathogenicity Endpoints .......................... 78 
Table 10-1: Protocol-required Safety Laboratory Assessments ........................................... 84 
Table 10-2: Classification of Adverse Event Relationship ................................................... 92 
Table 10-3: Classification of Adverse Event Outcome ........................................................ 93 
Table 10-4: Contact Details for Reporting All Serious Adverse Events .............................. 94 
 

hVIVO 
Study Number: HRD-vCS-006 
Clinical Study Protocol 
Version: Final V4.0 20DEC2024 
 
 
 
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1. 
SYNOPSIS 
Study Title 
An exploratory study to establish the dose, safety and 
pathogenicity of a new influenza A H3N2 challenge strain in 
healthy participants 18 to 55 years of age 
Brief Title 
Dose, safety, and pathogenicity of a new influenza A H3N2 
challenge strain 
hVIVO Study Number 
HRD-vCS-006 
Sponsor 
hVIVO Services Limited 
IRAS ID 
341061 
Study Phase 
Exploratory 
Study Site(s) 
hVIVO Services Limited 
21 Plumbers Row, London E1 1EQ, UK 
hVIVO Services Limited 
36 George Street, Manchester M1 4HA, UK 
hVIVO Services Limited 
40 Bank Street, Canary Wharf, London E14 5NR, UK 
Study Type 
Interventional 
Indication 
Not applicable 
Design 
This is an exploratory study of an influenza A H3N2 challenge 
strain to determine the optimum infectious titer of challenge agent 
in healthy participants 18 to 55 years of age. 

hVIVO 
Study Number: HRD-vCS-006 
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Version: Final V4.0 20DEC2024 
 
 
 
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Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
Pathogenicity & Safety 
 To 
determine 
the safe and 
optimal titer of 
the 
influenza 
challenge 
agent. 
To identify a safe and infectious dose of wild-type 
influenza virus in healthy participants, suitable for future 
intervention studies that: 
• Has an acceptable safety profile as measured by: 
o Occurrence of adverse events (AEs) related to 
the viral challenge from viral challenge (Day 
0) to the Day 28 (±3 days) follow-up visit. 
o Occurrence of serious adverse events (SAEs) 
related to the viral challenge from viral 
challenge (Day 0) to the Day 28 (±3 days) 
follow-up visit. 
• Induces laboratory-confirmed infection in ≥40% of 
inoculated participants (ideally between 50% and 
80%). Laboratory-confirmed infection is defined as: 
o Quantitative 
reverse 
transcriptase-
polymerase chain reaction (qRT-PCR)-
confirmed influenza infection, defined as 2 
quantifiable (≥ lower limit of quantification 
[LLOQ]) qRT-PCR measurements (reported 
over 4 planned consecutive assessments 
within 48 hours), from Day 1 pm to planned 
discharge from quarantine (Day 8 am). 
Secondary 
Pathogenicity 
 To evaluate the 
incidence 
of 
viral 
culture-
confirmed 
influenza 
infection. 
 Viral 
culture-confirmed 
influenza 
infection, defined as a quantifiable viral 
culture measurement, from Day 1 pm to 
planned 
discharge 
from 
quarantine 
(Day 8 am). 
 To evaluate the 
optimal titer of 
the 
influenza 
challenge 
agent, 
as 
measured by: 
The following endpoints will be determined by both 
qRT--PCR and viral culture on nasal and throat samples: 
 Area under the viral load-time curve (VL-
AUC) of the influenza challenge agent, 
from Day 1 pm to planned discharge from 
quarantine (Day 8 am). 

hVIVO 
Study Number: HRD-vCS-006 
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o Viral 
load-related 
endpoints. 
 Peak viral load (VLPEAK) of the 
influenza challenge agent, defined as the 
maximum viral load, from Day 1 pm to 
planned 
discharge 
from 
quarantine 
(Day 8 am). 
 To explore the 
optimal titer of 
the 
influenza 
challenge 
agent, 
as 
measured by: 
o Clinical 
symptom-
related endpoints. 
 Area under the total clinical symptom 
score-time 
curve 
(TSS-AUC) 
as 
measured by graded symptom scoring 
system collected 3 times daily from 
Day 1 am to planned discharge from 
quarantine (Day 8 am). 
 Peak daily symptom score: individual 
maximum daily sum of symptom score 
from Day 1 (am) to planned discharge 
from quarantine (Day 8 am). 
 Peak symptom diary card score: peak 
total symptom score (TSS) as measured 
by graded symptom scoring system 
collected 3 times daily from Day 1 am to 
planned 
discharge 
from 
quarantine 
(Day 8 am). 
 To explore the 
optimal titer of 
the 
influenza 
challenge 
agent, 
as 
measured 
by 
the 
incidence 
of 
influenza-
like 
illness 
(ILI) 
and 
laboratory-
confirmed 
symptomatic 
influenza 
infection. 
 Laboratory-confirmed febrile influenza 
infection, defined as: 
o Laboratory-confirmed infection, AND 
o A febrile episode, defined as a temperature of 
≥37.9°C, from Day 1 am to planned discharge 
from quarantine (Day 8 am). 
 qRT-PCR-confirmed ILI (Centers for 
Disease and Control [CDC]), defined as: 
o Laboratory-confirmed infection, AND 
o A febrile episode, defined as a temperature of 
≥37.8ºC, from Day 1 am to planned discharge 
from quarantine (Day 8 am), AND 
o Cough and/or sore throat, from Day 1 am to 
planned discharge from quarantine (Day 8 am), 
in the absence of a known cause other than 
influenza. 
 qRT-PCR-confirmed ILI (World Health 
Organization [WHO]), defined as: 
o Laboratory-confirmed infection, AND 
o A febrile episode, defined as a temperature of 
≥38.0ºC, from Day 1 am to planned discharge 
from quarantine (Day 8 am), AND 

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o Cough, from Day 1 am to planned discharge 
from quarantine (Day 8 am). 
 Laboratory-confirmed moderately severe 
symptomatic influenza infection, defined 
as: 
o Laboratory-confirmed infection, AND 
o Any symptoms from the symptom diary card of 
grade ≥2 at a single time point, from Day 1 am to 
planned discharge from quarantine (Day 8 am). 
 Laboratory-confirmed 
symptomatic 
influenza infection, defined as: 
o Laboratory-confirmed infection, AND 
o TSS ≥2 at a single time point, from Day 1 am to 
planned discharge from quarantine (Day 8 am). 
 Viral 
culture 
laboratory-confirmed 
moderately severe symptomatic influenza 
infection, defined as: 
o Viral culture laboratory-confirmed infection, 
AND 
o Any symptoms from the symptom diary card of 
grade ≥2 at a single time point, from Day 1 am to 
planned discharge from quarantine (Day 8 am). 
Further analyses may be performed on the above 
endpoints, using modified start or end times. Details will 
be provided in the statistical analysis plan (SAP). 
Further analyses may be performed on the above 
qRT-PCR-related endpoints where detection by qRT-
PCR is reported above the lower limit of detection 
(LLOD) instead of the LLOQ. Details will be provided 
in the SAP. 
Exploratory* 
 To 
further 
explore 
the 
pathogenicity 
phenotype 
of 
wild-type 
influenza 
in 
healthy 
participants, as 
measured by: 
o Safety assessments. 
 safety laboratory tests, 
 lung function,  
 electrocardiograms [ECGs],  
 physical examinations, and concomitant 
medications. 

hVIVO 
Study Number: HRD-vCS-006 
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 To 
further 
explore 
the 
pathogenicity 
phenotype 
of 
influenza 
challenge 
agent, 
as 
measured by: 
o Nasal 
discharge 
endpoints. 
 Total weight of mucus produced from 
Day 1 
to 
planned 
discharge 
from 
quarantine (Day 8 am). 
 Total number of tissues used by 
participant from Day 1 to planned 
discharge from quarantine (Day 8 am). 
 To 
further 
explore 
the 
pathogenicity 
phenotype 
of 
the 
influenza 
challenge 
agent, 
as 
measured by: 
o Viral 
load-related 
endpoints. 
The following endpoints may be determined by both 
qRT--PCR and viral culture on nasal and throat samples: 
 Duration of quantifiable influenza, from 
Day 1 pm to planned discharge from 
quarantine 
(Day 8 am). 
Duration 
is 
defined as the time (hours) from first 
quantifiable 
(≥LLOQ) 
until 
first 
confirmed 
unquantifiable 
(<LLOQ) 
assessment after their peak measure (after 
which no further virus is quantified). 
 Time to resolution from VLPEAK. Time 
to resolution is defined as the time (hours) 
from VLPEAK until first confirmed 
unquantifiable 
(<LLOQ) 
assessment 
(after 
which 
no 
further 
virus 
is 
quantified). 
 Time to resolution from first quantifiable 
(≥LLOQ) assessment. Time to resolution 
is defined as the time (hours) from first 
quantifiable (≥LLOQ) assessment until 
first confirmed unquantifiable (<LLOQ) 
assessment (after which no further virus 
is quantified). 
 Slope of the viral load over time 
(clearance rate), from VLPEAK to 4 days 
after VLPEAK. 
 To 
further 
explore 
the 
pathogenicity 
phenotype 
of 
the 
influenza 
challenge 
agent, 
as 
measured by: 
o Clinical 
symptom-
related endpoints. 
 Duration (hours) of grade ≥2 clinical 
symptoms from Day 1 am to planned 
discharge from quarantine (Day 8 am). 
 Time to resolution of symptoms. Time to 
resolution is defined as the time (hours) 
from first occurrence of TSS above 
baseline until TSS returns to baseline or 
below (after which no further increase 
above baseline is observed). 

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 Time to resolution from peak clinical 
symptoms as measured by graded 
symptom scoring system collected 3 
times daily. Time to resolution is defined 
as the time (hours) from peak clinical 
symptoms until TSS returns to baseline or 
below (after which no further increase 
above baseline is observed). 
 Time to resolution of grade ≥2 symptoms. 
Time to resolution is defined as the time 
(hours) from first occurrence of any grade 
≥2 symptom to occurrence of no grade ≥2 
symptoms (after which no further 
grade ≥2 symptoms occur). 
 To explore the 
incidence 
of 
symptomatic 
infection after 
influenza viral 
challenge. 
 Clinical symptom-related endpoints may 
be further explored, as measured with 
either the full 13 symptoms within the 
graded symptom scoring system, a subset 
of these 13 symptoms, or including 
additional symptoms. 
 Patient perception questionnaire results 
(presence or absence of cold, change in 
severity of cold) may be compared to 
other 
virological 
and 
symptomatic 
endpoints in relation to respiratory viral 
disease including, but not limited to, 
construct validations. 
 To 
explore 
immunity 
to 
influenza 
at 
baseline 
and 
follow-up. 
 Baseline, and change from baseline of 
antibodies (hemagglutination inhibition 
[HAI], 
neutralization) 
after 
viral 
challenge. 
 Seroconversion, defined as follows: 
o HAI: If the pre-challenge serum is <10 
(undetectable), the post-challenge serum must 
have a titer ≥40; if the pre-challenge serum is 
≥10, at least a 4-fold titer increase is required. 
o Foci reduction neutralization assay (FRNA): at 
least a 4-fold titer increase is required. 
 Development of antibodies against the 
virus may be evaluated in serum samples 
 To 
explore 
baseline 
immunology 
and response to 
 Blood and respiratory samples may be 
used for exploratory assays related to 
respiratory viral infection, microbiology, 
genetics, and immunology. 

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infection with 
influenza. 
 To 
explore 
incidence 
of 
influenza virus 
particles 
in 
exhaled breath 
after 
virus 
challenge  
 Air samples and sampling masks may be 
used for exploratory assays to for viral 
load assessments related to transmission 
potential of influenza virus 
* Note that exploratory objectives and endpoints are optional and might be assessed only if 
needed; therefore, not all testing might be performed and reported. 
 
