A Phase 2a, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Immunogenicity and Efficacy of A Respiratory Syncytial Virus Vaccine (RSVpreF) in A Virus Challenge Model in Healthy Adults
Phase: PHASE2
Conditions: Respiratory Syncytial Virus Infections
Sponsor: Hvivo

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
1
CLINICAL STUDY PROTOCOL
A Phase 2a, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate 
the Safety, Immunogenicity and Efficacy of A Respiratory Syncytial Virus 
Vaccine (RSVpreF) in A Virus Challenge Model in Healthy Adults
Short Title:
Phase 2a Study of RSVpreF Vaccination and RSV Challenge in 
Healthy Adults
Version and Date of Protocol:
Final v3.0 _ Date 22 Jan 2021
Protocol Number:
HVO-CS-005
Sponsor:
Compound Number:
RSVpreF (PF-06928316)  
EudraCT Number:
2020-003887-21
 
 
 
 
 
 
 
 
 
 
 
 
 
 

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
2
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:
Date

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
3
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 staff under my control.
Principal Investigator Signatory: 
Name (typed or printed):
Institution and Address:
Signature:
Date:
(DD MMM YYYY)

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
4
Study Personnel Contact Information
CONTACT
DETAILS
Sponsor
Sponsor’s Representative 
Funder:
Principal Investigator (PI) and 
Clinical Trial Unit
Sponsor's Medical Monitor
Refer to the local study contact list document
Key Protocol Contributors
Refer to the local study contact list document

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
5
Protocol Amendment Summary of Changes Table
PROTOCOL HISTORY
Document
Date
Amendment Type
Initial Clinical Trial Protocol 
(v1.0)
14 Sep 2020
Not applicable. First Version.
Amendment 01 (v2.0)
26 Oct 2020
Substantial Amendment 
Amendment 02 (v3.0)
22 Jan 2021
Non-substantial Amendment
Amendment 01 (26-Oct-2020)
Overall Rationale for the Amendment:
Section # and Name
Description of Change
Brief Rationale
Section 5.2 
Exclusion Criteria
Update to exclusion criterion 4 to amend the upper 
limit of the body mass index to 30 kg/m2.
Update to exclusion criterion 6 to include 
hypersensitivity to any component of the study 
vaccine.
Clarification of exclusion criterion 9 related to the 
receipt of, or planning to receive, licensed vaccines 
before or after study vaccination and the viral 
challenge.
Protocol amendment 
in response to 
Grounds for Non-
Acceptance and 
Request to Amend 
from the MHRA.
Section 6.5 
Concomitant 
Therapies
Update to Table 3 (Permitted Medication) to remove 
the use of anti-depressants.
The use of concomitant vaccination during an 
outbreak or a pandemic has been removed from 
exclusion criterion 9 and included into Section 6.5.
Section 7.5 Stopping 
Rules 
Amendment to correct inconsistencies, errors and 
duplications related to the study stopping rules. 
Stopping rule scenario related to SUSAR reporting 
in one (or more) participant(s) removed. The report 
of a SUSAR is covered by the reporting of SAR in 
one participant.
Update added to all stopping rules to clarify that 
regulatory authority approval via a substantial 
amendment would be required in order to
recommence the study.
Amendment 02 (22-Jan-2021)
Overall Rationale for the Amendment:

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
6
Section # and Name
Description of Change
Brief Rationale
Section 7.2 
Participant 
Discontinuation 
Clarification that reserve vaccinated participants 
may not be inoculated with the challenge virus 
when the target evaluable number is achieved for a 
given quarantine group and for the overall study.
Minor clarification. 

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
7
Table of Contents
Sponsor Statement ..........................................................................................2
Investigator Agreement:...................................................................................3
Study Personnel Contact Information ..............................................................4
Protocol Amendment Summary of Changes Table .........................................5
Table of Contents...........................................................................................7
1.
Protocol Summary.......................................................................10
1.1.
Synopsis ........................................................................................10
1.2.
Study Schematic: On-study Participant Progression.....................18
1.3.
Schedule(s) of Activities (SoA) ......................................................19
2.
Introduction..................................................................................26
2.1.
Study Rationale .............................................................................28
2.2.
Benefit/Risk Assessment...............................................................28
3.
Objectives and Endpoints...........................................................34
4.
Study Design................................................................................39
4.1.
Overall Design ...............................................................................39
4.2.
Scientific Rationale for Study Design ............................................40
4.3.
Justification for Dose .....................................................................41
4.4.
End of Study Definition ..................................................................41
5.
Study Population .........................................................................42
5.1.
Inclusion Criteria ............................................................................42
5.2.
Exclusion Criteria...........................................................................44
5.3.
Lifestyle Considerations.................................................................46
5.4.
Screen Failures..............................................................................47
6.
Study Intervention .......................................................................48
6.1.
Study Intervention(s) Administered ...............................................48
6.2.
Preparation/Handling/Storage/Accountability................................49
6.3.
Randomisation and Blinding..........................................................50
6.4.
Study Intervention Compliance......................................................52
6.5.
Concomitant Therapy ....................................................................52
7.
Discontinuation of Study Intervention/Withdrawal ..................54
7.1.
Participant Withdrawal...................................................................54
7.2.
Participant Discontinuation ............................................................54
7.3.
Lost to Follow up............................................................................55
7.4.
Participant Replacement Strategy .................................................55
7.5.
Stopping Rules ..............................................................................55
8.
Study Assessments and Procedures ........................................58
8.1.
Medical and Medication History.....................................................58
8.2.
Demographics................................................................................58
8.3.
Height, Weight and Body Mass Index ...........................................58
8.4.
Alcohol Breath Testing...................................................................58
8.5.
Complete Physical Examination ....................................................58
8.6.
Direct Physical Examination ..........................................................59
8.7.
Vital Signs......................................................................................59
8.8.
Temperature ..................................................................................59
8.9.
Electrocardiogram..........................................................................60
8.10.
Lung Function ................................................................................60

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
8
8.11.
Participant Diary Cards..................................................................61
8.12.
Questionnaires...............................................................................62
8.13.
Nasal Discharge Collection from Paper Tissues ...........................62
8.14.
Urine Samples and Assessments..................................................62
8.15.
Blood Samples...............................................................................63
8.16.
Nasal Samples...............................................................................64
8.17.
Recording of Adverse Events and Serious Adverse Events .........65
8.18.
Treatment of Overdose..................................................................68
8.19.
Biomarkers.....................................................................................68
8.20.
Immunogenicity Assessments .......................................................68
9.
Statistical Considerations...........................................................69
9.1.
Statistical Hypotheses ...................................................................69
9.2.
Sample Size Determination ...........................................................69
9.3.
Populations for Analyses ...............................................................69
9.4.
Statistical Analysis.........................................................................70
9.5.
Statistical Analysis Plan.................................................................70
9.6.
General Considerations.................................................................71
9.7.
Interim Analyses ............................................................................73
10.
Supporting Documentation and Operational Considerations 74
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations...............................................................................74
10.2.
Appendix 2: Clinical Laboratory Tests...........................................78
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .........................80
10.4.
Appendix 4: Normal Ranges..........................................................96
10.5.
Appendix 7: Abbreviations.............................................................97
10.6.
Appendix 9: Definitions..................................................................99
11.
References .................................................................................102

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
9
List of Tables
Table 1 Study Interventions ..................................................................................................................48
Table 2 Prohibited Medication ..............................................................................................................52
Table 3 Permitted Medication ...............................................................................................................53
Table 4 Study Stopping Rules ..............................................................................................................56
Table 5 Protocol-required Safety Laboratory Assessments .................................................................78
Table 6 Classification of Adverse Events Severity ...............................................................................86
Table 7 Classification if Adverse Events Relationship..........................................................................87
Table 8 Classification of Adverse Events Outcome..............................................................................88
Table 9 Grading Scale for Local Reactions ..........................................................................................91
Table 10 Derived Variables for Each Local Reaction ...........................................................................92
Table 11 Derived Variables for Any Local Reaction .............................................................................92
Table 12 Grading Scale for Systemic Events .......................................................................................94
Table 13 Grading Scale for Fever in the VDC ......................................................................................95

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
10
1.
Protocol Summary
1.1.
Synopsis
Title
A Phase 2a, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate 
the Safety, Immunogenicity and Efficacy of A Respiratory Syncytial Virus Vaccine 
(RSVpreF) in A Virus Challenge Model in Healthy Adults
Short Title
Phase 2a Study of RSVpreF Vaccination and RSV Challenged in Healthy Adults
Sponsor
Protocol number
HVO-CS-005
Eudract number
2020-003887-21
Phase
2a
Sites
Single centre, 
Indication
Prevention of RSV-associated moderate to severe lower respiratory tract disease 
in adults 60 years of age and older by active immunisation.
Study Type
Interventional
Design
Subjects will receive a single vaccination with either RSVpreF or Placebo one 
month prior to challenge with RSV-A Memphis 37b. 
Investigational
Medicinal 
Product (IMP)
PF-06928316 also known as RSVpreF
IMP dose(s)
120 mcg
Pharmaceutical form
Powder for solution for injection
IMP route(s)
Intramuscular
Control compound
Placebo
Randomisation
1:1
Challenge virus 
RSV-A Memphis 37b
Challenge virus route
Intranasal delivery
Challenge virus titre
Total dose of approximately 4.5 log10 plaque forming units

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
11
Study population
Healthy male and female participants aged 18-50 years of age, screened for
susceptibility to RSV infection, i.e., levels of RSV neutralizing antibodies
compatible with susceptibility to RSV infection
Summary of study design
This is an exploratory proof-of-concept randomised, Phase 2a, double-blind, 
placebo-controlled study to evaluate the safety, immunogenicity and efficacy of an 
RSV vaccine against RSV-A Memphis 37b infection in healthy subjects.
The study is divided into the following study phases:
Screening:
x
Screening prior to vaccination from Day -84 to Day -29 (Day -118 for RSV 
serology). Pre-screening data collected through the hVIVO generic 
screening process prior to signing the study specific consent form, and 
prior to vaccination from Day -84 to Day -29 (Day -118 for RSV serology),
may be transferred to this study after study-specific consent form has 
been signed by the participant. Pre-screening data obtained prior to this 
window can be re-assessed any time prior to vaccination from Day -84 to 
Day -29.
Vaccination & follow up visits:
x
Vaccination on Day -28 (±3 days), participants will be randomised 1:1 to 
receive RSVpreF or placebo 
x
Follow up clinic visit 1 day post vaccination
x
Follow up clinic visit 7 days post vaccination (±1 day)
Quarantine & virus challenge:
x
Admission to the Quarantine Unit on Day -2/-1; resident in the Quarantine 
Unit for approximately 15 days, from admission on Day -2 to planned 
discharge on Day +12.
x
Challenge with Challenge Virus on Day 0.
x
Discharge from quarantine planned on Day +12
Follow-Up Clinic visits:
x
Day +28 (±3 days).
x
Day +155 (±14 days)
Expected 
duration 
of 
subject participation
Approximately 6 months from randomisation to the subject’s last scheduled visit.
Overall duration of clinical 
phase
The length of the clinical phase is expected to be 9 months from start of 
vaccination for the first participant (FPFV) to the last scheduled study visit for the 
last participant (LPLV).
End of study
The end of the study will be considered as the last visit of the last participant in 
the study.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
12
Procedures 
and 
assessments
During the study the following assessments and procedures will be
performed:
x
Vaccination
x
Vaccination diary cards
x
Informed Consent
x
Medical History and Prior Medication Review (including hVIVO Medical 
Questionnaire)
x
Demographics
x
Height, Weight and Body Mass Index (BMI)
x
Complete Physical Examination
x
Directed Physical Examination
x
Vital Signs
x
Temperature
x
Electrocardiogram (ECG)
x
Spirometry
x
Subject Diary Cards
o
Categorical Scale
o
Visual Analogue Scale
x
Patient Health Questionnaire (PHQ-9)
x
Generalised Anxiety Disorder Questionnaire (GAD-7)
x
Nasal Discharge Collection
x
Blood Samples
x
Nasal Samples
x
Urine Collection
x
Breath Alcohol
x
AEs and Concomitant Medications
Sample size
Approximately 62 (up to 72) participants will be vaccinated. This will take account 
for withdrawals between vaccination and challenge.
Replacement policy
If a participant discontinues from study intervention OR withdraws from the study 
a replacement participant may be enrolled if deemed appropriate by the 
investigator and Sponsor. The replacement participant will generally receive the 
same intervention as the participant being replaced. The replacement participant 
will be assigned a unique treatment/randomisation number. 
Statistics
The statistical powering selected for this study is estimated to be sufficient for 
the primary objective and the primary endpoint family. The primary endpoint 
family consists of 3 endpoints listed below with their associated sample size 
estimates. As an exploratory proof of concept study, no adjustment for Type 1 
error is planned in regard to the primary endpoint family. The sample size of 62 
participants (31 in each arm) will allow:
x
Detection of a 70% relative reduction in the RT-PCR-AUC virology with 
RSVpreF assuming a 96% Coefficient of Variation (CV) in the control arm. 
The power for this endpoint is for 80% using a two-sided type-I error rate of 
5%. The RT-PCR-AUC data is based on log transformed PCR data.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
13
x
Detection of a 60% relative reduction in the symptomatic-infection rate with 
RSVpreF assuming a 59.26% rate in the control arm (i.e. a rate of 23.7% in 
the RSVpreF arm). The power for this endpoint is 80% using a two-sided type-
I error rate of 5%. Symptomatic-infection is defined as:
o
Lab confirmed infection (two detectable (≥Lower Limit of Detection 
LLOD) RT-PCR measurements (reported on 2 or more consecutive 
days), starting two days post-viral challenge (Day +2) up to discharge 
from quarantine), and
o
Either one or more positive clinical symptoms of any grade from two 
different categories in the symptom scoring system (Upper 
Respiratory, Lower Respiratory, Systemic), or one Grade 2 symptom 
from any category.
x
Detection of a 80% relative reduction in the sum total symptoms (sum of all 
symptom diary cards total score from day +1 post inoculation up to and 
including Day +12am) with RSVpreF assuming a 113.55% CV in the control 
arm. The power for this endpoint is at least 80% using a one-sided type-I error 
rate of 5%.
The sample sizes indicate the number of vaccinated participants to be inoculated 
with the challenge virus per group, more will be vaccinated in order to achieve 
the inoculation numbers. Therefore, up to 72 participants will be enrolled and 
vaccinated with the study vaccine, with 62 participants challenged with the study 
virus.
OBJECTIVES
ENDPOINTS
PRIMARY