Hypothesis 
Experimental infection with an influenza A H3N2 challenge agent 
in healthy adults is safe and well tolerated. 
Experimental infection with an influenza A H3N2 challenge agent 
allows viral replication and signs and symptoms of disease to be 
measured and selection of a preferred dose for future 
interventional studies. 
There will be no inferential statistical analysis for the study, the 
analysis will be purely descriptive. 
Investigational 
Medicinal Product 
(IMP) 
Not applicable 
Challenge Agent 
Influenza A/England/7763/2022 H3N2 virus 
Challenge Agent Route 
Intranasal 
Challenge Agent Titer 
Part A 
 Dose Arm 1: Medium dose, expected to be 
approximately 104.5 tissue culture infective dose 
50% (TCID50)/mL (titer may be adjusted based on 
stock titer) 
 Dose Arm 2: High dose, expected to be 
approximately 105.5 TCID50/mL (titer may be 
adjusted based on stock titer) 
Part B 
 Expansion Dose: Expansion of one of the Part A 
dose arms, to be determined (TBD), depending on 
outcome of Part A, AND/OR 
 Optional Dose Arm 3: TBD, depending on 
outcome of Part A 

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Study Population 
Healthy adult male and female participants aged between 18 and 
55 years, with a total body weight ≥50 kg and body mass index 
(BMI) ≥18 kg/m2 and ≤35 kg/m2, who have been screened to be 
serosuitable for infection with the influenza challenge agent. 
Summary of Study 
Design 
This is a single-center, randomized, single-blind, proof-of-
concept study in healthy adult male and female participants 18 to 
55 years of age, inclusive, utilizing an intranasally administered 
influenza A H3N2 challenge agent. The primary goal of this 
exploratory study is to establish the optimal dose of the influenza 
challenge agent that is safe and infectious in healthy adults for use 
in subsequent intervention studies. 
A total of up to 80 participants may be given the 
influenza A/England/7763/2022 H3N2 challenge agent. 
In Part A of the study, up to 40 participants will be randomized 
and enrolled (up to 20 participants in Dose Arm 1 [medium dose] 
and up to 20 participants in Dose Arm 2 [high dose]). Further to 
the outcome and analysis of inoculations in Part A, additional 
participants may be enrolled into an optional Part B to: 
• Expand the number of participants in one of the Part A dose 
arms, AND/OR 
• Inoculate different challenge agent titers in optional dose 
arms. 
The study is divided into the following study phases: 
• Screening phase: Screening will occur between Day -90 to 
Day -2/-1. Historical generic screening data collected through 
the hVIVO generic screening process may be transferred to 
this study after the study-specific informed consent form has 
been signed by the participant. 
• Inpatient phase: Participants will be resident in the 
quarantine unit for approximately 11 days (from Day -2/-1 to 
Day 8). 
o Pre-human viral challenge (HVC): 
▪ Quarantine admission on Day -2/-1. 
▪ (Baseline) assessments, randomization (where 
applicable), and eligibility checks will be 
conducted as per Schedule of Events (SoE) up 
to Day 0, pre-challenge. 
o HVC: Influenza challenge agent inoculation on 
Day 0. 
o Post-HVC: 
▪ Day 1 onwards and each day – study 
assessments will be conducted as per SoE. 

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▪ Participants will be discharged from the 
quarantine unit on Day 8 (or may remain 
longer at the discretion of the principal 
investigator [PI]/investigator). 
 Outpatient phase: 
o Final follow-up visit: Day 28 (±3 days). 
Randomization 
Part A will be randomized in a ratio of 1:1. 
Part B: Expansion and/or additional dose arms to be confirmed. If 
more than one dose arm is enrolled in Part B, Part B will be 
randomized. 
Participant 
Replacement Policy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Expected Duration of 
Participation per 
Participant 
Approximately 4 months from screening to the participant’s last 
scheduled visit. 
Overall Duration of 
Clinical Phase 
The length of the clinical phase is expected to be approximately 
6 months from first participant's planned first screening visit to the 
last participant’s last scheduled study visit. 
End-of-Study 
Definition 
The end of the study is defined as the date of the last visit of the 
last participant in the study. 
Sample Size 
Determination 
No formal sample size calculation has been performed for this 
exploratory phase study; the sample size is consistent with earlier 
influenza virus, respiratory syncytial virus, and human rhinovirus 
characterization studies conducted at hVIVO. 
Statistics 
The study will be summarized in terms of descriptive statistics; no 
formal statistical comparisons of groups are planned. 
Continuous variables will be summarized using number of 
available data, number of missing data, arithmetic mean (and/or 

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geometric mean, where applicable), standard deviation, median, 
lower quartile, upper quartile, minimum, and maximum values. 
When relevant, confidence intervals (CIs) will be computed for 
the mean and/or the median. 
Categorical variables will be summarized using number of 
available data, number of missing values, frequency counts for 
each category and corresponding percentage. Percentages will be 
calculated using the number of available data as the denominator 
(i.e., not including missing values). When relevant, CIs will be 
computed. If not otherwise specified in the SAP, the Wilson Score 
Method will be used to compute CIs for proportions. 
 Participants will be grouped and presented against 
the titer of challenge agent they received. 
 The number of participants enrolled, randomized 
(where applicable), withdrawing (also split by 
reason for withdrawal) from and completing the 
study, and the number in each analysis population 
will be summarized for all participants and by 
group. 
 Any missing data will be accounted for, and the 
way their possible impact on the study analysis will 
be evaluated will be described within the SAP. 
Full details of the planned analysis will be presented in the SAP. 
Any deviations from the SAP will be documented in the clinical 
study report. 
Analysis Sets: 
The following analysis sets are defined for this study: 
 The safety analysis set is the same as the intent-to-
treat (ITT) analysis set, defined as all participants 
that have been randomized (where applicable) and 
inoculated. 
 The per protocol (PP) population is defined as all 
participants having received the planned dose of 
challenge agent who have a valid result for at least 
80% of the planned qRT-PCR nasal and throat 
sample analyses from Day 1 (pm) up to Day 8 
(am), i.e., at least 11 out of 14 samples, and who 
present no important protocol deviations likely to 
impact the evaluation of the primary endpoint. 
 Intent-to-treat infected (ITT-I) analysis set is 
defined as all participants that have been 
inoculated with any dose of challenge agent and 
who are infected with challenge agent as per the 
definition of laboratory-confirmed infection for 
this protocol. 

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For the pathogenicity analysis, the PP analysis set will be the 
primary analysis population. The ITT and the ITT-I analysis sets 
will be used for supportive analyses on all or part of the 
pathogenicity endpoints, as defined in the SAP. The safety 
evaluation will be performed on the safety analysis set. 
 
 
 
 

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1.1. 
Study Schematic: On-study Participant Progression 
SCREENING 
PHASE 
 
INPATIENT PHASE: QUARANTINE/ISOLATION, HUMAN VIRAL 
CHALLENGE (HVC) 
 
OUTPATIENT 
PHASE 
 
 
 
 
 
 
 
 
 
 
 
Day -90 to 
Day -2/-1 
Screening* 
 
 
Day -2/-1 
 
Quarantine 
admission 
 
Day 0 
 
Inoculation with 
challenge agent 
 
Days 1 to 7 
 
Dosing and 
assessments 
 
Day 8 
 
Discharge from 
quarantine unit** 
 
Day 28 (±3 days) 
 
Follow-up visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.2. 
Schedule of Events 

hVIVO 
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hVIVO 
Study Number: HRD-vCS-006 
Clinical Study Protocol 
Version: Final V4.0 20DEC2024 
 
 
 
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hVIVO 
Study Number: HRD-vCS-006 
Clinical Study Protocol 
Version: Final V4.0 20DEC2024 
 
 
 
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hVIVO 
Study Number: HRD-vCS-006 
Clinical Study Protocol 
Version: Final V4.0 20DEC2024 
 
 
 
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KEY NOTES FOR SCHEDULE OF EVENTS 
 
 
 
 
 
 
 
 
 
 
 
 

hVIVO 
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hVIVO 
Study Number: HRD-vCS-006 
Clinical Study Protocol 
Version: Final V4.0 20DEC2024 
 
 
 
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hVIVO 
Study Number: HRD-vCS-006 
Clinical Study Protocol 
Version: Final V4.0 20DEC2024 
 
 
 
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hVIVO 
Study Number: HRD-vCS-006 
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Version: Final V4.0 20DEC2024 
 
 
 
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2. 
INTRODUCTION 
2.1. 
Background 
Influenza viruses are associated with significant human disease and cause annual epidemics 
during autumn and winter. Although most people recover within 1 to 2 weeks without requiring 
medical attention, seasonal influenza yearly results in approximately 3 to 5 million cases of 
severe illness and up to 500,000 deaths worldwide, particularly among the very young, elderly, 
and chronically ill. Influenza caused an estimated yearly average of 23,600 deaths between 
seasons 1976 and 2007 and more than 200,000 hospitalizations in the United States. 
Comparable mortality and morbidity rates have been reported for European countries. 
Currently, the influenza type A viruses H1N1 and H3N2 are circulating in humans, along with 
influenza type B viruses. H3N2 viruses have been predominant in most seasons and have 
caused a higher number of deaths and hospitalizations than H1N1 and influenza B viruses 
(Nunes et al, 2011; Thompson et al, 2004; Zucs et al, 2005). 
The neuraminidase inhibitors zanamivir and oseltamivir are currently recommended for the 
treatment and/or (post-exposure) prophylaxis of influenza A and B virus infections (Fiore et 
al, 2011; Weinstock and Zuccotti, 2009). However, new drugs are now required as there have 
been reports of the emergence of resistance after oseltamivir treatment (Dharan et al, 2009; 
Poland et al, 2009; Stephenson et al, 2009) and the increasing use of zanamivir monotherapy 
may lead to the development of zanamivir resistance. Xofluza (baloxavir marboxil) was 
subsequently developed and is available in several countries for treatment and post-exposure 
prophylaxis for influenza A and B. However, there remains a need to develop better vaccines 
(demonstrating high efficacy, with longer or broader protection, or with faster manufacturing) 
as well as additional antivirals and immunomodulators to manage infection, transmission, and 
disease. 
The influenza human challenge model was established to not only aid understanding of 
influenza disease and transmission, but to also assess the efficacy of antivirals, 
immunomodulators, and vaccines (as reviewed by Bueno de Mesquita et al, 2021; Lambkin-
Williams et al, 2018; Nguyen-Van-Tam et al, 2020; Ramos-Sevillano et al, 2019; Yogaratnam 
et al, 2019). hVIVO has given different influenza strains to over 2,000 volunteers over the last 
20 years. The various influenza challenge strains have been well tolerated with no challenge 
agent-related serious adverse events (SAEs) occurring in any of the participants inoculated to 
date. Furthermore, the influenza challenge viruses have been shown to induce measurable 
disease profiles with clear distinction from non-infected participants and study participants 
have approximately 60% to 75% chance of becoming infected following the administration of 
the viruses. Typical influenza illness is characterized by an abrupt onset of rhinitis, nasal 
stuffiness, fever, malaise, myalgia (muscle aches), and sore throat. In healthy adults the illness 
usually resolves without any treatment, with relief of symptoms occurring naturally within 
3 to 5 days. The disease profiles of the challenge agents are consistent with the mild to 
moderate disease profiles expected with wild-type challenge viruses in healthy adult 
participants (Fragaszy et al, 2017). 
Both influenza A and B types circulate seasonally, and both types contribute to the morbidity 
and mortality seen each year. This study is specifically intended to characterize a new, more 
recent influenza A H3N2 strain for further usage in a vaccine efficacy study. However, prior 
to the study, hVIVO will know the virus stock titer and based on this, will select the doses to 
be given to the participants. The doses planned in this study are based on hVIVO’s experience 
with other H1N1 and H3N2 influenza challenge viruses and may be adjusted based on the final 
virus stock titer. 

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The known risks to participants in this study have been addressed in the study eligibility 
criteria, and qualified study site staff in the quarantine unit will manage any symptoms that 
develop during the study. 
2.2. 
Study Rationale 
The purpose of this exploratory study is to establish the dose, safety, and pathogenicity of a 
new influenza challenge strain in healthy participants 18 to 55 years of age. 
2.3. 
Benefit/Risk Assessment 
Healthy participants will not directly benefit from this clinical study. Some limited protection 
from related circulating influenza A strains may be imparted on those who seroconvert 
following viral challenge. Results from this clinical study may be useful in developing new 
approaches to controlling influenza A H3N2 virus-related infections and disease. 
2.3.1. 
Risk Assessment 
The known risks to participants are detailed below. However, there may also be risks that are 
unforeseen and unanticipated (e.g., unknown allergies). Every effort will be made to monitor 
the health of the participants to ensure that such risks are minimized. Trained medical staff and 
appropriate facilities will be available to provide medical emergency care. 
 

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Potential Risk of Clinical 
Significance 
Description of Risk 
Mitigation Strategy 
Study Intervention 
Study Procedures 
Blood sampling 
Pain or bruising at the site where blood is drawn. 
Blood samples will be obtained by a trained 
professional.  
Syncope (fainting) can occur following or even 
before any blood draw as a psychogenic response to 
the needle insertion. 
Blood samples will be obtained by a trained 
professional and procedures will be put in place to 
avoid injury from fainting. 
There is a possibility that, in the process of collecting 
blood, a nerve may be injured. 
Procedure to be performed by qualified personnel. 
Blood tests performed to address the health of the 
participants at screening and during the study may 
indicate that a participant has an infection that they 
were not previously aware of (such as human 
immunodeficiency virus [HIV] or hepatitis) or an 
unexpected illness. 
If the participant agrees, the hVIVO doctor will 
provide the participant’s general practitioner (GP) or 
other appropriate doctor with a referral letter. 
Nasal and throat sampling 
Collection of respiratory (nasal) and throat samples 
may cause e.g., discomfort, sneezing, watery eyes, 
irritated nose, or nose bleeding. 
Sample collection will be performed by appropriately 
qualified and trained study staff to minimize the 
discomfort. 