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
14
x
To evaluate the effect of 
RSVpreF, in reducing 
the 
incidence 
or
severity of infection or 
disease due to RSV-A
Memphis 
37b 
when 
compared to placebo 
To evaluate the reduction in one or more of the following endpoints within the 
primary endpoint family:
x
Area under the viral load-time curve (VL-AUC) of RSV-A Memphis 37b as 
determined by qRT-PCR on nasal samples collected twice daily starting two 
days post-viral challenge (Day +2) up to discharge from quarantine.
x
RT-PCR-confirmed symptomatic RSV infection (Variant 1), defined as:
o
RT-PCR-confirmed RSV infection [two detectable (≥LLOD) qRT-PCR 
measurements (reported on 2 or more consecutive days), starting two 
days post-viral challenge (Day +2) up to discharge from quarantine],
AND
o
Either one or more positive clinical symptoms of any grade from two 
different categories in the symptom scoring system (Upper 
Respiratory, Lower Respiratory, Systemic), or one Grade 2 symptom 
from any category 
x
Sum total symptoms diary card score: sum total clinical symptoms (TSS) as 
measured by graded symptom scoring system collected three times daily 
starting one day post-viral challenge (Day +1) up to discharge from quarantine
SECONDARY
x
To further evaluate the 
effect of RSVpreF, in 
reducing the incidence 
of infection or disease 
due to RSV-A Memphis 
37b, 
compared 
to 
placebo
To evaluate the reduction in the following endpoints:
x
RT-PCR-confirmed symptomatic RSV infection defined as:
o
RT-PCR-confirmed RSV infection (two quantifiable [≥LLOQ] qRT-
PCR measurements (reported on 2 or more consecutive days), 
starting two days post-viral challenge [Day +2] up to discharge from 
quarantine.), AND
o
Either one or more positive clinical symptoms of any grade from two 
different categories in the symptom scoring system (Upper 
Respiratory, Lower Respiratory, Systemic), or one Grade 2 symptom 
from any category 
x
Culture lab-confirmed reduction of symptomatic RSV infection defined as:
o
Lab-confirmed culturable RSV infection (one quantifiable (≥LLOQ)
viral culture measurement starting two days post-viral challenge 
(Day +2) up to discharge from quarantine), AND
o
Either one or more positive clinical symptoms of any grade from two 
different categories in the symptom scoring system (Upper 
Respiratory, Lower Respiratory, Systemic), or one Grade 2 symptom 
from any category 
x
To further evaluate the 
effect of RSVpreF, in 
reducing infection due 
To evaluate the reduction in the following endpoints:
x
Peak viral load of RSV-A Memphis 37b as defined by the maximum viral load 
determined by quantifiable qRT-PCR measurements in nasal samples 

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
15
to RSV-A Memphis 37b 
compared to placebo
starting two days post-viral challenge (Day +2) up to discharge from 
quarantine.
x
Peak viral load of RSV-A Memphis 37b as defined by the maximum viral load 
determined by quantitative viral culture measurements in nasal samples 
starting two days post-viral challenge (Day +2) up to discharge from 
quarantine.
x
Duration of RSV-A Memphis 37b quantifiable qRT-PCR measurements in 
nasal samples starting two days post-viral challenge (Day +2) up to discharge 
from quarantine. Duration is defined as the time (hours) from first detectable 
until first confirmed undetectable assessment after their peak measure (after 
which no further virus is detected).
x
Duration of RSV-A Memphis 37b quantitative RSV viral culture measurements 
in nasal samples starting two days post-viral challenge (Day +2) up to 
discharge from quarantine. Duration is defined as the time (hours) from first 
detectable until first confirmed undetectable assessment after their peak 
measure (after which no further virus is detected).
x
Area under the viral load-time curve (VL-AUC) of RSV-A Memphis 37b as 
determined by quantitative viral culture on nasal samples starting two days 
post-viral challenge (Day +2) up to discharge from quarantine
x
To further evaluate the 
effect of RSVpreF, in 
reducing 
symptomatic 
infection due to RSV-A
Memphis 
37b, 
compared to placebo
To evaluate the reduction in the following endpoints:
x
Area under the curve over time (TSS-AUC) of total clinical symptoms (TSS) 
as measured by graded symptom scoring system (categorical and visual 
analogue scales) collected three times daily starting one day post-viral 
challenge (Day +1) up to discharge from quarantine.
x
Peak symptoms diary card score: peak total clinical symptoms (TSS) as 
measured by graded symptom scoring system (categorical and visual 
analogue scales) collected three times daily starting one day post-viral 
challenge (Day +1) up to discharge from quarantine
x
Peak daily symptom score: Individual maximum daily sum of Symptom score 
starting one day post-viral challenge (Day +1) up to the end of quarantine.
x
Number (%) of participants with Grade 2 or higher symptoms
x
To evaluate the effect of 
RSVpreF, in reducing 
the incidence of RSV-A
Memphis 37b infection
compared to placebo
To evaluate the reduction in the following endpoints:
x
Occurrence of at least two positive quantifiable (≥LLOQ)
qRT-PCR 
measurements in nasal samples at different timepoints reported on 2 or more 
consecutive days starting two days post-viral challenge (Day +2) up to 
discharge from quarantine.
x
Occurrence of at least two positive detectable (≥LLOD)
qRT-PCR 
measurements in nasal samples at different timepoints reported on 2 or more 
consecutive days starting two days post-viral challenge (Day +2) up to 
discharge from quarantine.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
16
x
Occurrence of at least one positive quantitative (≥LLOQ) cell culture 
measurement in nasal samples starting two days post-viral challenge (Day 
+2) up to discharge from quarantine.
x
To evaluate the effect of 
RSVpreF, in reducing 
nasal discharge, when 
compared to placebo
To evaluate the reduction in the following endpoints:
x
Total weight of mucus produced starting one day post-viral challenge (Day +1) 
up to discharge from quarantine.
x
Total number of tissues used by participants starting one day post-viral 
challenge (Day +1) up to discharge from quarantine.
x
To evaluate the safety 
and reactogenicity of 
RSVpreF,
when 
compared to placebo
To evaluate the incidence of the following endpoints:
x
Occurrence of solicited local reactions and systemic events within 7 days (i.e., 
on the day of vaccination and 6 subsequent days) after vaccination.
x
Occurrence of unsolicited adverse events (AEs) within 30 days (i.e., on the 
day of vaccination and 29 subsequent days) after vaccination
x
Occurrence of medically attended AEs (MAEs) and serious adverse events 
(SAEs) from vaccination (Day -28) up to study end (Day +155).
x
To evaluate the safety 
of the RSV challenge 
model.
To list the incidence of the following endpoints:
o
Occurrence of unsolicited AEs within 30 days post-viral challenge (Day 0) up 
to Day +28 follow up.
o
Occurrence of SAEs related to the viral challenge from the viral challenge 
(Day 0) up to Day +28 follow up.
o
Occurrence of haematological and biochemical laboratory abnormalities 
during the quarantine period.
x
Use of concomitant medications within 30 days post-viral challenge (Day 0 up 
to Day +28 follow up).
TERTIARY
Tertiary/exploratory endpoints include, but are not limited to the following.
x
To evaluate the effect of 
baseline immune status 
on immunogenicity and 
efficacy 
of 
the 
RSVpreF, 
when 
compared to placebo
x
The primary, secondary, and tertiary endpoints may be explored in relation to 
the baseline status of participants and the response to vaccination. 
x
To 
characterize 
the 
innate, 
humoral 
and 
cellular immunity at a) 
baseline 
(prior 
to 
RSVpreF 
administration), b) after 
The primary, secondary, and tertiary endpoints may be explored in relation to 
immunological levels at baseline, after vaccination, and after RSV challenge.
Assays performed on serum and nasal samples may include, but are not limited 
to:

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
17
RSVpreF
administration, and c) 
after RSV-A Memphis 
37b challenge
x
Humoral immunity / systems serology (for example RSV A & B neutralizing
titres, PreF and PostF ELISAs to IgG, IgA, sIgA, ADCC)
x
Immunological measures of RSV A & B exposure/infection in community
post vaccination
x
Proteomic levels and changes (for example, cytokine and chemokines)
x
Cellular cell quantification and quality of immunity (for example T and B cell 
frequencies, phenotypes and functionality assays: ELISPOTs, ICS, 
cytokine/chemokine responses)
x
Transcriptome levels and changes (for example, RNAseq, single cell 
RNAseq, microarray, PCR)
x
Genomics in relation to RSV susceptibility, infection and vaccine 
responsiveness (e.g. HLA typing, SNPs, GWAS)
x
To evaluate the effect of 
RSVpreF, in reducing 
the incidence of RSV-A
Memphis 37b disease,
when 
compared 
to 
placebo
To evaluate the reduction in the incidence of:
x
Upper Respiratory Tract illness (URT)
x
Lower Respiratory Tract illness (LRT)
x
Systemic illness (SI)
x
Febrile illness (FI)
x
Proportion of Participants with Grade 2 or higher symptoms on any occasion 
at any time from the last assessment on Day 0 to quarantine discharge
x
Proportion of participants with Grade 2 or higher Symptoms on two separate 
occasions at any time from the last assessment on Day 0 to quarantine 
discharge
x
Proportion of participants with any symptom (grade >=1) on any occasion at 
any time from the last assessment on Day 0 to quarantine discharge
x
Proportion of participants with any symptom (grade >=1) on two separate 
occasions at any time from the last assessment on Day 0 to quarantine 
discharge

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
18
1.2.
Study Schematic: On-study Participant Progression
*NOTE: Release from quarantine is foreseen at Day 12 in case no virus is detected by the nasal RSV 
discharge test and the participant has no clinically significant symptoms. If the participant continues to 
have clinically significant symptoms and/or detectable virus on Day 12, additional extended quarantine 
stay may be required at the discretion of the Investigator.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
19
1.3.
Schedule(s) of Activities (SoA)
Screening
*
Visit 
1
Visit 
2
Visit 
3
Visit 4
Visit 
5
Visit 
6
Early 
Withdrawal
Study Phase
Outpatient 
Inpatient Quarantine 
Follow-Up
Study Day (with 
respect to 
challenge virus 
inoculation)
Day -84 to 
Day -29 (Day-118 for 
RSV serology)
Vaccination
D -28 (+/-3days)
Clinic Visit 1 day post-
vaccination
Clinic Visit 7 days post-
vaccination (+/-1day)
D-2  (#)
D-1 (#)
Day 0 Pre
D0 Challenge
Day 0 Post
D1 
D2
D3
D4
D5
D6
D7
D8 
D9
D10
D11
D12
D28 
(+/- 3 days)
D155
(+/- 14 days)
Pre-Challenge
Post-Challenge
Written consent (a)
X
X
Eligibility criteria (+)
X
X
Xj
X
Medical & 
medication history
X
X
Demographics
X
Height & weight, 
BMI (b)
X
X
Xj
(X)
(X)
(X)
(X)
(X)
Patient Health 
Questionnaire 
(PHQ-9)
(X)
(X)
(X)j
Generalised 
Anxiety Disorder 
Questionnaire 
(GAD-7)
(X)
(X)
(X)j
Alcohol breath test
X
X
Xj
X
X
Urinalysis
X
X
X
Xj
X
X
X
X
X
X
X
Urine drugs of 
abuse and nicotine 
screen
X
X
Xj
X
X
Urine pregnancy 
test
X
X
X
X
X
X
X

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
20
Screening
*
Visit 
1
Visit 
2
Visit 
3
Visit 4
Visit 
5
Visit 
6
Early 
Withdrawal
Study Phase
Outpatient 
Inpatient Quarantine 
Follow-Up
Study Day (with 
respect to 
challenge virus 
inoculation)
Day -84 to 
Day -29 (Day-118 for 
RSV serology)
Vaccination
D -28 (+/-3days)
Clinic Visit 1 day post-
vaccination
Clinic Visit 7 days post-
vaccination (+/-1day)
D-2  (#)
D-1 (#)
Day 0 Pre
D0 Challenge
Day 0 Post
D1 
D2
D3
D4
D5
D6
D7
D8 
D9
D10
D11
D12
D28 
(+/- 3 days)
D155
(+/- 14 days)
Pre-Challenge
Post-Challenge
Complete physical 
examination
X
X
Xj
X
X
X
X
X
X
X
Directed physical 
examination (inc 
nasal)
X
X
X
X
X
X
X
X
X
X
X
Vital signs (HR, 
RR, SBP, DBP, 
SpO2 (d)
X
2 Xn
X
TDS
TDS
TDS
TDS
TDS
TDS
TDS
TDS
TDS
TDS
TDS
TDS
TDS
X
X
X
X
X
Temperature (d)
X
2 Xn
X
TDS
TDS
TDS
TDS
TDS
TDS
TDS
TDS
TDS
TDS
TDS
TDS
TDS
X
X
X
X
X
Symptom diary 
card
X
TDS
TDS
TDS
TDS
TDS
TDS
TDS
TDS
TDS
TDS
TDS
TDS
TDS
X
24-hour tissue 
count & nasal 
discharge weight 
(c)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
(X)
Spirometry (d)
X
Xj
X
X
X
X
X
X
12-lead ECG
X
Xj
X
X
X
X
X
Product Administration
Randomisation
X
Pre-Vaccination 
symptoms
X
IMP/Placebo 
Dosing
X
Post vaccination 
observation (o)
X
Vaccine symptom 
diary card 
distribution
X
Vaccine symptom 
diary card review
X
X