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Potential Risk of Clinical 
Significance 
Description of Risk 
Mitigation Strategy 
Influenza A/England/7763/2022 H3N2 Infection from Inoculation 
Influenza A/England/7763/2022 
H3N2 
infection 
& 
severe 
complications 
There is a chance of becoming infected with 
influenza A/England/7763/2022 H3N2 virus. One of 
the objectives of this study is to establish this 
infectivity rate. Typical influenza illness: abrupt 
onset of rhinitis, nasal stuffiness, fever, malaise, 
myalgia (muscle aches), and sore throat. 
Severe complications are not expected as these tend 
to occur almost exclusively in infants, the elderly, and 
persons of any age with chronic comorbidities and 
significant immune compromise and not in young, 
healthy 
cohorts 
with 
no 
comorbidities 
or 
coinfections. 
Influenza virus, like many viruses, can cause more 
substantial health issues such as myocarditis 
(inflammation or damage to the heart muscle). 
However, the chance of this resulting in serious or 
permanent changes is rare, as most cases are minor 
and resolve without any lasting changes. 
Characterizing 
the 
safety 
profile 
of 
the 
influenza A/England/7763/2022 H3N2 virus is an 
objective of this study. However, influenza infection 
in healthy adults is usually mild and resolves without 
treatment within around 7 days (Woods et al, 2013; 
Wilkinson et al, 2012; Zaas et al, 2009; Florman et al, 
1946). 
Strict inclusion and exclusion criteria will apply to 
ensure only healthy adults are enrolled in this study. 
There will be daily medical monitoring in a 
quarantine unit for at least 8 days post viral challenge. 
Qualified medical and nursing staff in the quarantine 
unit will monitor for and manage any symptoms. 
Transmission 
of 
influenza A/England/7763/2022 
H3N2 to participants’ close 
contacts 
The presence in nasal secretions can cause infection 
in close contacts. 
Virus is usually absent from the nose by the time 
participants are discharged from quarantine. This will 
be confirmed by testing a nasal swab sample by using 
a qualitative virus antigen test (influenza discharge 
test [e.g., rapid viral antigen test {RVAT}]) or PCR 
to determine participants’ suitability for discharge. 

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Potential Risk of Clinical 
Significance 
Description of Risk 
Mitigation Strategy 
In addition, participants will be instructed to avoid 
close contact with vulnerable individuals as described 
in Section 2.3.1.1, Vulnerable Persons, for 2 weeks 
after they leave the quarantine unit. 
Risk of reactivation of herpes 
infection 
If a participant ever had a herpes infection (e.g., cold 
sores, genital herpes, or shingles) there is a low 
possibility that this infection could return after viral 
challenge. 
Participants will be instructed to inform the study 
staff if they currently have an active herpes infection 
or have had one during the 30 days before enrollment. 
If a participant develops any cold sore, herpes, or 
shingles they may be treated symptomatically while 
at the quarantine unit. If it continues, they will be 
followed up until resolved or, if necessary and 
dependent on medical history, will be referred to their 
GP or any specific department at hospital, as required. 
 

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2.3.1.1. 
Vulnerable Persons 
For the purposes of possible contact after leaving the quarantine unit, the participant should 
avoid close contact with vulnerable individuals for 2 weeks after they leave the quarantine unit. 
A vulnerable individual is a person including but not limited to: 
 Persons ≥65 years of age. 
 Children ≤2 years of age. 
 Residents of nursing homes. 
 Women who are pregnant or who are trying to become pregnant. 
 Persons of any age with significant chronic medical conditions such as: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.3.1.2. 
Risk Associated With Coronavirus Disease 2019 Pandemic 
hVIVO has implemented enhanced infection control measures during the pandemic to 
minimize risks of COVID-19 infection. 
Risk of Increased Severity of COVID-19 Infection if Contracted After Challenge Agent 
Inoculation: 
 
 
 
 
 
 
 
 
 
2.3.2. 
Benefit Assessment 
Healthy participants will not receive direct benefit from treatment during their participation in 
this clinical study. 
Participants may develop some immunity to influenza A/England/7763/2022 H3N2 challenge 
agent and benefit from a general health check at screening. Benefit may also be derived from 
the medical evaluations and assessments associated with study procedures. In addition, 

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participants are contributing to the process of developing new therapies in an area of unmet 
medical need. 
2.3.3. 
Overall Benefit/Risk Conclusion 
Considering the measures taken to minimize risk to participants in this study, the potential risks 
identified in association with influenza A/England/7763/2022 H3N2 virus infection are 
justified by the anticipated benefits linked to characterization of a new influenza challenge 
strain for future evaluation of the efficacy of novel vaccines and therapies in an influenza 
challenge model. 

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3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
Pathogenicity & Safety 
 To 
determine 
the 
safe 
and 
optimal titer of 
the 
influenza 
challenge agent. 
To identify a safe and infectious dose of wild-type 
influenza virus in healthy participants, suitable for future 
intervention studies that: 
 Has an acceptable safety profile as 
measured by: 
o Occurrence of adverse events (AEs) related to the 
viral challenge from viral challenge (Day 0) to the 
Day 28 (±3 days) follow-up visit. 
o Occurrence of SAEs related to the viral challenge 
from viral challenge (Day 0) to the Day 28 (±3 
days) follow-up visit. 
 Induces laboratory-confirmed infection in 
≥40% of inoculated participants (ideally 
between 50% and 80%). Laboratory-
confirmed infection is defined as: 
o Quantitative 
reverse 
transcriptase-polymerase 
chain reaction (qRT-PCR)-confirmed influenza 
infection, defined as 2 quantifiable (≥ lower limit 
of 
quantification 
[LLOQ]) 
qRT-PCR 
measurements 
(reported 
over 
4 planned 
consecutive assessments within 48 hours), from 
Day 1 pm to planned discharge from quarantine 
(Day 8 am). 
Secondary 
Pathogenicity 
 To evaluate the 
incidence 
of 
viral 
culture-
confirmed 
influenza 
infection. 
 Viral 
culture-confirmed 
influenza 
infection, defined as a quantifiable viral 
culture measurement, from Day 1 pm to 
planned 
discharge 
from 
quarantine 
(Day 8 am). 
 To evaluate the 
optimal titer of 
the 
influenza 
challenge agent, 
as measured by: 
The following endpoints will be determined by both 
qRT-PCR and viral culture on nasal and throat samples: 
 Area under the viral load-time curve (VL-
AUC) of the influenza challenge agent, 

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Objectives 
Endpoints 
o Viral 
load-related 
endpoints. 
from Day 1 pm to planned discharge from 
quarantine (Day 8 am). 
 Peak viral load (VLPEAK) of the influenza 
challenge agent, defined as the maximum 
viral load, from Day 1 pm to planned 
discharge from quarantine (Day 8 am). 
 To explore the 
optimal titer of 
the 
influenza 
challenge agent, 
as measured by: 
o Clinical 
symptom-
related endpoints. 
 Area under the total clinical symptom 
score-time curve (TSS-AUC) as measured 
by graded symptom scoring system 
collected 3 times daily from Day 1 am to 
planned 
discharge 
from 
quarantine 
(Day 8 am). 
 Peak daily symptom score: individual 
maximum daily sum of symptom score 
from Day 1 (am) to planned discharge from 
quarantine (Day 8 am). 
 Peak symptom diary card score: peak total 
symptom score (TSS) as measured by 
graded symptom scoring system collected 
3 times daily from Day 1 am to planned 
discharge from quarantine (Day 8 am). 
 To explore the 
optimal titer of 
the 
influenza 
challenge agent, 
as measured by 
the incidence of 
influenza-like 
illness (ILI) and 
laboratory-
confirmed 
symptomatic 
influenza 
infection. 
 Laboratory-confirmed febrile influenza 
infection, defined as: 
o Laboratory-confirmed infection, AND 
o A febrile episode, defined as a temperature of 
≥37.9°C, from Day 1 am to planned discharge 
from quarantine (Day 8 am). 
 qRT-PCR-confirmed ILI (Centers for 
Disease and Control [CDC]), defined as: 
o Laboratory-confirmed infection, AND 
o A febrile episode, defined as a temperature of 
≥37.8ºC, from Day 1 am to planned discharge 
from quarantine (Day 8 am), AND 
o Cough and/or sore throat (symptoms and signs), 
from Day 1 am to planned discharge from 
quarantine (Day 8 am), in the absence of a known 
cause other than influenza. 
 qRT-PCR-confirmed ILI (World Health 
Organization [WHO]), defined as: 
o Laboratory-confirmed infection, AND 

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Objectives 
Endpoints 
o A febrile episode, defined as a temperature of 
≥38.0ºC, from Day 1 am to planned discharge 
from quarantine (Day 8 am), AND 
o Cough, from Day 1 am to planned discharge from 
quarantine (Day 8 am). 
 Laboratory-confirmed moderately severe 
symptomatic influenza infection, defined 
as: 
o Laboratory-confirmed infection, AND 
o Any symptoms from the symptom diary card of 
grade ≥2 at a single time point, from Day 1 am to 
planned discharge from quarantine (Day 8 am). 
 Laboratory-confirmed 
symptomatic 
influenza infection, defined as: 
o Laboratory-confirmed infection, AND 
o TSS ≥2 at a single time point, from Day 1 am to 
planned discharge from quarantine (Day 8 am). 
 Viral 
culture 
laboratory-confirmed 
moderately severe symptomatic influenza 
infection, defined as: 
o Viral culture laboratory-confirmed infection, AND 
o Any symptoms from the symptom diary card of 
grade ≥2 at a single time point, from Day 1 am to 
planned discharge from quarantine (Day 8 am). 
Further analyses may be performed on the above 
endpoints, using modified start or end times. Details will 
be provided in the statistical analysis plan (SAP). 
Further analyses may be performed on the above 
qRT-PCR-related endpoints where detection by qRT-PCR 
is reported above the lower limit of detection (LLOD) 
instead of the LLOQ. Details will be provided in the SAP. 
Exploratory* 
 To 
further 
explore 
the 
pathogenicity 
phenotype 
of 
wild-type 
influenza 
in 
healthy 
participants, as 
measured by: 
 Safety laboratory tests,  
 lung function,  
 electrocardiograms [ECGs], 
 physical examinations, and concomitant 
medications. 

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Objectives 
Endpoints 
o Safety assessments. 
 To 
further 
explore 
the 
pathogenicity 
phenotype 
of 
influenza 
challenge agent, 
as measured by: 
o Nasal 
discharge 
endpoints. 
 Total weight of mucus produced from 
Day 1 
to 
planned 
discharge 
from 
quarantine (Day 8 am). 
 Total number of tissues used by participant 
from Day 1 to planned discharge from 
quarantine (Day 8 am). 
 To 
further 
explore 
the 
pathogenicity 
phenotype 
of 
the 
influenza 
challenge agent, 
as measured by: 
o Viral 
load-related 
endpoints. 
The following endpoints may be determined by both 
qRT-PCR and viral culture on nasal and throat samples: 
 Duration of quantifiable influenza, from 
Day 1 pm to planned discharge from 
quarantine (Day 8 am). Duration is defined 
as the time (hours) from first quantifiable 
(≥LLOQ) 
until 
first 
confirmed 
unquantifiable (<LLOQ) assessment after 
their peak measure (after which no further 
virus is quantified). 
 Time to resolution from VLPEAK. Time to 
resolution is defined as the time (hours) 
from VLPEAK until first confirmed 
unquantifiable (<LLOQ) assessment (after 
which no further virus is quantified). 
 Time to resolution from first quantifiable 
(≥LLOQ) assessment. Time to resolution is 
defined as the time (hours) from first 
quantifiable (≥LLOQ) assessment until 
first confirmed unquantifiable (<LLOQ) 
assessment (after which no further virus is 
quantified). 
 Slope of the viral load over time (clearance 
rate), from VLPEAK to 4 days after 
VLPEAK. 
 To 
further 
explore 
the 
pathogenicity 
phenotype 
of 
the 
influenza 
challenge agent, 
as measured by: 
 Duration (hours) of grade ≥2 clinical 
symptoms from Day 1 am to planned 
discharge from quarantine (Day 8 am). 
 Time to resolution of symptoms. Time to 
resolution is defined as the time (hours) 
from first occurrence of TSS above 
baseline until TSS returns to baseline or 

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Objectives 
Endpoints 
o Clinical 
symptom-
related endpoints. 
below (after which no further increase 
above baseline is observed). 
 Time to resolution from peak clinical 
symptoms as measured by graded symptom 
scoring system collected 3 times daily. 
Time to resolution is defined as the time 
(hours) from peak clinical symptoms until 
TSS returns to baseline or below (after 
which no further increase above baseline is 
observed). 
 Time to resolution of grade ≥2 symptoms. 
Time to resolution is defined as the time 
(hours) from first occurrence of any grade 
≥2 symptom to occurrence of no grade ≥2 
symptoms (after which no further grade ≥2 
symptoms occur). 
 To explore the 
incidence 
of 
symptomatic 
infection 
after 
influenza viral 
challenge. 
 Clinical symptom-related endpoints may 
be further explored, as measured with 
either the full 13 symptoms within the 
graded symptom scoring system, a subset 
of these 13 symptoms, or including 
additional symptoms. 
 Patient perception questionnaire results 
(presence or absence of cold, change in 
severity of cold) may be compared to other 
virological and symptomatic endpoints in 
relation 
to 
respiratory 
viral 
disease 
including, but not limited to, construct 
validations. 
 To 
explore 
immunity 
to 
influenza 
at 
baseline 
and 
follow-up. 
 Baseline, and change from baseline of 
antibodies (hemagglutination inhibition 
[HAI], neutralization) after viral challenge. 
 Seroconversion, defined as follows: 
o HAI: If the pre-challenge serum is <10 
(undetectable), the post-challenge serum must 
have a titer ≥40; if the pre-challenge serum is ≥10, 
at least a 4-fold titer increase is required. 
o Foci reduction neutralization assay (FRNA): at 
least a 4-fold titer increase is required. 
 Development of antibodies against the 
virus may be evaluated in serum samples 
 To 
explore 
baseline 
 Blood and respiratory samples may be used 
for exploratory assays related to respiratory 

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Objectives 
Endpoints 
immunology 
and response to 
infection 
with 
influenza. 
viral infection, microbiology, genetics, and 
immunology. 
 To explore the 
incidence 
and 
magnitude 
of 
influenza virus 
particles 
from 
exhaled breath 
after 
virus 
challenge 
 Air samplers and sampling masks to collect 
exhaled breath samples to be used for 
exploratory assays to for viral load 
assessments 
related 
to 
transmission 
potential of influenza virus 
 
* Note that exploratory objectives and endpoints are optional and might be assessed only if needed; 
therefore, not all testing might be performed and reported. 
 
 
 

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4. 
STUDY DESIGN 
4.1. 
Overview of Study Design 
This is a single-center, randomized, single-blind, proof-of-concept study in healthy adult male 
and female participants 18 to 55 years of age, inclusive, utilizing: 
 Intranasally administered influenza A H3N2 challenge agent. 
A total of up to 80 participants may be given the influenza A/England/7763/2022 H3N2 
challenge agent. 
In Part A of the study, up to 40 participants will be randomized and enrolled (up to 
20 participants in Dose Arm 1 [medium dose] and up to 20 participants in Dose Arm 2 [high 
dose]. Further to the outcome and analysis of inoculations in Part A, additional participants 
may be enrolled into an optional Part B to: 
 Expand the number of participants in one of the Part A dose arms, AND/OR 
 Inoculate different challenge agent titers in optional dose arms. 
Both parts of the study will be single-blinded; participants will not know the challenge agent 
dose level (or relative dose level [i.e., higher or lower than other participants]) that they receive. 
The primary goal of this exploratory study is to establish the optimal dose of the influenza 
challenge agent that is safe and infectious in healthy adults for use in subsequent intervention 
studies. 
The expected duration of study participation for a participant is 4 months, with the following 
sequence and duration of study phases: 
• Screening phase: From Day -90 to Day -2/-1.  
Historical generic screening data collected through the hVIVO generic screening process 
may be transferred to this study after the study-specific informed consent form (ICF) has 
been signed by the participant. 
 Inpatient phase: Participants will be resident in the quarantine unit for 
approximately 11 days (from Day -2/-1 to Day 8). Procedures will include: 
o Pre-human viral challenge (HVC): 
▪ Quarantine admission on Day -2/-1. 
▪ (Baseline) assessments, randomization (where applicable), and eligibility checks 
will be conducted as per Schedule of Events (SoE) up to Day 0, pre-challenge. 
o HVC: 
▪ Influenza challenge agent inoculation on Day 0 
Following challenge agent inoculation, participants will be closely observed 
specifically for potential allergic reactions and any AEs for the following 24 hours. 
Post inoculation, participants will remain under observation for 30 minutes. 
Participants will continue to be monitored throughout the clinical phase of the study. 
o Post-HVC: 
▪ Day 1 onwards and each day – study assessments will be conducted as per SoE. 
▪ Participants will be discharged from the quarantine unit on Day 8 
 
 

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 Outpatient phase: 
o Final follow-up visit: Day 28 (±3 days). 
The Study Schematic, showing participant progression through the study, is presented in 
Section 1.1, Study Schematic. The SoE is presented in Section 1.2, Schedule of Events. 
4.2. 
Scientific Rationale for Study Design 
The study will be conducted by hVIVO Services Limited, which has extensive experience with 
influenza challenge studies. Numerous studies have been performed using experimental 
influenza infection in human participants. To date, in hVIVO’s studies, over 2,000 participants 
have been successfully and safely inoculated with influenza. These studies demonstrated that 
adults could be infected by nasal inoculation and that experimental infection was safe. 
Influenza challenge strains have been shown to cause symptoms and virus shedding that closely 
match natural infection. In this study a new influenza challenge strain will be used; 
influenza A/England/7763/2022 H3N2 virus. 
Challenge with influenza will take place in hVIVO’s specialized quarantine unit. Standard 
study procedures (including collection of blood, urine, and nasopharyngeal secretions for 
assessment of safety and pathogenicity) have been employed in previous studies conducted by 
hVIVO. 
Randomization and Blinding 
Randomization and participant blinding will be applied in Part A (and in Part B, if more than 
one dose arm is enrolled) of the study. 
Randomization will be used to prevent bias in the assignment of participants to dose arms, to 
increase the likelihood that known and unknown participant characteristics (e.g., demographic 
and baseline characteristics) are equally balanced across dose arms, and to enhance the validity 
of statistical comparisons across dose arms. 
Blinding will prevent the occurrence of conscious and unconscious bias in the conduct and 
interpretation of the study. 
Together, the randomized, and blinded features of the study will allow a causal interpretation 
of the study results. 
4.3. 
Justification for Dose 
An inoculum titer of approximately 104.5 tissue culture infective dose 50% (TCID50)/mL to 
105.5 TCID50/mL of the influenza A/England/7763/2022 H3N2 challenge agent is expected to 
cause disease profiles that are consistent with the mild to moderate disease profiles expected 
with wild-type challenge viruses in healthy adult participants. The objective of this study is to 
confirm the optimal dose that is both safe and induces suitable infection rates in healthy adults. 
4.4. 
End-of-Study Definition 
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last scheduled visit shown in the SoE or the last unscheduled visit, as 
applicable. If a safety visit is required after the last scheduled visit, this will be at the discretion 
of the PI/investigator as a duty of care, e.g., repeat spirometry or laboratory tests. These 
discretionary follow-up visits will not be considered part of the study data unless they represent 
follow-up and closure on an AE or SAE identified during the study period. 
The end of the study is defined as the date of the last visit of the last participant in the study. 

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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all the following criteria apply: 
No. 
Inclusion Criteria 
1. 
Written study-specific informed consent signed and dated by the participant and 
the PI/investigator obtained before any study-specific assessment is performed. 
2. 
Aged between 18 and 55 years old, inclusive, on the day prior to signing the 
consent form. 
3. 
A total body weight ≥50 kg and body mass index (BMI) ≥18 kg/m2 and ≤35kg/m2. 
4. 
In good health with no history, or current evidence, of clinically significant 
medical conditions, 
 
 
 
 
 
5. 
Participants will have a documented medical history either prior to entering the 
study or following medical history review with the study physician at screening. 
6. 
The following criteria are applicable to female participants participating in the 
study: 
a) Females of childbearing potential must have a negative pregnancy test 
prior to enrollment. 
b) Females of non-childbearing potential: 
a. Postmenopausal females 
 
 
 
 
 
 
 
b. Documented status as being permanently sterile 
 
 

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7. 
The following criteria apply to female participants: 
Female participants of childbearing potential must use one form of highly 
effective contraception (birth control). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The following criteria applies to male participants: 
Male participants must agree to use at least one of the contraceptive requirements 
 
 
 
 
 
 
 
 
 
 
 
 

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No. 
Inclusion Criteria 
 
 
d) In addition to the contraceptive requirements above, male participants 
must agree not to donate sperm 
 
 
8. 
Serosuitable for the challenge agent: 
• The serology result obtained from the influenza A H3N2 virus antibody assay 
suggests that the participant is sensitive to influenza infection (i.e., they are 
likely to be infected following inoculation with the challenge agent). 
 
 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any the following criteria apply: 
No. 
Exclusion Criteria 
Medical History 
1. 
History of, or currently active, symptoms or signs suggestive of upper or lower 
respiratory tract infection within 4 weeks prior to the first study visit (i.e., 
quarantine admission). 
2. 
Any history or evidence of any clinically significant or currently active 
cardiovascular, respiratory, dermatological, gastrointestinal, endocrinological, 
hematological, 
hepatic, 
immunological 
(including 
immunosuppression), 
metabolic, urological, renal, neurological, or psychiatric disease and/or other 
major disease that, in the opinion of the PI/investigator, may interfere with a 
participant completing the study and necessary investigations. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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No. 
Exclusion Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. 
Any participants who have smoked ≥10 pack years at any time (10 pack years is 
equivalent to one pack of 20 cigarettes a day for 10 years), including any 
calculable or self-reported significant vaping history. 
4. 
Females who: 
a) Are breastfeeding, or 
b) Have been pregnant 
 or 
c) Have a positive pregnancy test at any point during screening or prior to 
viral challenge. 
5. 
Lifetime history of anaphylaxis and/or a lifetime history of severe allergic 
reaction. 
 
 
6. 
Venous access deemed inadequate 
 
 
7. 
a) Any significant abnormality altering the anatomy of the nose or throat in a 
substantial way or nasopharynx or throat  that may interfere with the aims 
of the study and, in particular, any of the nasal assessments or viral 
challenge, (historical nasal polyps can be included, but large nasal polyps 

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No. 
Exclusion Criteria 
causing current and significant symptoms and/or requiring regular 
treatments in the last month will be excluded). 
b) Any clinically significant history of epistaxis (large nosebleeds) within the 
last 3 months of the first study visit (i.e., quarantine admission) and/or 
history of being hospitalized due to epistaxis on any previous occasion. 
c) Any nasal or sinus surgery within 3 months of the first study visit (i.e., 
quarantine admission). 
Prior or Concomitant Medications and Assessments 
8. 
a) Evidence of vaccinations within the 4 weeks prior to the planned date of 
viral challenge. 
b) Intention to receive any vaccination(s) before the last day of follow-up 
(NB. no travel restrictions will apply after the Day 28 (±3 days) follow-up 
visit). 
9. 
Receipt of blood or blood products, or loss (including blood donations) of 550 mL 
or more of blood during the 3 months prior to the planned date of viral challenge 
or planned during the 3 months after the final visit. 
10. 
a) Receipt of any investigational medicinal product (IMP) within 3 months 
or 5 half-lives, whichever is longer, of the IMP used in the other study prior 
to the planned date of viral challenge. 
b) Receipt of 3 or more IMPs within the previous 12 months prior to the 
planned date of viral challenge. 
c) Receipt of influenza vaccine (or an IMP related to the treatment or 
prophylaxis of influenza) in the last 6 months prior to the planned date of 
viral challenge OR a diagnosis of influenza or ILI confirmed by a 
physician within the last 2 months prior to screening. 
d) Prior inoculation with a virus from the same virus subtype as the challenge 
agent. 
e) Prior inoculation with a virus from the same virus family as the challenge 
virus in the last 12 months. 
f) Prior participation in another HVC study with a respiratory virus in the 
preceding 3 months, taken from the date of viral challenge in the previous 
study to the date of expected viral challenge in this study. 
11. 
Use or anticipated use during the conduct of the study of concomitant medications 
(prescription and/or non-prescription), including vitamins or herbal and dietary 
supplements within the specified windows, unless in the opinion of the study 
physician or PI/investigator, the medication will not interfere with the study 