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
21
Screening
*
Visit 
1
Visit 
2
Visit 
3
Visit 4
Visit 
5
Visit 
6
Early 
Withdrawal
Study Phase
Outpatient 
Inpatient Quarantine 
Follow-Up
Study Day (with 
respect to 
challenge virus 
inoculation)
Day -84 to 
Day -29 (Day-118 for 
RSV serology)
Vaccination
D -28 (+/-3days)
Clinic Visit 1 day post-
vaccination
Clinic Visit 7 days post-
vaccination (+/-1day)
D-2  (#)
D-1 (#)
Day 0 Pre
D0 Challenge
Day 0 Post
D1 
D2
D3
D4
D5
D6
D7
D8 
D9
D10
D11
D12
D28 
(+/- 3 days)
D155
(+/- 14 days)
Pre-Challenge
Post-Challenge
Challenge Virus 
inoculation
X
Collection of blood samples
Serum FSH- (post-
menopausal 
women)
X
Serum β-HCG 
pregnancy test (all 
females) 
(X)m
Xj
HIV, Hepatitis A, B, 
& C
X
Haematology (e)
X
Xj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Biochemistry
X
(X)
Xj
X
X
X
X
X
X
X
Coagulation
X
(X)
(X)j
Cardiac enzymes
X
Xj
X
X
X
Thyroid function 
test
X
(X)j
Blood - serum 
markers Humoral 
immunity (f) (g)
X
X
Xj
X
X
X
X
X
Blood – serum 
markers 
cytokines/chemokin
es (g)
X
X
Xp
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
Blood - PBMCs 
CMI & cellular 
markers (g)
X
X
Xp
X
X
X
(X)
(X)
Blood Paxgene, 
(DNA – Genomics)
X r

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
22
Screening
*
Visit 
1
Visit 
2
Visit 
3
Visit 4
Visit 
5
Visit 
6
Early 
Withdrawal
Study Phase
Outpatient 
Inpatient Quarantine 
Follow-Up
Study Day (with 
respect to 
challenge virus 
inoculation)
Day -84 to 
Day -29 (Day-118 for 
RSV serology)
Vaccination
D -28 (+/-3days)
Clinic Visit 1 day post-
vaccination
Clinic Visit 7 days post-
vaccination (+/-1day)
D-2  (#)
D-1 (#)
Day 0 Pre
D0 Challenge
Day 0 Post
D1 
D2
D3
D4
D5
D6
D7
D8 
D9
D10
D11
D12
D28 
(+/- 3 days)
D155
(+/- 14 days)
Pre-Challenge
Post-Challenge
Blood Paxgene
(Transcriptomics)
X
X
Xp
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
Collection of respiratory samples
Nasal sample -
Respiratory 
pathogen screen 
(h)
T
X
X
(X)
Nasal sample -
RSV discharge test
(X)q
(X)q
Nasosorption – Ig, 
Cytokine and 
chemokine 
quantification
(X)
(X)
(X)p
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
Nasal sample –
Virology (i)
T
X
BD
BD
BD
BD
BD
BD
BD
BD
BD
BD
X
Safety Assessments
Solicited AE 
recording (k)
X
Unsolicited AE 
recording (l)
Medically Attended 
AEs (MAEs) and 
SAE recording
Concomitant 
medications
X
KEY NOTES FOR SCHEDULE OF EVENTS

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
23
X
Once
BD
Twice Daily, 12 hours between assessments (± 1 hour).
TDS
Three Times Daily, at the same time each day (± 1 hour).
T
To determine tolerance of the procedure only (sample will not be tested).
*
All screening assessments will be performed under hVIVO Generic Screening process. Results of tests or examinations 
performed under hVIVO Generic Screening process, and from Day -118 (Day -118 for viral serology and Day-84 for other 
assessments including safety laboratory test) prior to vaccination may be used to determine eligibility without the need to repeat 
the assessment following study specific consent.
+
Only the applicable Inclusion/Exclusion criteria will be reviewed at each time point.
#
Admission can occur on Day -2 or Day -1 and therefore procedures can be performed on Day-2 or Day-1. If admission is on Day 
-1 then those procedures which occur on both Day -2 and -1 will only be captured using the timepoints of Day -1.
For TDS assessments on Day -2/Day-1: When Quarantine Admission occurs on Day -1, assessments will be performed up to 
three times daily.
a
Study-specific consent may occur on the day of vaccination, providing all required eligibility information has been collected 
through the hVIVO generic screening process.
b
Height will be taken at Screening only.
c
Distribution of paper tissues and bags will start on Day -1, with the first collection on Day 0. Thereafter collection of tissues will 
occur at the same timepoints (± 1 hour) with tissues distributed 24h ahead.
d
Assessments will be performed at the same time each day during quarantine (± 1 hour).
e
Blood will be drawn under non-fasted conditions. Repeat bloods may be drawn under fasted conditions if a lipid profile (triglyceride) 
or glucose is required (at PI discretion).
f
Vaccine and viral challenge serology (e.g. RSV neutralisation antibody assay) will be performed to determine eligibility and 
seroconversion. Non-vaccine antigen-binding antibody assay will be used for serological detection/seroconversion of community 
acquired RSV infection between vaccination and viral challenge.
g
Samples for related exploratory research.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
24
h
Upper respiratory tract swab (e.g. nasopharyngeal swab, mid-turbinate swab, oropharyngeal swab) for respiratory virus screen 
to assess for the presence of other respiratory viruses; if found positive for any pathogen in the panel, the participant will not be 
eligible for the current quarantine. Sample will also be tested for SARSCoV-2 (COVID-19), which would contraindicate the 
participant’s participation.
i
Pre-inoculation nasal samples are optional under PI discretion.  Post inoculation Nasal virology samples will be collected at the 
same time each day during quarantine (± 1 hour) and used for RT-qPCR and viral culture assay (as appropriate).  Samples may 
be used for related exploratory research.
j
Can be performed on Study Day -2 or Study Day -1.
k
Solicited reactogenicity will be collected from vaccination until 7 days after vaccination.
l
Unsolicited AEs will be collected from vaccination until 30 days after vaccination.
m
Blood serum pregnancy test (ß-HCG) will be performed in all female participants who have been tested positive for urine 
pregnancy testing.
n
Assessments to be made pre and post dosing.
o
Participants will be closely observed for a minimum of 30 minutes post-vaccination. Any unsolicited, solicited AEs, and vital
signs will be documented by the Investigator following this observation period.
p
Sample will be taken on Day -2, Day-1 or Day 0 pre-challenge.
q
Nasal sample for RSV discharge test will be collected on Day 11 or Day 12. A repeat test may be requested at PI discretion at
subsequent days.
r
Sample collected only for subjects who consented to genetic testing. If a Day -28 sample is not taken, then it may be taken on 
the clinic visit 1 day post vaccination instead.
Notes:
Parenthesis indicates the assessment may be optional (will be identified in the Research Plan), or at the PI's discretion.
The PI may perform additional safety assessments as required.
For all participants TDS assessments will commence on Day 0, the first assessment will be pre-virus challenge.
Where any nasal sampling time points occur together, the order of sampling will typically be (1) Nasosorption followed by (2) 
Nasopharyngeal swab followed by (3) Nasal wash.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
25
GENOMIC, TRANSCRIPTOMIC AND PROTEOMIC SAMPLES
DNA/RNA/proteomic sample collection:
Yes
܈
No
տ
DNA
RNA.
Proteomic.
Consent considerations: 
Genetic consent.
Future use of remaining samples for new ethically approved health research and laboratory testing 
protocols according to the local laws.

 
HVO-CS-005 Protocol Final v3.0  
 
hVIVO template identifier: (G_0687) v3.0  
 
26 
2. 
Introduction 
RSVpreF is being developed to prevent RSV-associated moderate to severe lower respiratory tract disease 
in adults 60 years of age and older by active immunisation (older adult indication) and to prevent RSV- 
associated LRTI in infants by active immunisation of pregnant women (maternal indication). 
This study will be an exploratory proof of concept Phase 2a study for the older adult indication assessing 
the RSVpreF vaccine immunogenicity and efficacy in the RSV-A Memphis 37b human challenge model. 
 
x 
VACCINE 
The aim of RSV immunisation in adults 60 years of age and over is to boost the immune response 
sufficiently to protect against RSV disease. There are 2 antigenic variants of RSV, namely, RSV 
subgroup A (RSV A) and RSV subgroup B (RSV B). The RSV vaccine (RSVpreF) being 
investigated in this study is bivalent, composed of two stabilised RSV prefusion F antigens, each 
representing one subgroup, to optimise the breadth of protection against all circulating strains.  RSV 
F facilitates fusion of the virion and host cell membrane during cell entry through a dramatic 
transition from metastable prefusion confirmation to a very stable postfusion state. Preclinical 
studies show that prefusion F, when engineered to maintain the prefusion conformation, elicits 
much higher neutralising antibody titres than postfusion F and that the most potent neutralising 
antibodies from post-infection human sera target the prefusion form, 
x 
PRECLINICAL AND CLINICAL STUDIES.  
Pfizer’s RSVpreF has been evaluated in preclinical studies demonstrating robust RSV A– and RSV 
B–neutralising antibody responses in mice, cotton rats, and nonhuman primates. RSVpreF, with or 
without aluminum hydroxide (Al[OH]3), is currently being evaluated in a Phase 1/2, placebo 
controlled, randomised, observer-blind, dose-finding, first-in-human (FIH) study in healthy adults 
18 to 85 years old (C3671001). This study is also assessing RSVpreF vaccination with and without 
concomitant influenza vaccination. In an ongoing Phase 1/2, placebo-controlled randomised, 
observer-blind, dose-ranging, FIH study (C3671002), a CpG adjuvant containing formulation is 
being evaluated in older adults 65 to 85 years of age. RSVpreF has demonstrated an acceptable 
safety profile in these studies. Interim immunogenicity data demonstrated high neutralising 
antibody responses to the stabilized prefusion F antigens in RSVpreF. The maternal indication is 
supported by  a Phase 2b, placebo-controlled, randomised, observer-blind study in healthy 
pregnant women 18 to 49 years of age  assessing RSVpreF with and without Al(OH)3 (C3671003) 
and a Phase 2b, placebo-controlled, randomised, observer-blind study investigating concomitant 
administration of RSVpreF and a tetanus, diphtheria, acellular pertussis vaccine (Tdap) in healthy 
nonpregnant women 18 to 49 years of age (C3671004). A Phase 3, placebo-controlled, 
randomised, double-blind study has recently started to evaluate efficacy and safety of RSVpreF in 
infants born to women vaccinated during pregnancy (C3671008). There are no safety concerns at 
this time. Comprehensive non-clinical and clinical information regarding RSVpreF is further 
described in the Investigator’s Brochure (IB). 
 

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
27
Respiratory Syncytial Virus (RSV) is the most common cause of acute lower respiratory infection (ALRI) in 
infants and children (Nair et al. 2010; Hall et al. 2009; Bont et al. 2016). Globally, it was estimated in 2005 
that RSV caused 33.8 million episodes of ALRI (~22% of all ALRI) and 3.4 million episodes of severe ALRI 
requiring hospitalization among children <5 years old worldwide (Nair et al. 2010). Mortality from RSV 
infection is significant, with an estimated 66,000-199,000 childhood deaths in 2005 worldwide (Nair et al. 
2010). The overwhelming majority of these deaths occur in children below the age of 2 years and in 
developing countries (Nair et al. 2010; Bont et al. 2016). The most recent estimates of global RSV disease 
burden showed that, in 2015, there were no substantial changes in the number of new episodes of RSV-
ALRI and related hospital admissions compared to 2005, but a lower number of in-hospital deaths (Shi et 
al. 2015). Moreover, for children younger than 6 months, Shi et al reported about 1.4 million hospital 
admissions and 27,300 in-hospital deaths due to RSV-ALRI in 2015 worldwide (Shi et al. 2015).
RSV is also increasingly being recognised as a significant cause of morbidity and mortality in older adults 
and those with underlying chronic cardiopulmonary disorders (Falsey et al. 1995; Agius et al. 1990; Falsey 
et al. 2005). RSV is a predictable seasonal cause of respiratory illness that burdens the healthcare system, 
resulting in increased numbers of medical visits, hospitalizations, and deaths. Published estimates indicate 
that approximately 11,000 to 17,000 older adults die annually of RSV-related illnesses in the United States 
(US), with about 10-fold more (177,500) admitted to the hospital with respiratory symptoms (Matias et al. 
2014; Walsh and Falsey 2012).  Adults with underlying risk factors may present with RSV-associated 
disease of increased severity and duration. RSV may also trigger clinical deterioration in frail older adults, 
the immunocompromised, and those with chronic cardio-pulmonary disease, resulting in RSV-associated 
hospitalization (Falsey et al. 2005; Zhou et al. 2012; Fleming et al. 2015). No vaccine to treat or prevent 
RSV mediated disease is currrently available. 
The RSV human challenge model was developed to not only aid understanding of RSV disease, but also 
to assess the efficacy of RSV antivirals, immunomodulators and vaccines. The RSV-A Memphis 37b 
challenge strain has been used for over 10 years by both hVIVO and others and has helped assess the 
efficacy of numerous RSV therapies and vaccines (Lambkin-Williams et al. 2018). Specifically, hVIVO have 
safely and successfully used the RSV challenge strain in over 1300 healthy participants (18 to 55 years of 
age) and has also safely completed inoculation of twenty-four participants between 60 and 75 years of age. 
Additionally, another strain of live RSV (Memphis 37c) has been used as an inoculation agent and was 
shown to be safe in over 77 healthy young adults across three studies. RSV infection was not associated 
with any serious adverse side effects. Healthy RSV challenge study participants have approximately 65% 
to 85% chance of becoming infected with RSV following the administration of the virus (DeVincenzo et al. 
2010). Typical RSV illness in heathy adults is characterised by an abrupt onset of rhinitis, nasal stuffiness, 
sore throat, cough, malaise, and myalgia (muscle aches). In healthy adults, the illness usually resolves 
without any treatment, with relief of symptoms occurring naturally within 7 to 10 days.
RSV Vaccines
Despite the significant medical need, there are currently no vaccines approved for the prevention of lower 
respiratory tract illness caused by RSV and treatment options are limited. The first vaccine candidate for 
RSV naïve young children, which consisted of formalin-inactivated RSV (FI-RSV), was associated with
enhanced respiratory disease (ERD) upon infection with RSV (Kapikian et al. 1969). Although the
mechanisms for ERD are not fully
understood, it is thought that FI-RSV failed to induce adequate

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
28
neutralizing antibody titers and CD8 priming and induced a T-helper (Th) 2 skewed response
(Moghaddam et al. 2006).
An investigational adenovirus vectored virus RSV vaccine with the pre-fusion F protein (Ad26.RSV.preF)
has recently progressed through the human RSV-A Memphis 37b challenge model (NCT03334695). There 
were no safety concerns reported and exploratory endpoint efficacy was shown by significant reduction in
viral replication (DeVincenzo et al. 2019).
RSVpreF
The R S V  F protein undergoes a conformational transition from a metastable pre-fusion state to a
stable post-fusion conformation. Neutralizing sensitive epitopes specific to the pre-F protein are more
potent than those that only bind post-F protein (Gilman et al. 2016; Graham, Modjarrad, and McLellan 2015).
The creation of a stabilised prefusion F confirmation that is highly immunogenic and induces robust 
neutralisation antibodies forms the basis of the RSVpreF evaluated in this protocol.
An efficacious RSV vaccine is expected to induce high levels of neutralising antibodies. RSVpreF under 
evaluation in this protocol has been shown to promote a strong antibody response.
2.1.
Study Rationale
This is an exploratory proof of concept randomised, Phase 2a, double-blind, placebo-controlled human 
challenge study in healthy adults. Participants will receive a single intramuscular dose of either RSVpreF 
or placebo and 4 weeks later undergo intranasal challenge with RSV-A Memphis 37b virus. The 
immunogenicity and efficacy of RSVpreF vaccination on virus replication, clinical symptoms, and incidence 
of symptomatic RSV infection compared to placebo will be evaluated.
This study will serve as a pilot to explore the efficacy of RSVpreF in the human challenge model. Despite
the exploratory descriptive nature of the study, a primary objective is included. To explore the primary 
objective, significant reductions in any one of the three primary endpoints (primary endpoint family) will be 
explored. The primary endpoint family includes both an objective for a virological endpoint (reduction of 
area under curve of viral load,VL-AUC) and two subjective clinical based endpoints (reduction in sum total 
symptom score and incidence of symptomatic infection). Additional key secondary endpoints are included 
relating to reductions in clinical symptoms (AUC, peak and duration), reduction in mucous secretions, as 
well as several definitions of incidence of infection and symptomatic infection that include varying degrees 
of severity of symptoms within their definitions. Furthermore, the baseline immunity of the participants prior 
to vaccination will be explored in relation to RSVpreF responsiveness, and RSVpreF induced immune 
responses will be correlated with protection from RSV-A Memphis 37b infection and disease.
2.2.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably expected 
Adverse Events (AEs) of RSVpreF may be found in the IB.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
29
2.2.1.
Risk Assessment
The known risks to participants are detailed below. However, there may also be risks that are unforeseen 
and not anticipated (e.g., unknown allergies). Every effort will be made to monitor the health of the 
participants to ensure that such risks are minimised. Trained medical personnel and facilities will be 
available to provide medical emergency care.
During a pandemic, additional potential risks to participants may include interruptions to study visit 
schedule, adherence to protocol-specified safety monitoring or safety laboratory assessments. Refer to 
COVID-19 Crisis Management Plan for further details on the risks and risk mitigation strategy.
Potential Risk of
Clinical Significance
Rationale for Risk
Mitigation Strategy
Study Intervention 
Intramuscular Dosing 
with RSVpreF 
Prior studies showed RSVpreF to 
have an acceptable safety profile as 
described in Section 2. Signs and 
symptoms observed after vaccination 
with 
RSVpreF
include  
fatigue/tiredness, 
muscle 
pain, 
headache, and joint pain. These were 
mild or moderate.
These potential reactions, if they are 
observed, will be monitored but are
generally short-term and do not 
require treatment.
Local signs and symptoms associated 
with 
the 
injection 
may 
include
erythema, swelling/induration, and 
pain/tenderness at the injection site.
Local reactions will be monitored but 
are generally short-term and do not 
require treatment.
Systemic exposure to RSVpreF 
To minimise any risks associated with 
systemic exposure to RSVpreF, male 
and female participants must be on 
highly 
effective 
contraception 
methods 
during 
the 
study 
as 
described is Section 5.1.
General Risks related 
to Vaccines
General 
signs 
and 
symptoms 
associated with administration of a 
vaccine, or vaccination with placebo, 
including fatigue, headache, myalgia, 
arthralgia, chills and nausea.
These side effects will be monitored 
but are generally short-term and do 
not require treatment.
An allergic reaction to the vaccination. 
may cause a rash, hives or even 
difficulty breathing. Severe reactions,
including anaphylaxis, are rare but 
can occur with any vaccine.
Medications will be available in the 
clinic to treat serious allergic reactions 
promptly. Participants with a known 
allergy, or history of anaphylaxis or 
other serious adverse
reactions to vaccines or vaccine 
components will be excluded from the 
study.
The study site should have medical 
treatment available in case of severe 
allergic reactions following vaccine
administration.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
30
Potential Risk of
Clinical Significance
Rationale for Risk
Mitigation Strategy
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 
he/she was not previously aware of 
(such as HIV or hepatitis) or an 
unexpected illness.
The hVIVO doctor will provide the 
participant’s 
general 
practitioner 
(GP), or doctor with a referral letter if 
the participant agrees.
Nasal sampling
Collection of nasal wash samples or 
nasopharyngeal swabs may cause 
discomfort, sneezing, watery eyes, 
irritated nose or nose bleeding.
Sample collection will be performed 
by appropriately qualified and trained 
study staff to minimise the discomfort.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
31
Potential Risk of
Clinical Significance
Rationale for Risk
Mitigation Strategy
RSV infection from inoculation
RSV infection & 
severe complications
65% to 85% chance of becoming 
infected with RSV. Typical RSV 
illness: abrupt onset of rhinitis, nasal 
stuffiness, fever, malaise, myalgia 
(muscle aches), and sore throat.
Severe RSV infections are known to 
occur in both infants and adults. In
adult populations, multiple factors, but
not older age,
are independently 
associated 
with 
severe 
RSV 
complications including persons of 
any age with chronic co-morbidities 
and significant immune compromise.
The study 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. 
In previous virus challenge studies at 
hVIVO, uncommonly (3 cases in more 
than 1000 individuals who have 
received the challenge virus) blood 
tests 
have 
shown 
a 
change 
suggestive of myocarditis, although in 
these few participants the blood tests 
returned to normal without treatment.
The safety profile of the RSV-A
Memphis 37b challenge strain is well 
characterised in healthy young adults 
as this has been used for over ten 
years by hVIVO. At hVIVO more than 
1000 healthy adults aged 18 to 55 
years have been challenged with the 
RSV-A Memphis 37b strain. 
RSV infection in healthy adults 
usually resolves without treatment 
within 7 to 10 days. 
Strict inclusion and exclusion criteria 
will apply to ensure only healthy 
adults are enrolled in this study.
There 
will 
be 
a 
daily 
medical 
monitoring in a quarantine unit for at
least 12 days post-challenge. 
Qualified medical and nursing staff in 
the quarantine unit will monitor for, 
and manage any symptoms
Participants will be closely followed 
up 
while 
being 
in 
quarantine. 
Electrocardiogram will be performed, 
and cardiac enzymes will be tested at 
least 4 days, 7 days and 11 days post-
viral challenge
Transient 
increase 
in 
alanine 
aminotransferase (ALT) or aspartate 
aminotransferase 
(AST) 
without 
clinical presentation, with a good 
prognosis 
upon 
improvement 
of 
infection. 
ALT and AST will be monitored.
Transmission of RSV 
to participants’ close 
contacts
RSV virus 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 
sample using a viral diagnostic (e.g. 
RVAT, 
PCR)
to 
determine 
participants’ suitability for departure.
Passing the RSV Challenge Virus to 
others, including vulnerable people 
(see below for definition of vulnerable 
populations).
Participants will remain in individual 
isolated rooms in the quarantine unit 
for 12 days after inoculation with the 
challenge virus.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
32
Potential Risk of
Clinical Significance
Rationale for Risk
Mitigation Strategy
To reduce the risk of transmitting the 
virus into the community, participants 
will be asked to avoid, where possible, 
contact with vulnerable people for 
14 days after they leave quarantine 
(Section 2.2.1.1).
Passing the RSV Challenge Virus to 
study staff.
Clinic staff in contact with participants
in the quarantine unit will require to
wear Personal Protective Equipment
(PPE) to avoid the transmission of the
RSV Challenge Virus to study staff and
to 
prevent 
the 
risk 
of 
cross-
contamination by a viral disease being
brought up into the unit by staff.
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 small 
possibility that this infection could 
return after 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 enrolment.
Please consult the IB for detailed information.
2.2.1.1.
Vulnerable Persons
For the purposes of possible contact, a vulnerable individual is a person who has close or household (i.e., 
share the same apartment or house) high-risk contacts including but not limited to:
x
Persons ≥65 years of age
x
Children ≤2 years of age
x
Residents of nursing homes
x
Women who are pregnant or who are trying to become pregnant.
x
Persons of any age with significant chronic medical conditions such as: 
o
Chronic pulmonary disease (e.g., severe asthma, Chronic Obstructive Pulmonary Disease
(COPD)) 
o
Chronic cardiovascular disease (e.g., cardiomyopathy, congestive heart failure, cardiac 
surgery, ischemic heart disease, known anatomic defects)
o
Contacts that required medical follow-up or hospitalisation during the past 5 years because 
of chronic metabolic disease (e.g., insulin dependent diabetes mellitus, renal dysfunction, 
haemoglobinopathies)
o
Immunosuppression or cancer 
o
Neurological and neurodevelopmental conditions (e.g., cerebral palsy, epilepsy, stroke, 
seizures) 

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
33
2.2.2.
Benefit Assessment
Healthy participants who receive the study vaccine may not directly benefit from this vaccination as the 
efficacy of the vaccine has not yet been demonstrated.
Participants may develop some immunity to RSV 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, participants are contributing to the process of developing new vaccines in an area 
of unmet medical need.
2.2.3.
Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimise risk to participants in this study, the potential risks 
identified in association with RSVpreF are justified by the anticipated benefits linked to the evaluation of 
RSVpreF in the viral challenge model which will subsequently facilitate future assessment of RSV vaccines.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
34
3.
Objectives and Endpoints
OBJECTIVES
ENDPOINTS
PRIMARY
x
To evaluate the effect of 
RSVpreF, in reducing 
the incidence or severity 
of infection or disease 
due to RSV-A Memphis 
37b when compared to 
placebo 
To evaluate the reduction in one or more of the following endpoints within the 
primary endpoint family:
x
Area under the viral load-time curve (VL-AUC) of RSV-A Memphis 37b as 
determined by qRT-PCR on nasal samples collected twice daily starting two 
days post-viral challenge (Day +2) up to discharge from quarantine.
x
RT-PCR-confirmed symptomatic RSV infection (Variant 1), defined as:
o
RT-PCR-confirmed RSV infection [two detectable (≥LLOD) qRT-PCR 
measurements (reported on 2 or more consecutive days), starting two 
days post-viral challenge (Day +2) up to discharge from quarantine], 
AND
o
Either one or more positive clinical symptoms of any grade from two 
different categories in the symptom scoring system (Upper 
Respiratory, Lower Respiratory, Systemic), or one Grade 2 symptom 
from any category 
x
Sum total symptoms diary card score: sum total clinical symptoms (TSS) as 
measured by graded symptom scoring system collected three times daily 
starting one day post-viral challenge (Day +1) up to discharge from quarantine
SECONDARY

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
35
x
To further evaluate the 
effect of RSVpreF, in 
reducing the incidence 
of infection or disease 
due to RSV-A Memphis 
37b, 
compared 
to 
placebo
To evaluate the reduction in the following endpoints:
x
RT-PCR-confirmed symptomatic RSV infection defined as:
o
RT-PCR-confirmed RSV infection (two quantifiable [≥LLOQ] qRT-
PCR measurements (reported on 2 or more consecutive days), 
starting two days post-viral challenge [Day +2] up to discharge from 
quarantine.), AND
o
Either one or more positive clinical symptoms of any grade from two 
different categories in the symptom scoring system (Upper 
Respiratory, Lower Respiratory, Systemic), or one Grade 2 symptom 
from any category 
x
Culture lab-confirmed reduction of symptomatic RSV infection defined as:
o
Lab-confirmed culturable RSV infection (one quantifiable (≥LLOQ)
viral culture measurement starting two days post-viral challenge 
(Day +2) up to discharge from quarantine), AND
o
Either one or more positive clinical symptoms of any grade from two 
different categories in the symptom scoring system (Upper 
Respiratory, Lower Respiratory, Systemic), or one Grade 2 symptom 
from any category 
x
To further evaluate the 
effect of RSVpreF, in 
reducing infection due 
to RSV-A Memphis 37b 
compared to placebo
To evaluate the reduction in the following endpoints:
x
Peak viral load of RSV-A Memphis 37b as defined by the maximum viral load 
determined by quantifiable qRT-PCR measurements in nasal samples starting 
two days post-viral challenge (Day +2) up to discharge from quarantine.
x
Peak viral load of RSV-A Memphis 37b as defined by the maximum viral load 
determined by quantitative viral culture measurements in nasal samples 
starting two days post-viral challenge (Day +2) up to discharge from 
quarantine.
x
Duration of RSV-A Memphis 37b quantifiable qRT-PCR measurements in 
nasal samples starting two days post-viral challenge (Day +2) up to discharge 
from quarantine. Duration is defined as the time (hours) from first detectable 
until first confirmed undetectable assessment after their peak measure (after 
which no further virus is detected).
x
Duration of RSV-A Memphis 37b quantitative RSV viral culture measurements 
in nasal samples starting two days post-viral challenge (Day +2) up to 
discharge from quarantine. Duration is defined as the time (hours) from first 
detectable until first confirmed undetectable assessment after their peak 
measure (after which no further virus is detected).
x
Area under the viral load-time curve (VL-AUC) of RSV-A Memphis 37b as 
determined by quantitative viral culture on nasal samples starting two days 
post-viral challenge (Day +2) up to discharge from quarantine