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No. 
Exclusion Criteria 
procedures or compromise participant safety. Specifically, the following are 
excluded: 
a) Herbal supplements within 7 days prior to the planned date of viral 
challenge. 
b) Any medication or product (prescription or over the counter) for symptoms 
of nasal congestion within 7 days prior to the planned date of viral 
challenge. 
c) Short- and long-acting antihistamines within 7 days prior to the planned 
date of viral challenge. 
d) Chronically used medications, vitamins, or dietary supplements, including 
any medications known to be potent inducers or inhibitors of cytochrome 
P450 (CYP) enzymes, within 21 days prior to the planned date of viral 
challenge. 
e) Over the counter medications (e.g., paracetamol or ibuprofen) where the 
dose taken over the preceding 7 days prior to the planned date of viral 
challenge has exceeded the maximum permissible 24-hour dose (e.g., ≥4 g 
paracetamol per day) over the preceding week. 
f) Systemic (oral and parenteral) antiviral administration within 4 weeks of 
viral challenge. 
12. 
a) Confirmed positive test for drugs of misuse on first study visit (i.e., 
quarantine admission). 
 
 
b) Recent history or presence of alcohol addiction, or excessive use of alcohol 
(weekly intake in excess of 28 units alcohol; 1 unit being a half glass of 
beer, a small glass of wine or a measure of spirits). 
c) Excessive consumption of xanthine containing substances (e.g., daily 
intake in excess of 5 cups of caffeinated drinks, e.g., coffee, tea, cola). 
d) Presence of significant signs and symptoms of nicotine withdrawal on first 
study visit (i.e., quarantine admission). Cotinine testing may be performed 
at the PI/investigator’s discretion. 
13. 
A forced expiratory volume in 1 second (FEV1) 
 
14. 
Positive HIV, hepatitis B virus, or hepatitis C virus test. 
15. 
Presence of fever, 
 
on Day -2, Day -1, 
 
Other 
16. 
Those employed or immediate relatives of those employed at hVIVO. 
17. 
a) Any other medical, psychiatric, social, or occupational condition and/or 
responsibility that, in the opinion of the PI/investigator, would interfere 

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No. 
Exclusion Criteria 
with or serve as a contraindication to protocol adherence or the assessment 
of safety (including reactogenicity) will deem the participant unsuitable for 
the study. 
b) Any other reason that in the opinion of the PI/investigator raises a concern 
that the participant will not be able to cope with quarantine requirements.  
 
 
 
5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
 
 
5.3.2. 
Caffeine, Alcohol, and Tobacco 
 
 
 
 
 
 
 
 
 
 
5.3.3. 
Activity 
Participants must refrain from strenuous exercise 
 
 
 
 
 
5.3.4. 
Other Restrictions 
Participants will be instructed to avoid close contact with vulnerable people as described in 
Section 2.3.1.1, Vulnerable Persons, for 2 weeks after they leave the quarantine unit. 
Participants will be advised to avoid all but essential travel until the Day 28 (±3 days) follow-up 
visit. 
5.4. 
Screen Failures 
 
 

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6. 
STUDY INTERVENTIONS AND CONCOMITANT THERAPY 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol. 
6.1. 
Study Intervention(s) Administered 
Study interventions administered to participants are described in Table 6-1. 
Table 6-1: 
Study Interventions 
Intervention Name 
Influenza A/England/7763/2022 H3N2 virus 
Type 
Influenza virus 
Formulation 
Capped cryovial, liquid 
Unit Dose 
Strength(s) 
The challenge agent titer is determined in an infectivity assay. The 
doses are: 
Part A 
 Dose Arm 1: Medium dose, expected to be 
approximately 104.5 tissue culture infective dose 50% 
(TCID50)/mL (titer may be adjusted based on stock 
titer) 
 Dose Arm 2: High dose, expected to be approximately 
105.5 TCID50/mL (titer may be adjusted based on stock 
titer) 
Part B 
 Expansion Dose: Expansion of one of the Part A dose 
arms, to be determined (TBD), depending on outcome 
of Part A, AND/OR 
 Optional Dose Arm 3: TBD, depending on outcome 
of Part A 
Dosage Level(s) 
A single dose of challenge agent will be delivered. 
Route of 
Administration 
Intranasal 
Use 
Infectious challenge agent 
Sourcing 
Provided centrally by hVIVO 
Packaging and 
Labeling 
Influenza A/England/7763/2022 H3N2 virus will be provided in 
vials. The details of the challenge agent provision will be provided 
in the analytical plan (AP). 

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Intervention Name 
Influenza A/England/7763/2022 H3N2 virus 
Current/Former 
Name(s) or 
Alias(es) 
Not applicable 
 
6.2. 
Challenge Agent 
6.2.1. 
Preparation/Handling 
The challenge agent used in this study is influenza A/England/7763/2022 H3N2 virus. 
The challenge agent stock was manufactured under current Good Manufacturing Practice. The 
challenge agent stock has undergone quality testing performed during manufacturing (identity, 
appearance, sterility, infectivity, and contaminants) according to pre-determined specifications, 
and has subsequently also passed an extensive panel of adventitious agent testing. 
Each participant will be allocated a unique vial containing the challenge agent and will receive 
the inoculum intranasally. The inoculum will be prepared and/or provided according to the 
hVIVO AP and administered in accordance with hVIVO standard operating procedures 
(SOPs). The time from the challenge agent inoculum thawing to challenge agent administration 
should be no longer than 4 hours (on wet ice). 
Only participants who signed the study-specific informed consent may receive challenge agent 
and only authorized investigator site staff may supply or administer challenge agent. 
All administrations will be made by a member of the study staff and witnessed by a second 
study staff member. The exact time of challenge agent inoculation will be recorded in the 
administration log. Accurate records will be kept of when and how much inoculum is prepared 
and used. The oversight process will be signed off prior to administration of the challenge 
agent. Any noncompliance or problems with the inoculation will be recorded in the 
participant’s source notes and reported to the PI/investigator. 
6.2.2. 
Accountability/Storage 
The PI/investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all challenge agent received and that any discrepancies are 
reported and resolved before use of the challenge agent. 
The challenge agent is stored in a secure -80C freezer (normal temperature range -60°C 
to -90°C). All challenge agent must be stored in a secure, environmentally controlled area, and 
monitored (manual or automated) in accordance with the labeled storage conditions with access 
limited to the PI/investigator and authorized investigator site staff. 
The PI/investigator, institution, or the head of the medical institution (where applicable) is 
responsible for challenge agent accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study interventions are 
provided in accordance with hVIVO SOPs. 

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6.3. 
Randomization and Blinding 
6.3.1. 
Randomization 
Randomization will be applied to Part A of the study and to Part B, if more than one dose arm 
is enrolled in Part B. 
 
 
 
 
In Part A, the randomization number encodes 
the participant’s assignment to 1 of 2 dose arms (2 different doses of the challenge agent) in a 
1:1 ratio. If Part B is randomized, the ratio of randomization will depend on the sample sizes. 
A designated, unblinded statistician, separate from the conduct or analysis of the study, will be 
responsible for preparation of the computer-generated randomization code list(s) using SAS. 
Randomization numbers will be assigned sequentially in ascending order; and once assigned, 
that randomization number shall not be reassigned. The study site will keep a log of the 
randomization number assigned to each participant. 
Randomization numbers will follow a specific format, a 3-digit format, e.g., [001]. If 
participants are replaced as per Section 7.4, Participant Replacement Strategy, the replacement 
participant will be assigned a new, unique randomization number equaling the randomization 
number of the replaced participant plus 100, e.g. [101]. This will ensure that the replacement 
participant receives the same allocated blinded dose as the participant who is being replaced. 
6.3.2. 
Blinding 
Both parts will be single-blind; participants will not know the challenge agent dose level (or 
relative dose level [i.e., higher or lower than other participants]) that they receive. 
A limited number of staff designated to prepare the inoculum vials will know the virus titer on 
the inoculum vials in order to apply the randomization code. The participant will not know 
which virus titer the participant has been randomized to receive in Part A (and Part B, if 
applicable). Although this is a single-blind study, the investigator staff performing subjective 
assessments (e.g., directed physical examination) may also be blinded to which virus titer the 
participant is randomized to in Part A (and Part B, if Part B is randomized). In Part B, if Part B 
is not randomized, the virus titer will be known by the staff designated to prepare the inoculum 
vials and investigator staff performing the assessments. 
6.4. 
Study Intervention Compliance 
Participants will receive challenge agent directly from the PI/investigator or a delegated 
member of the investigator site staff. The date and time of each inoculation at the study site 
will be recorded in the source documents and recorded in the electronic case report form 
(eCRF). The dose of challenge agent and study participant identification will be confirmed at 
the time of dosing by a member of the PI/investigator site staff other than the person 
administering the challenge agent. 
Any noncompliance or problems with the administration of the challenge agent will be 
recorded in the participant’s source notes and reported to the sponsor, if appropriate. 

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6.5. 
Concomitant Therapy 
Any medications taken and changes in medications will be recorded in the source data from 
the time of the participant signing the study-specific ICF up to final study contact Day 28 
(±3 days). Any medication (including over the counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the quarantine/outpatient stage will be stored, prescribed, and administered in line with 
their label-specific requirements, and recorded according to the parameters required by the 
clinical database. 
Participants will be reminded to refrain from using any over the counter medication without 
the approval of the PI/investigator and must notify the study staff as soon as possible if they 
are prescribed any medication. All medications other than contraceptives must be stopped prior 
to the planned date of viral challenge unless in the opinion of the PI/investigator, the medication 
will not interfere with the study procedures or compromise participant safety. 
Medications prohibited throughout the study are shown in Table 6-2. 
Table 6-2: 
Prohibited Medication (Healthy Participants) 
Prohibited Medication 
Washout 
Systemic (oral and parenteral) antiviral 
drugs. 
 
Use or anticipated use during conduct of the 
study 
of 
concomitant 
medications 
(prescription 
and 
non-prescription), 
including vitamins or herbal and dietary 
supplements, unless in the opinion of the 
PI/investigator the medication will not 
interfere with the study procedures or 
compromise participant safety. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Any IMP used in another study. 
 
 
 
 
 
 
 
 

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Prohibited Medication 
Washout 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Influenza vaccine (or an IMP related to the 
treatment or prophylaxis of influenza) 
 
 
 
 
 
 
 
Vaccinations 
 
 
 
 
Any concomitant medication required for the participant’s welfare may be given by the 
PI/investigator. However, it is the responsibility of the PI/investigator to ensure that details 
regarding the medication and the reason for its use are recorded appropriately in the source 
notes to permit their transfer to the clinical database. 
 
 
 
 
 
 
Table 6-3: 
Permitted Medication 
Permitted Medication 
Time Period 
Paracetamol 
 
 
 
 
 
 
 
 
Oral contraceptives 
Allowed at any time during the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If, e.g., in an outbreak or pandemic, a newly instated national vaccination program is 
applicable to an individual participant, the PI/investigator and sponsor will discuss on an 
individual basis if concomitant vaccination may be allowed, viral challenge be postponed, 
or the participant be withdrawn from the study. 
6.6. 
Dose Modification 
This is not applicable in this study. 

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6.7. 
Treatment of Overdose 
This is not applicable in this study. 

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7. 
PARTICIPANT WITHDRAWAL / DISCONTINUATION / 
DISCONTINUATION OF STUDY INTERVENTION 
7.1. 
Participant Withdrawal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.2. 
Participant Discontinuation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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These participants should continue to be followed for safety. Additional unscheduled 
assessments or unscheduled visits may be performed for safety reasons. If the participant is not 
withdrawing consent, assessments as per the early withdrawal visit (see SoE) may still be 
collected if clinically required. Scheduled follow-up visits may also be attended as per the SoE. 
7.2.1. 
Temporary Discontinuation/Temporary Delay in Enrollment 
 
 
 
 
 
7.3. 
Lost to Follow-up 
A participant will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the study site for a required 
study visit: 
 The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether the participant wishes to 
and/or should continue in the study. 
 Before a participant is deemed lost to follow-up, the PI/investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a follow-up letter to the participant’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the participant’s medical record. 
 Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1, 
Regulatory, Ethical, and Study Oversight Considerations. 
7.4. 
Participant Replacement Strategy 
Participants may be replaced in this study. 
 
 
 
 
 
 
 
 

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In Part B, if Part B is not randomized, the replacement participant will receive the same 
allocated blinded dose as the participant who is being replaced. 
7.5. 
Stopping Rules 
The PI/investigator and sponsor will perform safety reviews on available clinical and virology 
data as appropriate during the quarantine period. 
Three clinical scenarios relating to the incidence of AEs and SAEs during the study and the 
procedures that should be performed in each case are presented in Table 7-1. 
Table 7-1: 
Study Stopping Rules 
Status 
Criterion 
Procedure 
1. 
A report has been received of one 
(or more) challenge agent-related 
SAEs in any 1 (or more) 
participant(s). 
If such a status occurs at any point during the 
study, the PI/investigator will review the data 
and make decisions on study continuation or 
termination. Participant follow-up should 
continue until resolution or stabilization of 
SAEs. 
2. 
No challenge agent-related SAEs 
have been reported but an overall 
pattern of clinical changes or 
symptoms exists, which may 
appear minor or moderate in terms 
of individual AEs or SAEs, but 
which collectively represent a 
concern for safety. 
3. 
Unexpected 
challenge 
agent-
related SAE(s) or unexpected 
challenge agent-related AE(s) of 
clinical 
concern 
have 
been 
reported following viral challenge. 
If such a status occurs at any point during the 
study, then the PI/investigator and the 
hVIVO safety governance committee will 
review the data and make decisions on study 
continuation 
or 
termination 
based 
on 
expectedness* of the viral event. 
If 
the 
event 
is 
unexpected, 
further 
administration of the virus will not take 
place. The PI/investigator and the safety 
governance committee will review the data 
and decide on whether it is appropriate to 
recommence inoculation (approval of a 
substantial amendment from the Competent 
Authorities is required) or terminate the 
study. 
* 
Expectedness will be assessed by referring to the challenge agent dossier. 
A final follow-up visit will be performed on Day 28 (±3 days). Follow-up of any event should 
continue until resolution, stabilization, it is judged by the PI/investigator to be no longer 
clinically significant, the participant is lost to follow-up, or an alternative explanation has been 
provided. 

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Further enrollment into the study may be either temporarily or permanently discontinued if: 
 An unacceptable number of severe or life-threatening exacerbations of AEs take 
place (as determined by the PI/investigator). 
 Any clinically significant life-threatening AEs considered related to the 
challenge agent as determined by the PI/investigator occur. 
7.6. 
Potential Adaptations to Operational Design 
This study is designed to be able to utilize adaptive features to enhance study safety, efficiency, 
and efficacy. These design elements are predefined in their scope and limit, as detailed in 
Table 7-2. 
The implementation of study-specific adaptive features will be documented in a non-substantial 
amendment. Generic adaptive features may be implemented at any time at the discretion of the 
PI/investigator. 

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Table 7-2: 
Adaptive Features 
Adaptive Design 
Category 
Feature 
Limit 
Generic 
Cohort(s) 
1. Participants who have been withdrawn (for any 
reason) may be replaced (sponsor and/or PI 
discretion). 
2. Participants who are replacing a withdrawn 
participant may be randomized for inclusion, and 
inoculated: 
a. In an ongoing cohort 
b. In a new cohort 
c. Separately. 
3. Any study cohort may run at the same time. 
4. The number of participants enrolled in each cohort 
may be reduced or increased (sponsor and/or PI 
discretion) to best meet the study objectives. 
1. The stopping rules of the study must be always adhered to, 
and replacement participants may not be enrolled to replace 
participants who have been withdrawn from the study due to 
the meeting of stopping rules. 
2. The total number of study participants will not exceed 80. 
3. Replacement participants will be given replacement 
randomization numbers, where applicable (see Section 7.4, 
Participant Replacement Strategy). 
4. All protocol-defined rules and safety criteria must be met 
before any study part, cohort, or participant commences the 
study. 
Sample/Specimen 1. The PI/investigator may perform additional safety 
assessments, at any time, if they believe them to be 
clinically required. 
2. Where clinically required (sponsor and/or PI 
discretion), participants may be referred for 
consultation(s) and/or investigation(s) under the 
care of a specialist physician. 
1. The maximum blood volume (described in Section 8, Study 
Assessments and Procedures) collected from the participant 
will not be exceeded. 
2. Any required additional safety assessments, or specialist 
referrals, will be conducted on a case-by-case basis. As such 
the maximum number needed cannot be prospectively 
defined. 

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Adaptive Design 
Category 
Feature 
Limit 
Duration 
of 
Inpatient Stay 
1. A participant’s inpatient stay may be prolonged if 
discharge criteria of minimal infectiousness is not 
met (sponsor and/or PI discretion). 
1. Must meet the terms and criteria as detailed in the participant 
information sheet. 
2. Participants must always be able to leave the study site 
unhindered if they wish to do so. 
3. The additional stay is triggered based on the minimal 
infectiousness discharge criteria not being met (as detailed in 
this protocol), and the participant’s suitability for residential 
stay will be assessed on a case-by-case basis. As such, a 
maximum length of stay cannot be prospectively defined. 
 

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8. 
STUDY ASSESSMENTS AND PROCEDURES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.1. 
Demographics and Baseline Characteristics 
8.1.1. 
Demographics 
Demographic data will be recorded at the screening visit. 
8.1.2. 
Height, Body Weight, and Body Mass Index 
Height and body weight measurements will be recorded in compliance with hVIVO’s standard 
procedures. 
Body mass index will be calculated as: BMI (kg/m2) = Body Weight (kg)  
 
Height (m)2 
8.1.3. 
Medical and Medication History 
Medical and medication histories will be recorded at screening and quarantine admission, 
including, but not limited to, detailed histories on current contraception, and allergies (e.g., 
rhinitis, dermatitis, food, aspirin/non-steroidal anti-inflammatory drugs, and asthma). 

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8.1.4. 
Challenge Agent Serology Samples 
A participant must be serosuitable to take part in the study, i.e., he/she must have no or low 
pre-existing serum levels of antibodies specific to the challenge agent. This antibody titer cut-
off for serosuitability will be described in the applicable hVIVO policy. 
Serum levels of pre-existing influenza A/England/7763/2022 H3N2 virus-specific antibodies 
will be determined using hemagglutination inhibition (HAI) or micro-neutralization assay. 
8.1.5. 
Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder 
(GAD-7) Questionnaire 
 
 
8.2. 
Respiratory Samples 
The following exploratory nasal and throat sampling procedures will be performed during the 
study and are detailed in the sections below: 
 Nasal wick (nasosorption) 
 Nasopharyngeal swab 
 Throat swab  
When any nasal sampling time points occur together, the order of sampling will typically be 
(1) nasal wick (2) nasopharyngeal swab. 
8.2.1. 
Nasal Wick 
A nasal wick (Class 1 Device) procedure will be used to collect samples of epithelial lining 
fluid for: 
 Inflammatory markers, e.g., cytokines/chemokines. 
 Other protein biomarkers, e.g., antibodies. 
Remaining epithelial lining fluid may be stored and used for exploratory purposes. 
8.2.2. 
Nasopharyngeal Swab 
Nasopharyngeal swabs will be performed to collect samples of nasal material for: 
 Respiratory pathogen screen 
 Influenza discharge test (e.g., RVAT) 
 Viral load assessments (see Section 8.3.3) 
 Exploratory assessments (see Section 8.3.4). 
Remaining material from the nasopharyngeal swabs may be stored and used for exploratory 
purposes. 
8.2.2.1. 
Throat swab  
Throat swab swabs will be taken for viral load assessments (see Section 8.3.3, Viral Load 
Assessment).  
Samples may be used and/or stored for exploratory purposes (see Section 8.3.4, Exploratory 
Assessments).  

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8.2.2.2. 
Respiratory Pathogen Screen 
On entry to quarantine, a nasopharyngeal swab will be collected and tested to detect the 
presence of a set of respiratory pathogens, including severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2), that could potentially contraindicate a person’s participation in 
the study. The methodology to be used to conduct the respiratory pathogen screen will be 
documented in the AP. 
 
 
 
 
8.2.2.3. 
Influenza Discharge Test 
Where required, an influenza discharge test (e.g., RVAT) will be used to determine the 
presence of influenza in a nasopharyngeal swab sample taken prior to discharge from the 
quarantine unit on Day 8. A PCR test may be used as an alternative test for this purpose, details 
of which will be documented in the AP. Additional RVAT/PCR tests may be performed at the 
discretion of the PI/investigator. 
 
8.2.3. 
Breath respiratory sampling  
To assess the potential of transmission endpoints additional exploratory assessments of virus 
in exhaled breath may be performed using the following methods:  
• Breath sampling 
o Participants will be asked to wear a single use face mask that has been fitted 
with a sampling matrix insert, capable of capturing virus. Similar masks have 
recently also been successfully demonstrated to detect SARS-CoV-2 in exhaled 
breath (Williams et al., 2020; Zhou et al., 2023). The insert will be harvested 
from used masks and analysed for virus and virus-related signals. 
o Handheld respiratory samplers  
• Air sampling  
o Air sampling to detect airborne virus may be performed using a free-standing 
mechanical air sampler. 
Any of the above assessments may be performed on subset of participants. A subset may 
include between none and up to all participants in the study. 
8.3. 
Pathogenicity Assessments 
8.3.1. 
Participant Diary Cards 
Symptom Diary Card  
Participants will report and assess the severity of any challenge agent-related signs and 
symptoms 3 times per day (except for felt nauseous, vomiting, and diarrhea, which are assessed 
once per day, in the morning, for the preceding 24 hours) during quarantine, at the same time 
each day (±1 hour), using the hVIVO symptom diary card. This information will be collected 
using a paper or electronic form. 

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The following symptoms are included in the 13-item symptom questionnaire and will be used 
in analyses of clinical symptom-related endpoints. These symptoms will be graded on a scale 
of 0 to 3 (grade 0: no symptoms; grade 1: just noticeable; grade 2: clearly bothersome from 
time to time but does not interfere with me doing my normal daily activities; grade 3: quite 
bothersome most or all of the time, and it stops me participating in activities); shortness of 
breath and wheeze have an additional grade, i.e., grade 4: symptoms at rest. 
 Runny nose 
 Stuffy nose 
 Sneezing 
 Sore throat 
 Earache 
 Malaise/tiredness 
 Headache 
 Muscle and/or joint ache 
 Chilliness/feverishness 
 Cough 
 Chest tightness 
 Shortness of breath 
 Wheeze 
The following influenza-related symptoms will be graded on a scale of 0 to 3 (grade 0: no 
symptoms; grade 1: just noticeable and no interference with activity [or 1 episode within the 
preceding 24 hours]; grade 2: clearly bothersome from time to time but does not interfere with 
me doing my normal daily activities [or 2 to 3 episodes in the preceding 24 hours]; grade 3: 
quite bothersome most or all of the time, and it stops me participating in activities [or ≥4 
episodes in the preceding 24 hours]): 
 Felt nauseous 
 Vomiting 
 Diarrhea 
Additional exploratory analyses may be performed which include these additional symptoms. 
Additional to the ordinal symptom diary card, a visual analog scale diary card using a 100 mm 
scale, with the same symptoms, will be completed by the participants. 
 
Participant Common Cold Perception Questions 
Two additional common cold-related questions will be answered by the participant each 
morning. The first question asks the participant’s perception of whether they have a cold or 
not, the second asks the participant’s perception of improvement/worsening of the cold. 
1. Do you have a cold: Yes/No 
If the participant selects Yes to having a cold, then the second 7-point Likert scale “global 
change since yesterday” question is completed by the participant, as below: 

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2. Compared to yesterday, I feel that my cold is: 
 Very much better 
 Somewhat better 
 A little better 
 The same 
 A little worse 
 Somewhat worse 
 Very much worse 
8.3.2. 
Nasal Discharge Collection from Paper Tissues 
Each participant will be given pre-weighed packets of paper tissues. Participants will be asked 
to place single tissues used for nose blowing or sneezing into a specified collection bag (for 
that participant only). 
A daily 24-hour paper tissue collection will take place throughout the quarantine period. 
Distribution of paper tissues and collection bags will start in the morning of Day -1, with the 
first collection on Day 0. Thereafter, distribution and collection of tissues will occur daily at 
the same time point (±1 hour) each day , with tissues collected 24 hours after distribution, until 
discharge from quarantine. 
24-hour paper tissue collections will be analyzed to determine the following over the quarantine 
period: 
 24-hour nasal discharge weight 
 The number of paper tissues used for nose blowing or sneezing over each 24-
hour period. 
8.3.3. 
Viral Load Assessment 
Viral titer may be determined by qRT-PCR and/or a viral culture assay to investigate the 
following parameters: 
 Viral load 
 Infectivity status and rate 
 Viral dynamics (e.g., duration, peak, time to peak) 
Viral culture will be performed on those samples that have been shown to be quantifiable by 
qRT-PCR. 
8.3.4. 
Exploratory Assessments 
To explore baseline immunology and response to infection with influenza, blood and 
respiratory samples may be used for exploratory assays related to respiratory viral infection 
and immunology. 
DNA/RNA analysis may be performed on nasal, throat and blood samples. Nasal samples may 
be tested for suspected community-acquired infections. Blood and respiratory samples may be 
used and/or retained for exploratory purposes related to the study objectives, respiratory virus 
infections, and host response to infection. 