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
36
x
To further evaluate the 
effect of RSVpreF, in 
reducing 
symptomatic 
infection due to RSV-A
Memphis 
37b,
compared to placebo
To evaluate the reduction in the following endpoints:
x
Area under the curve over time (TSS-AUC) of total clinical symptoms (TSS) 
as measured by graded symptom scoring system (categorical and visual 
analogue scales) collected three times daily starting one day post-viral 
challenge (Day +1) up to discharge from quarantine.
x
Peak symptoms diary card score: peak total clinical symptoms (TSS) as 
measured by graded symptom scoring system (categorical and visual 
analogue scales) collected three times daily starting one day post-viral 
challenge (Day +1) up to discharge from quarantine
x
Peak daily symptom score: Individual maximum daily sum of Symptom score 
starting one day post-viral challenge (Day +1) up to the end of quarantine.
x
Number (%) of participants with Grade 2 or higher symptoms
x
To evaluate the effect of 
RSVpreF, in reducing 
the incidence of RSV-A
Memphis 37b infection
compared to placebo
To evaluate the reduction in the following endpoints:
x
Occurrence of at least two positive quantifiable (≥LLOQ)
qRT-PCR 
measurements in nasal samples at different timepoints reported on 2 or more 
consecutive days starting two days post-viral challenge (Day +2) up to 
discharge from quarantine.
x
Occurrence of at least two positive detectable (≥LLOD)
qRT-PCR 
measurements in nasal samples at different timepoints reported on 2 or more 
consecutive days starting two days post-viral challenge (Day +2) up to 
discharge from quarantine.
x
Occurrence of at least one positive quantitative (≥LLOQ) cell culture 
measurement in nasal samples starting two days post-viral challenge (Day 
+2) up to discharge from quarantine.
x
To evaluate the effect of 
RSVpreF, in reducing 
nasal discharge, when 
compared to placebo
To evaluate the reduction in the following endpoints:
x
Total weight of mucus produced starting one day post-viral challenge (Day +1) 
up to discharge from quarantine.
x
Total number of tissues used by participants starting one day post-viral 
challenge (Day +1) up to discharge from quarantine.
x
To evaluate the safety 
and reactogenicity of 
RSVpreF,
when 
compared to placebo
To evaluate the incidence of the following endpoints:
x
Occurrence of solicited local reactions and systemic events within 7 days (i.e., 
on the day of vaccination and 6 subsequent days) after vaccination.
x
Occurrence of unsolicited adverse events (AEs) within 30 days (i.e., on the 
day of vaccination and 29 subsequent days) after vaccination
x
Occurrence of medically attended AEs (MAEs) and serious adverse events 
(SAEs) from vaccination (Day -28) up to study end (Day +155).

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
37
x
To evaluate the safety 
of the RSV challenge 
model.
To list the incidence of the following endpoints:
o
Occurrence of unsolicited AEs within 30 days post-viral challenge (Day 0) up 
to Day +28 follow up.
o
Occurrence of SAEs related to the viral challenge from the viral challenge 
(Day 0) up to Day +28 follow up.
o
Occurrence of haematological and biochemical laboratory abnormalities 
during the quarantine period.
x
Use of concomitant medications within 30 days post-viral challenge (Day 0 up 
to Day +28 follow up).
TERTIARY
Tertiary/exploratory endpoints include but are not limited to the following.
x
To evaluate the effect of 
baseline immune status 
on immunogenicity and 
efficacy 
of 
the 
RSVpreF, 
when 
compared to placebo 
x
The primary, secondary, and tertiary endpoints may be explored in relation to 
the baseline status of participants and the response to vaccination.
x
To 
characterize 
the 
innate, 
humoral 
and 
cellular immunity at a) 
baseline 
(prior 
to 
RSVpreF 
administration), b) after 
RSVpreF 
administration, and c) 
after RSV-A Memphis 
37b challenge
The primary, secondary, and tertiary endpoints may be explored in relation to 
immunological levels at baseline, after vaccination, and after RSV challenge.
Assays performed on serum and nasal samples may include, but are not limited 
to:
x
Humoral immunity / systems serology (for example RSV A & B neutralizing 
titres, PreF and PostF ELISAs to IgG, IgA, sIgA, ADCC)
x
Immunological measures of RSV A & B exposure/infection in community 
post vaccination
x
Proteomic levels and changes (for example, cytokine and chemokines)
x
Cellular cell quantification and quality of immunity (for example T and B cell 
frequencies, phenotypes and functionality assays: ELISPOTs, ICS, 
cytokine/chemokine responses)
x
Transcriptome levels and changes (for example, RNAseq, single cell 
RNAseq, microarray, PCR)
x
Genomics in relation to RSV susceptibility, infection and vaccine 
responsiveness (e.g. HLA typing, SNPs, GWAS)

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
38
x
To evaluate the effect of 
RSVpreF, in reducing 
the incidence of RSV-A
Memphis 37b disease,
when 
compared 
to 
placebo
To evaluate the reduction in the incidence of:
x
Upper Respiratory Tract illness (URT)
x
Lower Respiratory Tract illness (LRT)
x
Systemic illness (SI)
x
Febrile illness (FI)
x
Proportion of Participants with Grade 2 or higher symptoms on any occasion 
at any time from the last assessment on Day 0 to quarantine discharge
x
Proportion of participants with Grade 2 or higher Symptoms on two separate 
occasions at any time from the last assessment on Day 0 to quarantine 
discharge
x
Proportion of participants with any symptom (grade >=1) on any occasion at 
any time from the last assessment on Day 0 to quarantine discharge
x
Proportion of participants with any symptom (grade >=1) on two separate 
occasions at any time from the last assessment on Day 0 to quarantine 
discharge

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
39
4.
Study Design
4.1.
Overall Design
This is a randomised, Phase 2a, double blind, placebo-controlled study to evaluate the safety, 
immunogenicity and efficacy of an RSV vaccine against RSV-A Memphis 37b infection in healthy 
participants.
The total duration of study participation for a participant is approximately 6 months after vaccination, with 
the following sequence and duration of study periods:
Screening Phase:
x
Screening prior to vaccination from Day -84 to Day -29 (Day -118 for RSV serology) Pre-screening 
data collected through the hVIVO generic screening process prior to signing the study specific 
consent form, and prior to vaccination from Day -84 to Day -29Day -118 for days for RSV serology) 
may be transferred to this study after study-specific consent form has been signed by the 
participant. Pre-screening data obtained prior to this window can be re-assessed any time prior to 
vaccination from Day -84 to Day -29.
Vaccination Phase:
x
Vaccination on Day -28 (±3 days), participants will be randomised 1:1 to receive RSVpreF or 
placebo 
x
Follow up clinic visit 1 day post vaccination
x
Follow up clinic visit 7 days post vaccination (±1 day)
Quarantine Phase:
x
Admission to the Quarantine Unit on Day -2/-1; resident in the Quarantine Unit for approximately 
15 days, from admission on Day -2 to planned discharge on Day +12.
x
Challenge with Challenge Virus on Day 0.
x
Discharge from quarantine planned on Day +12
Follow-Up Phase:
x
Day +28 (±3 days).
x
Day +155 (±14 days)
Participants will be pre-screened for susceptibility to RSV infection, i.e., have levels of RSV neutralising 
antibodies compatible with susceptibility to RSV infection.
Participants will be randomised to receive a single intramuscular dose of RSVpreF or Placebo on Day -28 
(±3 days):
x
Reference article product
o
PF-06928316 also known as RSVpreF 
o
Dose: 120mcg 

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
40
x
Placebo product
o
Placebo to match vaccine
All participants will be closely observed for a minimum of 30 minutes post-vaccination, to monitor for the 
development of any acute reactions, or longer if deemed necessary by the investigator. Any unsolicited, 
solicited AEs and vital signs will be documented by study-site personnel following this observation period. 
Participants will be given a thermometer, a calliper/ruler and a vaccination diary card [VDC] (for daily 
assessment of symptoms) with instructions for the completion of the diary card. Each participant will record 
the presence/absence of symptoms, solicited AEs, and oral temperatures, beginning on the evening of the 
study vaccine dosing day (Day -28) and daily for a total of 7 days. Reminders (e.g. via text message will be
sent to participants from study site personnel to ensure compliance with the VDC. A study site personnel 
will collect and review the participant completed vaccination diary card at the post-vaccination clinic visit, 
approximately 7 days post vaccination and review the information and confirm the entries. Participants will 
be provided with an Emergency Contact Card to contact the Investigator when potentially severe reaction 
occurs. 
Post-vaccination clinic visits will occur 1 day post vaccination and approximately 7 days post-vaccination. 
Any unsolicited, solicited AEs and vital signs will be documented by the Investigator. Any clinically 
significant symptom/AE persisting after the 7 days will be followed up by the Investigator until resolution or 
until clinically stable outcome is reached.
One to two days prior to viral challenge, participants will be admitted to the quarantine unit. Quarantine
assessments will include relevant information since vaccination, ECG, Spirometry, Physical Examination 
and clinical laboratory testing. Participants will subsequently receive the following on Day 0:
x
RSV challenge virus
o
RSV-A Memphis 37b, total dose of approximately 4.5 log10 plaque forming unit, given 
intranasally 
Participants will reside in the Quarantine Unit for a total of approximately 15 days (from Day -2 to Day 12).
From Day 2 to Day 11, nasal samples will be collected approximately every 12 hours, and physical 
examination, vital signs measurements, ECG, clinical safety laboratory test, and Spirometry will be 
performed as per the Schedule of Activities (SOA) in Section 1.3. Release from quarantine is foreseen at 
Day 12, provided no virus is detected (by either the qualitative virus antigen test (RVAT) or equivalent viral 
test, as appropriate) and the participant has no clinically significant symptoms. If the participant continues
to have clinically significant symptoms and/or detectable virus on Day 12, additional extended quarantine
stay may be required based on the assessment of the Investigator. If appropriate, participants may reside 
in quarantine for an additional night or longer before discharge.
Participants will attend a follow up visit at 28 days post-challenge (Day 28), and a follow-up visit at 6 months 
post-vaccination.
4.2.
Scientific Rationale for Study Design
The study will be conducted by hVIVO Services Limited, which has extensive experience with RSV 
challenge studies. Numerous studies have been performed using experimental RSV infection in human 
participants. To date, in hVIVO’s studies, over 1300 participants have been successfully and safely 
inoculated with RSV-A Memphis 37b strain. These studies demonstrated that adults could be infected by 

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
41
nasal inoculation and that experimental infection was safe. This RSV-A Memphis 37b strain has been 
shown to cause symptoms and virus shedding that closely match natural infection in healthy adults.
Administration of study intervention and challenge with RSV-A Memphis 37b strain will take place in 
hVIVO’s specialised Clinical Units, either in the Quarantine Unit or Screening Clinic Units. Standard study 
procedures (including collection of blood, urine, and nasal secretions for assessment of safety and efficacy) 
have been employed in previous studies conducted by hVIVO.
Further details of study rational are included in Section 2.1.
4.3.
Justification for Dose
Three studies have compared different dose levels and formulations of RSVpreF.
x
The first-in-human (FIH) study in adults 18 to 85 years of age evaluated the safety, tolerability, and 
immunogenicity of 3 escalating dose levels of 60 μg, 120 μg, and 240 μg, with or without Al(OH)3,
when administered alone or concomitantly with seasonal inactivated influenza vaccine (SIIV) 
(C3671001). 
x
A study in older adults 65 to 85 years of age evaluated safety, tolerability and immunogenicity of 
60 μg, 120 μg, and 240 μg RSVpreF doses formulated with Al(OH)3 or CpG/Al(OH)3- adjuvant ,or 
240 μg RSVpreF with RSV antigens alone , when administered concomitantly with SIIV 
(C3671002).
x
A study in pregnant women 18 to 49 years of age evaluated safety tolerability and immunogenicity 
of 120 μg and 240 μg RSVpreF dose levels with and without Al(OH)3 (C3671003).
In none of these studies were substantial differences between the immunogenicity or reactogenicity of 120 
mg and 240 mg dose levels or of formulations with and without Al(OH)3 observed. Therefore, 120 mg
without Al(OH)3 is chosen for the human challenge study.
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 procedure shown in the SoA or the last unscheduled visit as applicable. If a 
safety visit is required after the last scheduled visit, this will be at the PI’s discretion as a duty of care, e.g., 
repeat spirometry or laboratory tests. These discretionary follow-up visits will not be considered part of the 
trial data unless they represent follow-up and closure on an AE or serious adverse event (SAE) identified 
during the trial period. 
The end of the study is defined as the date of the last visit of the last participant in the study.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
42
5.
Study Population
Prospective approval of protocol deviations to recruitment and enrolment 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 of the following criteria apply:
NO
STANDARD INCLUSION CRITERIA 
To be eligible for the study, participants must meet all the following inclusion criteria:
1
An informed consent document signed and dated by the participant and the Investigator.
2
Aged between 18 and 50 years old on the day of signing the consent form.
3
In good health with no history, or current evidence, of clinically significant medical 
conditions, and no clinically significant test abnormalities that will interfere with participant
safety, as defined by medical history, physical examination, (including vital signs), ECG, 
and routine laboratory tests as determined by the Investigator.
4
A documented medical history prior to enrolment.
5
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 
enrolment.
b)
Females of non-childbearing potential:
a.
Post-menopausal females; defined as having a history of amenorrhea for 
>12 months with no alternative medical cause, and /or by FSH level 
>40mIU/mL, confirmed by laboratory.
b.
Documented status as being surgically sterile (e.g. tubal ligation, 
hysterectomy, bilateral salpingectomy and bilateral oophorectomy).
6
The following criteria apply to female and male participants:
a)
Female participants of childbearing potential must use one form of highly 
effective contraception. Hormonal methods must be in place from at least 2 weeks 
prior to the first study visit. The contraception use must continue until 28 days after 
the date of viral challenge/last dosing with IMP (whichever occurs last). Highly 
effective contraception is as described below:
a.
Established use of hormonal methods of contraception described below (for 
a minimum of 2 weeks prior to the first study visit). When hormonal methods 
of contraception are used, male partners are required to use a condom with 
a spermicide: 
i.
combined (oestrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation: 