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Analyses on any type of breath/aerosol samples may be performed to assess the viral load 
released into the environment as a surrogate for viral transmission potential assessments.  
8.4. 
Safety Assessments 
8.4.1. 
Complete Physical Examination 
A complete physical examination to include a full systemic assessment. 
8.4.2. 
Directed Physical Examination 
Directed physical examinations will be conducted by the PI/investigator and will include 
examination of the eyes, ears, nose, throat, and respiratory system/chest (via stethoscope). 
Based upon the presence or absence of clinical signs and symptoms, PI/investigator discretion 
will be used to determine the requirement to perform further assessments or a complete 
physical examination. 
 
 
 
 
 
 
 
 
 
 
 
 
8.4.3. 
Vital Signs 
Vital signs assessments will be recorded 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study-specific normal ranges for vital signs are provided in Appendix 4, Normal Ranges. 
If a result is out of the normal range and meets the criteria for an AE, the severity of the AE 
will be guided by sponsor requirements using the Food and Drug Administration (FDA) 
toxicity grading scale September 2007 (FDA, 2007). 

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8.4.4. 
Tympanic Temperature 
 
 
 
 
Study-specific normal ranges for tympanic temperature are provided in Appendix 4, Normal 
Ranges. 
Temperature may be monitored more frequently during quarantine, if appropriate. 
 
 
 
 
 
 
 
8.4.5. 
Electrocardiogram 
Study-specific normal ranges are provided in Appendix 4, Normal Ranges. 
 
 
 
 
 
 
 
 
8.4.6. 
Clinical Safety Laboratory Assessments 
8.4.6.1. 
Urinalysis 
Clinical urine safety analysis will be undertaken using commercially available urine test strips 
(i.e., dipsticks) that provide an instant result, which will be documented in the source data. 
Urinalysis will be performed to evaluate the parameters described in Appendix 2, Clinical 
Laboratory Tests. 
 
 
 
 

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8.4.6.2. 
Drugs of Misuse and Cotinine 
 
 
 
 
 
8.4.6.3. 
Alcohol Breath Testing 
 
 
 
8.4.6.4. 
Safety Blood Assessments and Analysis 
 
 
 
 
8.4.7. 
Pregnancy Tests and Follicle-stimulating Hormone 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4.8. 
Lung Function 
Spirometry 
 
 
 
 
 
 
 
 
 
 
 
 

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8.5. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting 
The PI/investigator is responsible for ensuring that all AEs/SAEs and pregnancies are 
identified, evaluated, recorded, and reported in a timely manner as per regulatory requirements, 
hVIVO SOPs, and the study-specific protocol. The PI/investigator is also responsible for 
ensuring that the medical management (including follow-up) of AEs/SAEs and, where 
appropriate, pregnancy symptoms/complications is provided by competent investigator site 
staff. 
The sponsor of the study will also perform an evaluation of seriousness, severity, causality, and 
expectedness of all SAEs. 
The definitions of an AE/SAE, as well as the method of recording, evaluating, and assessing 
causality of AE and SAE and the procedures for completing and transmitting AE/SAE, and 
other reportable safety event reports can be found in Appendix 3, Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-up, and Reporting. 
8.5.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information 
All AEs/SAEs will be collected from signing of the study-specific ICF until the last scheduled 
follow-up visit at the time points specified in the SoE or until the resolution of the AE/SAE. 
Investigators are not obligated to actively seek AEs/SAEs after conclusion of study 
participation. However, if the PI/investigator learns of any SAE at any time after a participant 
has been discharged from the study, and he/she considers the event to be reasonably related to 
the study intervention or study participation, the PI/investigator must promptly notify the 
sponsor. 
8.5.2. 
Method of Detecting Adverse Events/Serious Adverse Events 
The method of recording, evaluating, and assessing causality of AEs/SAEs and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3, Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting. 
Care will be taken not to introduce bias when detecting AEs/SAEs. Open-ended and non-
leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
8.5.3. 
Follow-up of Adverse Events/Serious Adverse Events 
 
 
 
 
 
 
 

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8.5.4. 
Regulatory Reporting Requirements for Serious Adverse Events 
Any SAE will be reported immediately by the PI/investigator to the sponsor (in practice 
reporting within 24 hours of the PI/investigator’s knowledge of the event). 
 
 
 
 
 
 
 
 
 
 
 
8.5.5. 
Pregnancy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.6. 
Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this study. 
8.7. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.8. 
Immunogenicity Assessments 
Blood will be collected for immunological analysis. 
Humoral immune responses, e.g., antibodies to influenza A/England/7763/2022 H3N2 and 
cytokines/chemokines will be evaluated in serum samples collected from all participants 
according to the SoE. 
 
 
 
 
 
8.9. 
Genetics 
 
8.10. 
Biomarkers 
Biomarkers may be evaluated in this study. 

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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
There will be no inferential statistical analysis for the study, the analysis will be purely 
descriptive. 
Primary, secondary and exploratory endpoints may be compared between randomized groups 
using inference tests, but these results will have to be regarded as illustrative only and no 
definitive conclusions should be drawn from them, because of the potential risk of type-1 error 
(false positive). 
9.2. 
Sample Size Determination 
No formal sample size calculation has been performed for this exploratory phase study; the 
sample size is consistent with earlier influenza, respiratory syncytial virus, and human 
rhinovirus characterization studies conducted at hVIVO. 
A total of up to 80 participants may be given influenza A/England/7763/2022 H3N2 challenge 
agent, up to 20 participants in each of the dose arms in Part A and up to an additional 
20 participants in the expansion arm (if enrolled). 
9.3. 
Analysis Sets 
For the purposes of analysis, the following analysis sets are defined (Table 9-1). 
Table 9-1: 
Analysis Sets 
Participant Analysis 
Set 
Description 
Intent-to-treat 
(ITT) 
analysis set 
All participants that have been randomized (where applicable) and 
inoculated. 
Note: The safety analysis set and ITT analysis set will consist of 
the same participants. 
Intent-to-treat infected 
(ITT-I) analysis set 
All participants that have been inoculated with any dose of 
challenge agent and who are infected with challenge agent as per 
the definition of laboratory-confirmed infection for this protocol. 
Per 
protocol 
(PP) 
analysis set 
All participants having received the planned dose of challenge 
agent who have a valid result for at least 80% of the planned 
qRT-PCR nasal and throat sample analyses from Day 1 (pm) up to 
Day 8 (am), i.e., at least 11 out of 14 samples, and who present no 
important protocol deviations likely to impact the evaluation of the 
primary endpoint. 
Per protocol infected 
(PP-I) analysis set 
All participants in the PP analysis set and who are infected with 
challenge agent as per the definition of laboratory-confirmed 
infection for this protocol. 
Safety analysis set 
All participants that have been randomized (where applicable) and 
inoculated.  

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Participant Analysis 
Set 
Description 
Note: The safety analysis set and ITT analysis set will consist of 
the same participants. 
Membership of participants in each analysis set will be determined at a planned data review 
meeting, prior to any analysis and database lock. 
The primary pathogenicity analysis will be on the PP analysis set. The ITT, PP-I and ITT-I 
analysis sets will be used for supportive analyses on all or part of the primary and secondary 
pathogenicity endpoints, as defined in the SAP. The safety evaluation will be performed on the 
safety analysis set. Additional analysis sets may be defined in the SAP. 
9.4. 
Statistical Analysis 
This section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints. 
Data will be analyzed and reported using SAS® version 9.4 or later. 
9.4.1. 
Statistical Analysis Plan 
The SAP will be developed and finalized prior to database lock for the study. The finalized 
SAP will be signed prior to unblinding the study data. The SAP will provide a more technical, 
detailed, and comprehensive description of the statistical analyses that will be computed, 
expanding on the protocol-specified analysis. 
Any deviation(s) from the original statistical plan outlined in the protocol will be described and 
justified in an amendment to the protocol and/or SAP, as appropriate, and referenced in the 
final clinical study report. 
Further post-hoc evaluations of any exploratory endpoints may be conducted and reported 
separately. 
9.4.2. 
General Considerations 
9.4.2.1. 
Descriptive Statistics 
The study will be summarized in terms of descriptive statistics; no formal statistical 
comparisons are planned. 
Continuous variables will be summarized using number of available data, number of missing 
data, mean, standard deviation, median, lower quartile, upper quartile, minimum, and 
maximum values. When relevant, confidence intervals (CIs) will be computed for the mean 
and/or the median. Geometric mean and geometric SD may be provided for peak VL and VL-
AUC.  
Categorical variables will be summarized using number of available data, number of missing 
values, frequency counts for each category and corresponding percentage. Percentages will be 
calculated using the number of available data as the denominator (i.e., not including missing 
values). When relevant, CIs will be computed. If not otherwise specified in the SAP, the Wilson 
Score Method will be used to compute CIs for proportions. 
 Participants will be grouped and presented against the titer of challenge agent 
they received. 

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 The number of participants enrolled, randomized (where applicable), 
withdrawing (also split by reason for withdrawal) from and completing the 
study, and the number in each analysis population will be summarized for all 
participants and by group. 
 Any missing data will be accounted for, and the way their possible impact on 
the study analysis will be evaluated will be described within the SAP. 
Full details of the planned analysis will be presented in the SAP. Any deviations from the SAP 
will be documented in the clinical study report. 
9.4.2.2. 
Inferential Statistics and Significance Testing 
Inference tests comparing between groups may be provided but should be considered as purely 
illustrative.  
9.4.3. 
Planned Analysis 
The main analysis will occur at the end of Part B and will combine data from Part A and Part B 
for the common challenge agent dose arm, if applicable. 
9.4.3.1. 
Participant Accountability 
The number of participants enrolled, randomized (if applicable), receiving challenge agent, 
withdrawing from (also split by reason for withdrawal) and completing the study, and the 
numbers in each analysis set, will be summarized. 
9.4.3.2. 
Protocol Deviations 
Participant’s data will be reviewed for important protocol deviations prior to database lock at 
a planned data review meeting, and decisions will be documented within the meeting minutes. 
At this meeting, participants will be reviewed for their inclusion/exclusion from the analysis 
sets. Important protocol deviations will be defined in the protocol deviations management plan. 
9.4.3.3. 
Demographic and Baseline Characteristics 
Descriptive statistics of demographics (age, sex, height, body weight, BMI, race, and ethnicity) 
will be presented by dose arm and across all participants. Medical history information will be 
listed. Other baseline characteristics will be defined in the SAP. 
9.4.3.4. 
Compliance to Challenge Agent 
A table describing presence/absence of any compliance (challenge agent dose) issues will be 
presented by dose arm and overall. 
Any noncompliance or problems with the administration of the challenge agent will be listed. 
9.4.4. 
Primary Pathogenicity Analysis 
The primary pathogenicity analysis will be conducted on the PP analysis set. 
The main estimator of the primary pathogenicity endpoint, the laboratory-confirmed infection 
as determined by qRT-PCR on nasal and throat samples (virology) collected twice daily 
starting 1 day post viral challenge (Day 1 pm) up to discharge from quarantine (planned for 
Day 8 am), will be analyzed on the PP analysis set. 
Descriptive statistics and the 95% CI will be presented by dose arm. Further details will be 
described in the SAP. 

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9.4.5. 
Secondary Pathogenicity Analysis 
For the secondary pathogenicity endpoints outlined in Section 3, Objectives and Endpoints, 
descriptive statistics (see Section 9.4.2.1, Descriptive Statistics) will be summarized by dose 
arm as described in Table 9-2. For a subset of the secondary endpoints (details will be provided 
in the SAP), the descriptive analyses may be repeated on the ITT population. Further details 
will be provided in the SAP. 
Table 9-2: 
Methods for Analysis of Secondary Pathogenicity Endpoints 
Endpoint 
Analysis 
VL-AUC 
Calculation of the VL-AUC will be performed on log10-
transformed qRT-PCR data using the trapezoidal summation 
rule based on actual time intervals in hours. 
Descriptive 
statistics 
for 
continuous 
variables 
(Section 9.4.2, General Considerations). 
VLPEAK by qRT-PCR 
Descriptive 
statistics 
for 
continuous 
variables 
(Section 9.4.2, General Considerations). 
Peak TSS 
Descriptive 
statistics 
for 
continuous 
variables 
(Section 9.4.2, General Considerations). 
TSS-AUC 
Descriptive 
statistics 
for 
continuous 
variables 
(Section 9.4.2, General Considerations). 
9.4.6. 
Exploratory Analysis 
Exploratory endpoints as outlined in Section 3, Objectives and Endpoints, will be summarized 
by dose arm. Further details are described in the SAP. 
9.4.7. 
Safety Analysis 
All safety analyses will be computed on the safety analysis set. 
Unless otherwise stated in the SAP, safety endpoints will be presented in terms of descriptive 
statistics only. 
AEs will be coded using the most current version of the Medical Dictionary for Regulatory 
Activities (MedDRA) and summarized descriptively by system organ class, preferred term, and 
dose arm for the number of AEs/SAEs reported, the number of challenge-emergent AEs/SAEs 
reported, and the number and percentage of participants reporting each event. 
 