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
43
NO
STANDARD INCLUSION CRITERIA 
To be eligible for the study, participants must meet all the following inclusion criteria:
1.
oral
2.
intravaginal
3.
transdermal
ii.
progestogen-only 
hormonal 
contraception 
associated 
with 
inhibition of ovulation: 
1.
oral
2.
injectable
3.
implantable 
b.
Intrauterine device (IUD) 
c.
Intrauterine hormone-releasing system (IUS) 
d.
Bilateral tubal ligation
e.
Male sterilisation (with the appropriate post vasectomy documentation of 
the absence of sperm in the ejaculate) where the vasectomised male is the 
sole partner for that woman.
f.
True abstinence - sexual abstinence is considered a highly effective method 
only if defined as refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical 
trial and the preferred and usual lifestyle of the participant.
b)
Male participants must agree to the contraceptive requirements below at entry to 
quarantine and continuing until 28 days after the date of Viral challenge / last dosing 
with IMP (whichever occurs last):
a.
Use a condom with a spermicide to prevent pregnancy in a female partner 
or to prevent exposure of any partner (male and female) to the IMP.
b.
Male sterilisation with the appropriate post vasectomy documentation of the 
absence of sperm in the ejaculate (please note that the use of condom with 
spermicide will still be required to prevent partner exposure). This applies 
only to males participating in the study. 
c.
In addition, for female partners of child bearing potential, that partner must 
use another form of contraception such as one of the highly effective 
methods mentioned above for female participants. 
d.
True abstinence - sexual abstinence is considered a highly effective method 
only if defined as refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical 
trial and the preferred and usual lifestyle of the participant.
c)
In addition to the contraceptive requirements above, male participants must agree 
not to donate sperm following discharge from quarantine until 28 days after the date 
of Viral Challenge/last dosing with IMP (whichever occurs last).
7
Sero-suitable to the challenge virus, as defined in the study Analytical Plan.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
44
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
NO
STANDARD EXCLUSION CRITERIA 
Participants who meet any of the following exclusion criteria will not be included in the study.
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.
2
a)
Any history or evidence of any other clinically significant or currently active systemic 
comorbidities including psychiatric disorders (includes participants with a history of 
depression and/or anxiety).
b)
And/or other major disease that, in the opinion of the Investigator, may put the 
participant at undue risk, or interfere with a participant completing the study and 
necessary investigations (e.g autoimmune disease or immunodeficiency).
Guidance
The following conditions apply:
x
Participants with clinically mild atopic eczema/atopic dermatitis and clinically mild 
psoriasis may be included at the Investigator's discretion (e.g., if small amounts of 
regular topical steroids are used, no eczema in cubital fossa; moderate to large 
amounts of daily dermal corticosteroids is an exclusion). 
x
Any rhinitis (specifically upper respiratory tract symptoms related to hay fever) which 
is clinically active or history of moderate to severe rhinitis, or history of seasonal 
allergic rhinitis likely to be active at the time of inclusion into the study and/or requiring 
regular nasal corticosteroids on an at least weekly basis, within 30 days of admission 
to quarantine will be excluded. Participants with a history of currently inactive rhinitis 
(within the last 30 days) or mild rhinitis may be included at the PI’s discretion.
x
Participants with a physician diagnosed underactive thyroid who have been controlled 
on treatment for at least 6 months with evidence of a normal thyroid function test 
(TFT) can be included at the discretion of the PI.  
x
Any concurrent serious illness including history of malignancy that may interfere with 
the aims of the study or a participant completing the study. Basal cell carcinoma within 
5 years of initial diagnosis or with evidence of recurrence is also an exclusion.
x
Participants with a history of psychiatric illness including depression and/or anxiety of 
any severity within the last 2 years can be included if the Patient Health Questionnaire 
(PHQ-9) and / or the Generalised Anxiety Disorder Questionnaire (GAD-7) is less 
than or equal to 4. Participants with a PHQ-9 or GAD-7 score of between 5 and 9 may 
be included following consultation with a Senior Physician (Clinical Lead for 
Screening) who may advise further consultation with the PI.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
45
NO
STANDARD EXCLUSION CRITERIA 
Participants who meet any of the following exclusion criteria will not be included in the study.
x
Participants reporting physician diagnosed migraine can be included provided there 
are no associated neurological symptoms such as hemiplegia or visual loss. Cluster 
headache/migraine or prophylactic treatment for migraine is an exclusion.
x
Participants with physician diagnosed mild Irritable Bowel Syndrome (IBS) not 
requiring regular treatment can be included at the discretion of the PI.
3
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].
4
A total body weight ≤ 50 kg and Body Mass Index (BMI) ≤18 kg/m2 and ≥30kg/m2.
5
Females who:
a)
Are breastfeeding, or
b)
Have been pregnant within 6 months prior to the study.
6
History of anaphylaxis-and/or a history of severe allergic reaction or significant intolerance to 
any food or drug or vaccine, including hypersensitivity to any of the constituents of the study 
vaccine, as assessed by the PI. 
7
Venous access deemed inadequate for the phlebotomy and cannulation demands of the 
study.
8
a)
Any significant abnormality altering the anatomy of the nose in a substantial way or 
nasopharynx 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 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 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.
Prior or Concomitant Medications and Assessments
9
a)
Evidence of vaccinations with licensed live attenuated vaccines within the 4 weeks 
prior to the planned date of viral challenge/first dosing with IMP (whichever occurs 
first). Evidence of vaccinations with licensed vaccines which are not live attenuated 
within the 2 weeks prior to the planned date of viral challenge/first dosing with IMP 
(whichever occurs first).
b)
Intention to receive any vaccination(s) before at least 28 days after the viral 
challenge (NB. No travel restrictions will apply after the Day 28 Follow-up visit).
10
Receipt of blood or blood products, or loss (including blood donations) of 550 mL or more of
blood during the 2 months prior to the planned date of viral challenge/first dosing with IMP 
(whichever occurs first) or planned during the 2 months after the viral challenge.
11
a)
Receipt of any investigational drug within 3 months prior to the planned date of viral 
challenge/first dosing with IMP (whichever occurs first). 

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
46
NO
STANDARD EXCLUSION CRITERIA 
Participants who meet any of the following exclusion criteria will not be included in the study.
b)
Previous vaccination with any licensed or investigational RSV vaccine before 
enrolment into the study.
c)
Receipt of three or more investigational drugs within the previous 12 months prior to 
the planned date of viral challenge/first dosing with IMP (whichever occurs first).
d)
Prior inoculation with a virus from the same virus-family as the challenge virus. 
e)
Prior participation in another human viral challenge 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.
f)
Receipt of treatment with immunosuppressive therapy.
12
a)
Confirmed positive test for drugs of abuse and cotinine on first study visit. One repeat 
test allowed at PI discretion. 
b)
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), or excessive consumption of xanthine containing substances 
(e.g. daily intake in excess of 5 cups of caffeinated drinks e.g. coffee, tea, cola).
13
A forced expiratory volume in 1 second (FEV1) < 80%.
14
Positive human immunodeficiency virus (HIV), active hepatitis A (HAV), B (HBV), or C 
(HCV) test.
Other
15
Those employed or immediate relatives of those employed at hVIVO, Pfizer or any vendor.
16
Any other finding that, in the opinion of the Investigator, deems the Participant unsuitable for 
the study.
5.3.
Lifestyle Considerations
5.3.1.
Meals and Dietary Restrictions
No dietary restrictions are required before or after dose administration.
Participants must not consume any food containing poppy seeds or any codeine containing formulation 
starting 72 hours before screening, before vaccination and before admission to the quarantine Unit (in order 
to avoid false-positive urine drug screen).
5.3.2.
Caffeine, Alcohol, and Tobacco
Participants must abstain from ingesting caffeine- or xanthine-containing products (e.g., coffee, tea, cola 
drinks, and chocolate) for 48 hours prior and during quarantine and for 48 hours prior to all visits requiring 
spirometry.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
47
Participants must not consume alcohol for 72 hours prior and during quarantine and for 72 hours prior to 
any clinic visits.
Participants must not smoke or use tobacco or nicotine containing products for 72 hours prior to and during 
quarantine. Participants that are current smokers may be continued in the study if, in the opinion of the PI, 
cessation of smoking during quarantine will not lead to withdrawal symptoms which could interfere with the 
accurate recording on the Symptoms Diary Card.
5.3.3.
Activity
Participants must refrain from strenuous exercise for 48 hours prior and during quarantine and for 48 hours 
prior to each clinic visit (unless it is within the usual activity of the participant) in order to avoid potential 
spurious elevation of clinical laboratory safety parameters.
5.4.
Screen Failures
Screen failures are defined as participants who sign the study-specific Informed Consent Form (ICF) but
are not subsequently randomised to receive study intervention (i.e. vaccination).
If an individual does not meet the criteria for participation in this study (screen failure) and the Investigator
would like to re-screen the participant, and they are still within the allowed screening window (Day -118 to
Day -29), then only the assessments for which the participant failed must be re-assessed.
If an individual does not meet the criteria for participation in this study (screen failure) and the Investigator
would like to re-screen the participant at a later time (i.e. outside of the allowed screening window), then
full re-screening must be completed.
.

 
HVO-CS-005 Protocol Final v3.0  
 
hVIVO template identifier: (G_0687) v3.0  
 
48 
6. 
Study Intervention 
Study interventions administered to participants are described in Table 1. 
6.1. 
Study Intervention(s) Administered 
Table 1 Study Interventions 
Intervention 
Name 
RSVpreF  
Placebo 
RSV-A Memphis 37b 
virus] 
Type  
Biologic 
Other 
Virus 
Dose 
Formulation 
The active ingredients in 
RSVpreF are 2 stabilized RSV 
prefusion F antigens, in equal 
amounts from virus subgroups 
A and B, in a lyophilized dosage 
form for reconstitution. The drug 
product is supplied as a 
lyophilized white cake in a 2-mL 
glass vial, with a 13-mm 
lyophilization 
stopper, aluminum overseal, 
and flip-off cap.  The drug 
product will be reconstituted by 
a 
diluent consisting of sterile 
water in a prefilled syringe 
(PFS). 
 
Placebo will be a 
lyophile match to the 
vaccine, which will 
consist of excipients 
matched to 
those used in the 
RSVpreF formulation, 
minus the active 
ingredients.    
The physical 
appearance of the 
reconstituted RSVpreF 
and placebo will be 
matched, and the 
study will be 
conducted in a double-
blinded manner. 
Cryovial, Liquid 
Unit Dose 
Strength(s) 
120mcg vial 
0.5mL/vial 
The inoculum virus titre 
is determined in an 
infectivity (plaque) 
assay, the titre is 
reported in plaque 
forming units per mL 
(PFU/mL). The 
challenge dose is 
approximately 4.5log10 
PFU. 
Dosage 
Level(s) 
A single unit dose of 120 mcg 
RSVpreF will be reconstituted 
with sterile water for an 0.5 mL 
injection volume 
The fill volume of the 
placebo vial and 
diluent prefilled syringe 
is designed that the 
intended dose is 
delivered in a 0.5 mL 
injection volume. 
A single dose of virus 
will be delivered. Dose 
volume delivery method 
is provided in the 
Analytical Plan (AP). 
Route of 
Administration 
Intramuscular injection in left 
arm 
Intramuscular injection 
in left arm 
Intranasal 
Use 
Experimental reference article 
Placebo control 
Infectious challenge 
agent  

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
49
IMP and NIMP
IMP 
IMP 
NIMP challenge virus
Sourcing
Packaging and 
Labelling
The details of the study 
intervention packaging and 
labelling will be provided in the 
study-specific Pharmacy 
Manual.
The details of the 
study intervention 
packaging and 
labelling will be 
provided in the study-
specific Pharmacy 
Manual.
RSV Challenge 
Inoculum will be 
provided in vials. The 
details of the virus 
challenge agent 
packaging and labelling 
will be provided in the 
AP
Current/Former 
Name(s) or 
Alias(es)
n/a
n/a
n/a
All supplies indicated in Table 6.1 will be provided per the "Sourcing" row depending upon local country
operational requirements. If local sourcing, every attempt should be made to source these supplies from a
single lot/batch number where possible (e.g. not applicable in the case where multiple lots or batches may
be required due to the length of the study).
Refer to Section 6.2 and the pharmacy manual for details regarding administration of the study intervention.
6.2.
Preparation/Handling/Storage/Accountability
6.2.1.
Investigational Product
RSVpreF (PF-06928316) will be supplied in single use vials at a dose level of 120 mcg/vial powder for 
reconstitution for injection. Placebo will be supplied in single use vials of powder for reconstitution for 
injection. Bulk supplies of the Investigational product will be stored at 
 Pharmacy. The IMP must be 
stored according to the manufacturer’s instructions. 
Individual participant kits will be prepared by unblinded pharmacist for reconstitution with sterile Water for 
Injection (sWFI) and dispensing at site. A Qualified Person (QP) will release and deliver the Investigational 
product to hVIVO prior to administration of the vaccine to the participant. 
 Pharmacy and hVIVO will 
maintain drug accountability as detailed in the study-specific Pharmacy Manual. The Investigator will ensure 
that all supplies are received by a responsible person, all deliveries and returns are documented and signed 
for, and the condition of study vaccine/placebo is monitored. Accountability records will be available for 
verification by the Study Monitor at each monitoring visit. At the completion of the study, there will be a final 
reconciliation of all study vaccine/placebo.
6.2.2.
Challenge Virus
The RSV-A Memphis 37b challenge virus was produced via a nasal aspirate collected from a paediatric 
patient infected with RSV. The Challenge Virus stock, RSV-A Memphis 37b, was manufactured under 
current good manufacturing practices (cGMP). The Challenge Virus stock has undergone quality testing 

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
50
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. The Challenge virus is stored in a secure -80 oC freezer (normal temperature range -60 °C to -90
°C).
Challenge Virus inoculum will be prepared according to the hVIVO Analytical Plan (AP) and administered
in accordance with hVIVO's standard operating procedures (SOPs). Each participant will be allocated a
unique vial containing the Challenge Virus and will receive the inoculum intranasally.
The time from the Challenge Virus inoculum thawing to inoculation should be no longer than 2 hours. All 
administrations will be made by a member of the clinical team and witnessed by a second member of the 
team. The exact time of inoculation will be recorded in the administration log. Accurate records will be kept 
of when and how much study inoculum is prepared and used. The oversight process will be signed off prior 
to administration of the Challenge Virus. Any non-compliance or problems with the inoculation will be 
recorded in the participant’s source notes and reported to the PI.
Following inoculation, participants will be closely observed specifically for potential allergic reactions and
any AEs for the following 24 hours. Post inoculation participants will lie flat for 10 min then sit up with nose
pegs on for 20 min. Participants will continue to be monitored throughout the clinical phase of the study.
All study interventions:
1.
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are reported and 
resolved before use of the study intervention.
2.
Only participants enrolled in the study may receive study intervention and only authorised site staff 
may supply or administer study intervention. All study intervention must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labelled storage conditions with access limited to the Investigator and authorised site staff.
3.
The Investigator, institution, or the head of the medical institution (where applicable) is responsible 
for study intervention accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records).
4.
Disposal of used and unused Challenge Virus inoculum vials will be in accordance with hVIVO’s 
SOPs.
5.
Unless specifically instructed by Sponsor, the Investigator will not destroy any partly used or 
unused IMP supply. On written authorisation from the Sponsor, the Investigator will send unused 
and partly used IMP supplies and any empty containers for destruction to the address provided at 
the time of authorisation. Alternatively, the destruction of unused and partly used drug supplies and 
any empty containers may be facilitated by the Investigator using a partner service, according to 
local procedures, and a destruction certificate will be provided.
6.3.
Randomisation and Blinding
hVIVO assigns a unique 6 digit number to each participant in the hVIVO database. This number will be 
used to identify a participant up to the point of randomisation, on source documents, on all study 
correspondence and in the study database. A separate randomisation number will be allocated to the 
participants at randomisation and will be used for allocation of study intervention (RSVpreF or Placebo).

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
51
The randomisation number encodes the participant’s assignment to receive RSVpreF or Placebo in a 1:1 
ratio.
Randomisation numbers will be assigned sequentially in ascending order; and once assigned, that 
randomisation number shall not be reassigned. The study site will keep a log of the randomisation number 
assigned to each participant.
A designated unblinded statistician, separate from the conduct or analysis of the study, will be responsible 
for the computer-generated randomisation schedule. Sealed copies of the randomisation code will be stored 
in a secure location. 
Randomisation numbers will follow a 3-digit format e.g., [001]. Participants who are replaced as per Section 
7.4 will be replaced and assigned a new, unique randomisation number equaling the randomisation number 
of the replaced participant, plus 100. This will ensure that the replacement participant receives the same 
allocated, blinded treatment as the participant who is being replaced.
A copy of the randomisation code list will be sent to the unblinded pharmacist preparing the study 
intervention, so that study intervention/placebo can be prepared for each participant as appropriate. An 
independent Statistician 
 will prepare the randomisation schedule, and the 
IMP Manufacturer’s pharmacist/designee 
 will prepare the 
participant level IMP doses in line with the randomisation schedule.
Each participant will be dispensed blinded study intervention, labelled with his/her unique randomisation 
number, throughout the study. With the exception of the unblinded  pharmacist, the unblinded statistician 
preparing the randomisation code list and the Quality Assurance (QA) auditors where necessary, the 
Investigator and all other clinical and non-clinical staff, (including the Study Statistician, data management 
staff), and the participants will remain blinded to the treatment allocation until after the database has been 
locked and approval for study unblinding has been given.
Following database lock, on receipt of authorisation from the Sponsor, a copy of the randomisation code 
list will be provided to the Study Statistician to conduct study unblinding prior to analysis.
The PI/Investigator will be provided with a tamper evident sealed envelope containing details of the 
treatment for each participant. All opened and unopened envelopes will be collected or destroyed after the 
end of the study, as agreed with the Sponsor.
Individual emergency code break envelopes will be provided to the PI/Investigator should it be necessary 
to break the blind for a participant. The Investigator will ensure there is an appropriate procedure in place 
to allow access to the code break envelopes in case of an emergency arising during the quarantine period,
as per hVIVO's standard operating procedures (SOPs). An emergency means that the relevant medical 
decision on the further care of a participant is dependent on the actual identity of the study treatment that 
the participant has received.
The emergency code break envelopes will contain details of the treatment for each participant.
When the code break envelope is opened, the Investigator must note the date, time, reason for unblinding 
and the details of the investigator and or designated site staff that broke the blind and record this information 
according to hVIVO SOPs. The Investigator must also immediately notify the Sponsor’s Medical Monitor
(SMM) that the code has been broken. If possible, the Sponsor should be consulted before the code is 
broken, but this will only occur if the safety of the participant will not be compromised.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
52
Even if the code is broken, blood samples for safety, efficacy and other assessments will continue to be 
drawn for the remainder of the planned study period following the last dose as long as doing so will not 
compromise participant welfare.
The study intervention must be discontinued after unblinding, but the participant will be followed up until 
resolution of any AEs.
6.4.
Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention and challenge virus directly 
from the Investigator or designee, under medical supervision.  The date and time of each dose administered 
in the clinic will be recorded in the source documents and recorded in the case report form (CRF).  The 
dose of study intervention and study participant identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study intervention. 
Any non-compliance or problems with the administration of the study intervention will be recorded in the 
participant’s source notes and reported to the Sponsor if appropriate.
6.5.
Concomitant Therapy
Any medications taken and changes in medications from the time the participant signing the study specific 
informed consent, up to final study contact Day +155 (±14 days) will be recorded in the source data. Any 
medication (including over-the-counter or prescription medicines, vitamins, and/or herbal supplements) or 
other specific categories of interest) that the participant is receiving at the time of enrolment 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 Investigator and must notify the site as soon as possible if they are prescribed any medication. All 
medications must be stopped prior to the planned date of dosing with IMP/viral challenge (whichever occurs 
first) unless in the opinion of the Investigator and/or Sponsor’s Medical Monitor (SMM), the medication will 
not interfere with the study procedures or compromise participant safetyMedications prohibited throughout 
the study are shown in Table 2.
Table 2 Prohibited Medication
Prohibited medication
Washout
Systemic (oral and parenteral) antiviral drugs.
4 weeks prior to first study visit.
Use or anticipated use during conduct of the study 
of concomitant medications (prescription and non-
prescription), including vitamins or herbal and 
dietary supplements within the specified windows, 
unless in the opinion of the Investigator the 
medication will not interfere with the study 
procedures or compromise participant safety.
7 days prior to the planned date of viral challenge:
•Herbal supplements
•Any medication or product (prescription or over 
the counter) for symptoms of nasal congestion 
•Short and long-acting antihistamines.
Within 21 days prior to the planned date of viral 
challenge:

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
53
Prohibited medication
Washout
•Chronically used medications, vitamins or dietary 
supplements, including any medication known to 
be moderate/potent inducers or inhibitors of 
CYP450 enzyme.
Any investigational medicinal product used in 
another trial
Within 3 months (or 5 half-lives of the 
investigational product used in the other trial), 
whichever is greater, prior to the planned date of 
viral challenge or dosing with IMP (whichever 
occurs first).
Any concomitant medication required for the participant’s welfare may be given by the 
Investigator.However, it is the responsibility of the 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. 
The use of paracetamol and/or other allowed medications is permissible up to 7 days before the date of 
first dosing with IMP/viral challenge (whichever occurs first). During the study periods, the Investigator may 
permit a limited amount of paracetamol (no more than 4 g per day i.e. maximum daily dose) or topical 
medication, as clinically required for the treatment of headache or any other pain. Other medication to treat 
AEs may be prescribed if required.
Medications which are permitted throughout the study are shown in Table 3 below:
Table 3 Permitted Medication
Permitted medication
Time period
Paracetamol
Maximum 4g daily throughout the study duration 
at PI discretion.
Oral contraceptives
Allowed at any time during the study.
If, e g in an outbreak or pandemic, a newly instated national vaccine program is applicable to an 
individual participant, the PI and sponsor will discuss on an individual basis if concomitant vaccination 
may be allowed, study vaccine/inoculation postponed or the participant withdrawn from the study.
Prescription and non-prescription medications, including vitamins or herbal and dietary supplements, 
not listed in prohibited medications are subject to approval by the PI.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
54
7.
Discontinuation of Study Intervention/Withdrawal
7.1.
Participant Withdrawal
A participant may withdraw their consent to participate in the study at any time, for any reason, without
prejudice to his/her future medical care. Participants may decline to give a reason for their withdrawal.
Additionally, the PI may withdraw a participant if, in their clinical judgement, it is in the best interest of the 
participant or if the participant cannot comply with the protocol. Wherever possible, the tests and
evaluations listed for the Early Withdrawal Visit should be carried out, and if clinically indicated, the 
participant should be invited back for a final follow up visit.
The Sponsor should be notified of all study withdrawals in a timely manner, and in cases where the 
withdrawal is due to a medical reason the participant would be referred to his/her GP.
Participants will be counselled that early withdrawal from the viral challenge phase of the study is strongly 
discouraged, as it may pose a risk both to the participant and his/her contacts. In the event of a participant
insisting on early withdrawal during the challenge isolation period, the participant will be encouraged to stay 
and would be advised of the potential risks of carrying RSV infection into the community, and to vulnerable 
groups in particular, as described in Section 2.3.1.
If the participant withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent.
If a participant withdraws from the study, he/she may request destruction of any samples taken and not 
tested, and the Investigator must document this in the site study records.
7.2.
Participant Discontinuation
Participants will be withdrawn from study intervention for the reasons listed below. These participants must 
not receive any additional intervention but should continue to be followed for safety. Additional unscheduled 
visits may be performed for safety reasons. 
x
Non-compliance with the study requirements and restrictions.
x
Clinically significant abnormal laboratory findings, which in the opinion of the Investigator(s) 
and/or Sponsor, precludes further participation in the study.
x
Development of inter-current illness which, in the opinion of the Investigator would compromise 
the health of the participant or the study objectives.
x
The Investigator’s decision that withdrawal from further participation would be in the participant’s 
best interest.
x
Termination of the study at the discretion of the Investigator(s) or Sponsor for safety, behavioural, 
or administrative reasons.
x
The wish of the participant.
x
Any intervention related SAEs.
x
Anaphylactic reaction following dosing.
x
The participant becomes pregnant.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
55
When the target evaluable participant number is achieved, for a given quarantine group or for the overall 
study, reserve vaccinated participants may not be inoculated with challenge virus. In addition to post 
vaccination visits (1 and 7 days post vaccination), participants may additionally have assessments 
performed on Day -2/-1/0 and the final follow up visit Day +155 (±14days) for safety and immunogenicity.
Participants who are withdrawn from the study, will be requested to attend an Early Withdrawal Visit, with 
assessments as detailed in the SoA.
7.2.1.
Temporary Discontinuation / Temporary Delay in Enrolment 
At the first study visit if a participant is found to be ineligible due to transient circumstances (such as acute 
disease and/or fever), dosing will be postponed until the transient circumstances have been resolved and 
the participant will be re-invited to a later quarantine group within the allowed time window. For participant 
rescreening refer to Section 5.4.
7.3.
Lost to Follow up
A participant will be considered lost to follow-up if he or 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 clinic for a required study visit:
x
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 or not the participant wishes to and/or should continue in the study.
x
Before a participant is deemed lost to follow up, the 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.
x
Should the participant continue to be unreachable, he/she will be considered to have withdrawn 
from the study.
7.4.
Participant Replacement Strategy
Participants who have been vaccinated but not inoculated may be replaced in order to achieve the planned 
evaluable number of participants if deemed appropriate by the PI and with the approval of the Sponsor.
The replacement participant will be assigned to the same group as the original (discontinued) participant.
The replacement participant will be assigned a new, unique randomisation number equaling the 
randomisation number of the replaced participant, plus 100; for example, participant 001 would be replaced 
by participant 101). This will ensure that the replacement participant receives the same allocated blinded 
treatment as the participant who is being replaced.
7.5.
Stopping Rules
The PI and the SMM will perform safety reviews on available clinical and virology data as appropriate 
during the quarantine period. 