 
 
 
 
 

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9.5. 
Interim Analysis 
No formal statistical interim analysis of data is planned. However, after Part A of the study, 
preliminary analysis of Part A data will be undertaken to identify the optimum challenge agent 
dose for the use in Part B of the study. Results of Part A will be kept securely and will be 
limited to a predefined selection of staff. The SAP will describe this in greater detail. 
9.6. 
Data Monitoring Committee 
Not applicable. 

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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Ethical and Study Oversight Considerations 
10.1.1. 
Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines. 
 Applicable International Council for Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines. 
 Applicable laws and regulations. 
 
 
 
 
 
 
The PI/investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the REC annually, or 
more frequently, in accordance with the requirements, policies, and procedures 
established by the REC. 
 Notifying the REC of SAEs or other significant safety findings as required by 
REC procedures. 
 Providing oversight of the conduct of the study at the site and adherence to 
requirements of ICH guidelines, the REC, the REC, UK SI 2004/1031 The 
Medicines for Human Use (Clinical Trials) Regulations, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations. 
10.1.2. 
Financial Disclosure 
 
 
 
 
 
10.1.3. 
Confidentiality 
The PI/investigator will preserve the confidentiality of participants taking part in the study and 
is registered under the Data Protection Act. 

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10.1.4. 
Informed Consent Process 
The trained and delegated study staff competent to perform the informed consent procedure 
will obtain a signed study-specific ICF from each participant before any study-specific 
procedures are performed. 
Historical screening data may be collected through the hVIVO generic screening process, 
which is a comprehensive assessment of health status including previous medical history. 
For assessments taken under the hVIVO generic screening, a separate informed consent is 
obtained. 
When historical screening data collected through the hVIVO generic screening process is used 
for screening, the study-specific ICF will be obtained at the first study visit (i.e., quarantine 
admission) from each participant before any study-specific procedures are performed. 
Potential participants will typically be sent a copy of the REC approved study-specific 
participant information sheet (PIS)/ICF at the time of invite to the first study visit (i.e., 
quarantine admission) and at least a day prior to the visit and will be encouraged to read it prior 
to their appointment. Upon arrival at the screening visit/quarantine admission visit (as 
applicable), the study-specific PIS/ICF is discussed by the trained and delegated study staff 
competent to perform the informed consent procedure, and the participants will be given the 
opportunity to ask any questions and may take the information sheet away to consider their 
participation. 
All participants will be required to have a good understanding of English and the 
PI/investigator will be responsible for ensuring that the participant understands the information 
contained in the PIS/ICF. Once the PI/investigator has confirmed that the participant has 
capacity and has understood the study, including the benefits and risks of participation, the 
participant and the PI/investigator can sign and date the study-specific ICF. 
The study-specific ICF must be signed and dated by the participant and countersigned by the 
trained and delegated study staff competent to perform the informed consent procedure 
(whoever conducted the consent discussion). A copy of the study-specific PIS/ICF will be 
given to the participant, and the original will be held in the hVIVO TMF. 
Participants will be assured that they can withdraw from the study at any time and for any 
reason without prejudice to their future medical care, and that they will be informed in a timely 
manner if new information becomes available that may affect their willingness to continue their 
participation in the study. This information will be included within in the study-specific 
PIS/ICF. 
The study-specific PIS/ICF will contain a separate section that addresses the use of samples for 
future research. The PI/investigator or authorized designee will explain to each participant the 
objectives of the exploratory research. Participants will be told that they are free to refuse to 
participate (with no requirements to disclose the reason for withdrawal) and may withdraw 
their consent at any time and for any reason. 
A separate PIS/ICF for genetic testing of samples will be required to document a participant’s 
agreement to allow any specimens to be used for related exploratory genetic research. 
Participants who decline to participate in this optional research will not provide this separate 
signature. 

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10.1.5. 
Data Protection 
Participants will be assigned a unique identifier by hVIVO. Any participant records or datasets 
that are transferred to the sponsor will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant in ICF. 
The participant must be informed that his/her medical records may be examined by clinical 
quality assurance auditors or other authorized study staff appointed by the sponsor, by 
appropriate REC members, and by inspectors from regulatory authorities. 
10.1.6. 
Committee(s) Structure 
This study will not include an early safety data review. However, participant safety will be 
continuously monitored by the PI/investigator and sponsor, which includes ongoing safety 
oversight (to include safety signal detection at any time during the study). 
10.1.7. 
Dissemination of Clinical Study Data 
The key design elements of this protocol will be posted on publicly accessible registry. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.1.8. 
Data Quality Assurance 
Participant data will be collected at site using paper source casebooks which will then be data 
entered into the eCRF database unless transmitted to the sponsor or designee electronically 
(e.g., laboratory data). The PI/investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the eCRF. 
The PI/investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. This can be paper source and/or eSource. 
The PI/investigator must permit study-related monitoring, audits, REC review, and regulatory 
agency inspections and provide direct access to source data documents. 
 
 
 
 
 
 
 

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10.1.9. 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
 
 
 
 
 
 
10.1.10. 
Study Discontinuation 
The sponsor reserves the right to temporarily suspend or terminate the study for any reason at 
any time. In addition, the study may be temporarily suspended or terminated at any time if, in 
the opinion of the PI/investigator, the safety data suggests that the medical safety of participants 
is being compromised. 
 
 
 
 
 
 
Termination of the clinical study may also be initiated by the REC. 
10.1.11. 
Publication Policy 
By signing the study protocol, the PI/investigator agrees that the results of this study may be 
used for the purposes of national and international registration, for publication, and as 
information for medical and pharmaceutical professionals by the sponsor. 
The publication policy and clauses will be covered in the clinical trial agreement. 

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10.2. 
Appendix 2: Clinical Laboratory Tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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10.3. 
Appendix 3: Adverse Events – Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting 
10.3.1. 
Adverse Event 
Adverse Event Definition 
 
 
 
 
 
 
 
 
 
 
 
 
 
Events Meeting the Adverse Event Definition 
 
 
 
 
 
 
 
 
 
 
 
 
Events NOT Meeting the Adverse Event Definition 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Events NOT Meeting the Adverse Event Definition 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.3.2. 
Serious Adverse Event 
Serious Adverse Event Definition 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death 
b) Is life-threatening 
 
 
 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
 
 
 
 
 
 
 
 
 
 
 
 
 
d) Results in persistent disability/incapacity 
 
 
 

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Serious Adverse Event Definition 
 
 
 
 
 
e) Is a congenital anomaly/birth defect 
f) Is an important medical event 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.3.3. 
Recording, Assessment, and Follow-up of Adverse Events/Serious Adverse 
Events 
10.3.3.1. Adverse Event/Serious Adverse Event Recording 
All AEs/SAEs will be collected from the time of written study-specific informed consent until 
study completion/final study contact or until the resolution of the AE. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The PI/investigator will record all relevant information regarding an AE/SAE in the source 
documents and evaluate AEs/SAEs using the following guidelines: 
 
 
 
 
 
 
 

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10.3.3.2. Assessment 
Description 
 
 
Onset and End 
The dates and times of the onset and end of the event should be recorded. 
Assessment 
Challenge Agent-related Symptoms 
 
 
 
 
 
 
 
 
Physical Examination 
 
 

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Assessment 
Directed Physical Examination 
 
 
 
 
 
 
Vital Signs 
 
 
 
 
Temperature 
 
 
 
 
 
 
 
Spirometry 
 
 
 
 
 
 
 

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Assessment 
Laboratory Values 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-reactive Protein 
 
 
 
 
10.3.3.3. Assessment of Intensity 
 
 
 
 
 
 
 
10.3.3.4. Frequency 
 
 
 
 
 
 
 
10.3.3.5. Assessment of Causality 
 
 
 
 
 
 
 

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The relationship of an AE to the IMP will be categorized as shown in Table 10-2. 
Table 10-2: 
Classification of Adverse Event Relationship 
Classification 
Definition 
Not related 
 
 
 
Unlikely related 
 
 
Possibly related 
 
 
 
 
 
Probably related 
 
 
 
Definitely related 
 
 
 
 
 
 

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10.3.3.6. Action Taken 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.3.3.7. Outcome 
 
 
 
Table 10-3: 
Classification of Adverse Event Outcome 
Classification 
Definition 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.3.3.8. Follow-up 
 
 
 
 
 

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10.3.4. 
Reporting of Serious Adverse Events 
Serious AEs must be documented and reported as per hVIVO SOPs. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 10-4: 
Contact Details for Reporting All Serious Adverse Events 
Contact 
Details 
SAE email address: 
SAE_HRD-VCS-006@hvivo.com 
 
 
 
 
 
 
 
 
 
 
 
 
 

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10.4. 
Appendix 4: Normal Ranges 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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10.5. 
Appendix 5: Genetics 
 
 
 
 
 
 
 
 
 

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10.6. 
Appendix 6: Abbreviations 
Abbreviation  
Term 
AE 
Adverse event 
AP 
Analytical plan 
ATS 
American thoracic society 
AUC 
Area under the curve 
β-hCG 
beta-human chorionic gonadotrophin 
BMI 
Body mass index 
BP 
Blood pressure 
CDC 
Centers for Disease Control and Prevention 
CI 
Confidence interval 
DBP 
Diastolic blood pressure 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram  
(e)CRF 
(Electronic) case report form 
ERS 
European Respiratory Society  
FDA 
Food and Drug Administration 
FEV1 
Forced expiratory volume (in 1 second) 
FRNA 
Foci reduction neutralization assay 
FSH 
Follicle-stimulating hormone 
FVC 
Forced vital capacity 
GAD 
Generalized Anxiety Disorder 
GCP 
Good Clinical Practice 
GP 
General practitioner 
HAI 
Haemagglutination inhibition 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
HVC 
Human viral challenge  
ICF 
Inform consent form 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
ILI 
Influenza-like illness 
IMP 
Investigational medicinal product 
IRAS ID 
Integrated Research Application System identification 
ISRCTN 
International Standardised Randomised Controlled Trial Number 
ITT 
Intent-to-treat 
ITT-I 
Intent-to-treat infected 
IUD 
Intrauterine device 
LLOD 
Lower limit of detection 
LLOQ 
Lower limit of quantifiation 
LRT 
Lower respiratory tract 
MedDRA 
Medical Dictionary for Regulatory Activities 
NPS 
Nasopharyngeal swab 
PBMC 
Peripheral blood mononuclear cell 
PCR 
Polymerase chain reaction 
PHQ 
Patient Health Questionnaire 
PI 
Principal investigator 
PIS 
Participant information sheet 

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PP 
Per protocol 
PT 
Prothrombin time 
qRT-PCR 
Quantitative reverse transcriptase-polymerase chain reaction 
REC 
Research Ethics Committee 
RNA 
Ribonucleic acid 
RVAT 
Rapid viral antigen test 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SBP 
Systolic blood pressure 
SoE 
Schedule of events 
SOP 
Standard Operating Procedure  
SpO2 
Peripheral arterial oxygen saturation 
SUSAR 
Suspected unexpected adverse reaction 
TBD 
To be determined 
TMF 
Trial Master File 
TSS 
Total symptoms score 
UK 
United Kingdom 
URT 
Upper respiratory tract 
WHO 
World Health Organization 
 

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10.7. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Clinical Study Protocol 
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hVIVO 
Study Number: HRD-vCS-006 
Clinical Study Protocol 
Version: Final V4.0 20DEC2024 
 
 
 
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hVIVO 
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Clinical Study Protocol 
Version: Final V4.0 20DEC2024 
 
 
 
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10.8. 
Appendix 8: Protocol Amendment History 
Amendment 2 dated 20 December 2024   has been updated with the following changes: 
• Administrative updates throughout 
• Section 1.2: Schedule of events 
• Included twice daily throat swab assessment.  
• Endpoints 
o Throat samples included with nasal samples within Endpoints.  
 

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11. 
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