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
56
Four clinical scenarios relating to the incidence of SAEs/SUSAR during the study and the procedures that 
should be performed in each case are presented in the Table 4 below:
Table 4 Study Stopping Rules
Status
Criterion
Procedure
1
No SUSAR have been reported but an 
overall pattern of clinical changes or 
symptoms exists, attributed to the IMP, 
which may appear minor or moderate in 
terms of individual AEs but which 
collectively represent a concern for 
safety.
If such a status occurs at any point during the 
study, then further administration of IMP will 
not take place. The PI and the SMM will 
review the data and make a decision on 
whether it is appropriate to recommence 
dosing or terminate the study.
Regulatory authority approval via a substantial 
amendment would be required in order to 
recommence the study.
2
Unexpected virus-related SAE or 
unexpected virus-related AEs of clinical 
concern have been reported following 
Human Viral Challenge.
*Expectedness will be assessed by 
referring to the challenge virus dossier
If such a status occurs at any point during the 
study then the PI and the SMM will review the 
data and make a decision based on 
expectedness* of the viral event. 
If the event is unexpected, further 
administration of the virus will not take place. 
The PI and the SMM will review the data and 
make a decision on whether it is appropriate 
to recommence inoculation or terminate the 
study. 
Regulatory authority approval via a substantial 
amendment would be required in order to 
recommence the study.
3
A serious adverse reaction (SAR) (i.e. a
SAE considered at least possibly related
to the IMP administration) has been
reported in one participant.
If such a status occurs at any point during the
study, then further administration of RSVpreF 
will not take place. The PI and the SMM will
review the data and make decisions on
whether it is appropriate to recommence
dosing or terminate the study.
Regulatory authority approval via a substantial
amendment would be required in order to
recommence the study.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
57
Status
Criterion
Procedure
4
A severe non-serious adverse reaction 
(i.e. severe non-serious adverse events 
considered at least possibly related to the 
IMP administration) is reported in two 
participants, independent of whether or 
not within the same system-organ/class.
If such a status occurs at any point during the
study, then further administration of RSVpreF 
will not take place. The PI and the SMM will 
review the data and make decisions on 
whether it is appropriate to recommence 
dosing (via a substantial amendment, if 
indicated) or terminate the study.
Regulatory authority approval via a substantial 
amendment would be required in order to 
recommence the study.
In any event, participant follow-up should continue until resolution or stabilisation of AEs and final follow-up
on Day +155 (± 14 days).
.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
58
8.
Study Assessments and Procedures
Unless otherwise stated, study assessments will be performed according to hVIVO SOPs.
Study procedures and their timing are summarised in the SoA. Protocol waivers or exemptions are not 
allowed. Adherence to the study design requirements, including those specified in the SoA, is essential and 
required for study conduct. Immediate safety concerns should be discussed with the Sponsor upon 
occurrence or awareness to determine if the participant should continue or discontinue study intervention
All screening evaluations must be completed and reviewed to confirm that potential participants meet all 
eligibility criteria. The investigator will maintain a screening log to record details of all participants screened 
and to document eligibility or record the reasons for screening failure, as applicable.
For all study assessments, the value obtained nearest to dosing will be used as the baseline measure for 
assessments, unless stated otherwise.
Procedures conducted as part of the hVIVO Generic Screening process and obtained before signing of the 
study specific Informed Consent Form (ICF) may be utilised for screening or baseline purposes provided 
the procedures met the protocol-specified criteria and were performed within the time frame defined in the 
SoA.
Where applicable, unless otherwise stated, normal ranges will be identified in the Investigator Trial Master 
File (TMF).
8.1.
Medical and Medication History
Medical and medication histories including any allergies will be recorded at screening, including, but not 
limited to, detailed histories on allergies [e.g. rhinitis, dermatitis, food, aspirin/non-steroidal anti-
inflammatory drugs (NSAIDs) and asthma].
8.2.
Demographics
Demographic data will be recorded at the Screening Visit
8.3.
Height, Weight and Body Mass Index
Height and weight measurements will be recorded in compliance with hVIVO’s standard procedures.
BMI will be calculated as: BMI (kg/m2) = 
Weight (kg)
Height (m)2
8.4.
Alcohol Breath Testing
Breath alcohol testing will be conducted to determine compliance with the study alcohol restrictions. 
Additional tests may be conducted for assessing eligibility at the discretion of the Investigator. Results will 
be recorded in the source documents.
8.5.
Complete Physical Examination
A complete physical examination to include a full systemic assessment.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
59
8.6.
Direct Physical Examination
Directed physical examinations will be conducted as deemed appropriate by the Investigator and will 
include examination of the ears, nose, throat and chest (via stethoscope).
Assessment and grading of any upper respiratory tract (URT) (nasal discharge, otitis, pharyngitis, sinus 
tenderness) and lower respiratory tract (LRT) symptoms (abnormal breath sounds externally [e.g. stridor] 
and on chest auscultation [wheezing or rhonchi, crepitations] will be performed. Physician-reported 
assessments of viral challenge related illness will be graded in accordance with their intensity and 
documented in the source data.
Following viral challenge, URT and LRT symptoms (as described above) will be expected and presumed 
to represent virus infection consequent to viral challenge and will not be additionally captured as AEs unless 
they meet the definition of an AE, and are deemed to be clinically significant (in the opinion of the 
Investigator) to be classed as AEs.
Following viral challenge all unexpected (in the opinion of the Investigator) directed physical examination 
findings will be captured as AEs, along with all other occurrences that meet the criteria for an AE.
8.7.
Vital Signs
Vital signs assessments will be recorded as follows:
x
Heart rate (HR) will be recorded in beats per minute.
x
Respiratory rate (RR): respirations will be counted and recorded as breaths per minute.
x
BP: systolic BP and diastolic BP will be measured in millimetres of mercury (mmHg); 
measurements will be made supine. Where possible, the same arm will be used for all 
measurements.
x
Peripheral arterial oxygen saturation (SpO2%) will be assessed using pulse oximetry.
In the event of a participant having an unexpected abnormal or out of normal range result, the assessment 
may be repeated after at least 2 minutes to exclude a technical fault and confirm the original reading. The 
assessment may then be repeated at the PI’s discretion and in accordance with hVIVO’s SOPs.
Study specific normal ranges are provided in Appendix 10.4 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 the the United States Food and Drug 
Administration (FDA) Adult Toxicity Grading Scale for Preventive Vaccine Clinical Trials September 2007. 
Deterioration in a vital sign (compared to baseline) should only be reported as an AE if the deterioration 
fulfils the criteria for an AE. If deterioration in a vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated vital sign will be considered as additional 
information.
8.8.
Temperature
Body temperature will be measured by ether oral or tympanic route. The study specific normal range for 
temperature is detailed in Appendix 10.4.The severity of out of normal range values will be assigned using 
the FDA toxicity scale as a guide.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
60
Temperature may be more frequently monitored in quarantine if appropriate.
Following viral challenge, pyrexia will be expected and presumed to represent virus infection consequent 
to viral challenge and will not be additionally captured as an AE unless it meets the definition of an AE, and 
is deemed to be clinically significant (in the opinion of the Investigator) to be classed as an AE.
Following viral challenge all unexpected (in the opinion of the Investigator) pyrexia will be captured as an 
AE, along with all other occurrences that meet the criteria for an AE.
Febrile illness (FI) is defined as any occurrence of temperature ≥ 37.9oC
Vaccine reactogenicity temperature monitoring will be recorded in the vaccine dairy card, as detailed in 
Section 8.11.1.
8.9.
Electrocardiogram
Study specific normal ranges are provided in Appendix 10.4.
Twelve-lead ECGs will be obtained to evaluate the electrical activity of the heart. ECGs will be read on site 
by an appropriately qualified Investigator. Wherever possible the same Investigator will review subsequent 
ECGs from the same participant for the assessment of any change from baseline.
Any changes from baseline during the study will be assessed for their clinical significance. Clinically 
significant changes will be reported as AEs. The PI or delegate will assess non-clinically significant changes 
to determine whether they should be recorded.
8.10.
Lung Function
Spirometry will be performed according to hVIVO’s procedures. Height at screening will be used as the 
baseline measurement for all spirometry assessments.
Spirometry should meet the ATS/ERS guidelines criteria (Miller et al. 2005). For FEV1 and FVC, the highest 
value from a minimum of 3 technically satisfactory attempts will be considered. For FEV1 and FVC the 
highest and the second highest value difference should not exceed more than 150 mL or 5% (whichever is 
greater). If the difference is larger, up to 8 technically acceptable measurements will be made with 
repeatability assessed after each additional attempt. If after 8 technically acceptable attempts the difference 
remains greater than 150 mL or 5% (whichever is greater) the highest values will be reported, and an 
operator comment will be made to the source data. FEV1 and FVC will be assessed and reported as the 
highest values regardless of curve.
Predicted values will be calculated according to the formula of the European Coal and Steel Community 
(ECCS). 
Spirometry may be repeated at any time in the event of respiratory signs or symptoms (repeated coughing, 
bradypnoea, tachypnoea, rales and rhonchi) or respiratory difficulties.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
61
8.11.
Participant Diary Cards
8.11.1.
Vaccination Diary Cards
Participants will be provided with a VDC, thermometer and calliper/ruler to measure and record local 
reactions and systemic events (including body temperature), for 7 days post-vaccination (Appendix 10.3).
The diary card includes instructions on how to capture the data. Study site personnel are responsible for 
providing training for diary completion to avoid missing or incorrect data. Grading scales to assess severity 
of the symptoms are described in (Appendix 10.3).
Diary cards will be distributed on the day of vaccination (Day-28 (±3days)). Study site personnel will review 
the cards during the post vaccination visits (1 day and 7 days post-vaccination).
8.11.2.
Symptom Diary Cards
Participants will report and assess the severity of any challenge virus-related signs and symptoms three 
times/day during quarantine, at the same time each day (r 1 hour), using the hVIVO Symptom Diary Card.
This information will be collected using a paper form.
The following symptoms in the 13-item symptom questionnaire will be graded on a scale of 0-3 (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 4: Symptoms at rest
o
Runny nose
o
Stuffy nose
o
Sneezing
o
Sore throat
o
Earache
o
Malaise/tiredness
o
Headache
o
Muscle and/or joint ache
o
Chilliness/Feverishness
o
Cough
o
Chest tightness
o
Shortness of breath
o
Wheeze
Additional to the categorical symptom diary card, a Visual Analogue Scale diary card using a 100 mm scale,
with the same symptoms, will be completed by the participants.
Participant cold perception questions

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
62
Two additional cold-related questions will be answered by the participant each morning. The first question 
asks whether 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.
2.
Compared to yesterday, I feel that my cold is:
x
Very much better
x
Somewhat better
x
A little better
x
The same
x
A little worse
x
Somewhat worse
x
Very much worse
8.12.
Questionnaires
Patient Health Questionnaire (PHQ-9) and Generalised Anxiety Disorder (GAD-7) Questionnaire
PHQ-9 and GAD questionnaires will be used at the discretion of the Investigator to assess participants’ 
eligibility in terms of ability to tolerate isolation in the quarantine unit.
8.13.
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 bag (for that participant only).
A daily 24-hour collection will take place throughout the quarantine period. Distribution of paper tissues and 
bags will start on Day -1, with the first collection on Day 0. Thereafter distribution and collection of tissues 
will occur at 08:00h (± 1 hour). Tissues will be handed out daily and collection will occur until the discharge 
from quarantine.
In the event of a participant staying in quarantine beyond the planned day of discharge, the 24-hour 
distribution and collection of tissues and bags will continue until the participant is finally discharged from 
quarantine.
24-hour paper tissue collections will be analysed to determine the following over the quarantine period:
x
24-hour nasal discharge weight.
x
The number of paper tissue used for nasal discharge over 24-hour period.
8.14.
Urine Samples and Assessments
8.14.1.
Urinalysis
Clinical urine safety analysis will be undertaken using commercially available urine test strips that provide 
an instant result that will be documented in the source data.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
63
Urinalysis will be performed to evaluate the parameters described in Appendix 10.2.
If the dipstick yields abnormal results, a urine sample may be sent for microscopy, culture and sensitivity 
(MCS), at the Investigator’s discretion. MCS will include but is not limited to RBC, WBC, epithelial cells, 
crystals, casts, and bacteria.
Urine safety analysis values will be evaluated by the Investigator for clinical relevance. Those deemed to 
be clinically significant will be reported as AEs.
8.14.2.
Drugs of Abuse and Cotinine
Urinalysis will be performed for drugs of abuse and cotinine using commercially available kits that provide 
an instant result, which will be documented in the source data.
Drugs of abuse screen will include (but is not limited to) amphetamines, barbiturates, cocaine, opiates, 
cannabinoids and benzodiazepines.
8.14.3.
Pregnancy Test
Female participants of childbearing potential are to have a urine pregnancy test at screening. Participants
will only be enrolled if the pregnancy test is negative.
Note: Pregnancy test must be performed even if the participant is menstruating at the time of the study 
visit.
All female participants will have a serum sample tested for β-human chorionic gonadotrophin (β-hCG) on 
admission to quarantine.
Blood samples will be tested for serum FSH in post-menopausal women only.
8.15.
Blood Samples
A maximum volume of 550 mL of blood may be taken from each participant from screening through to the 
final study contact. If additional samples are required in excess of this amount, e.g., to monitor 
abnormalities , these will be collected at the discretion of the Investigator.
8.15.1.
Safety Blood Analysis and Assessments
Appendix 10.2 describes the safety blood tests that will be performed including, but not limited to, 
haematology, biochemistry, thyroid function test and cardiac enzymes. Additional safety assessments (e.g. 
coagulation) will be conducted at the discretion of the PI/Investigator, as required.
Serum samples will be tested for serum follicle stimulating hormone (FSH) in post-menopausal women 
only.
8.15.2.
Challenge Virus Serology Samples
A participant must be sero-suitable to take part in the study; i.e. he/she must have low pre-existing serum 
levels of antibodies specific to the Challenge Virus. This antibody titer cut-off for serosuitability will be 
described in the AP.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
64
8.15.3.
Blood for Immunology Biomarker Evaluations
Blood will be taken for analysis related to the study exploratory endpoints. Immunology analysis will be 
performed in relation to the vaccine as well as viral infection and susceptibility, and may include, but not 
limited to:
x
Serum for:
o
Humoral immune response (e.g. serum PreF and PostF IgG, IgA, sIgA, MNA)
o
Innate cytokines and chemokines response
o
Non-vaccine antigen-binding antibody assay for serological detection/seroconversion of 
community acquired RSV infection between vaccination and viral challenge.
x
Whole blood for:
o
Genomics (e.g. HLA typing, SNPs, GWAS)
o
Transcriptomics (e.g. RNA-Seq, single cell RNA-Seq)
o
Cell mediated immunity (e.g. IFNγ T cell ELISPOT)
o
Cellular markers (e.g. Flow cytometry ICS, cytokine secretion from peptide stimulated 
PBMCs)
The detailed description of the assays performed in the study will be documented in the AP as appropriate.
8.16.
Nasal Samples
The following upper respiratory sampling will be performed:
x
Nasal sample (Nasopharyngeal swab or nasal wash) will be performed to collect samples of nasal cells 
and epithelial lining fluid for;
o
Respiratory Pathogen Screen
o
RSV discharge test
o
RSV quantification
o
Antibody binding and neutralisation assays
o
Exploratory purposes (remaining cells and epithelial lining fluid from the nasal samples may be 
stored for exploratory purposes).
o
Tolerance of the procedure may be determined at the screening visit.
x
Nasosorption (Nasal wick) may be performed to collect epithelial lining fluid for assays such as:
o
Antibody binding and neutralisation assays
o
Proteomics (e.g. cytokines and chemokines)
o
RSV quantification
o
Transcriptomics
o
Exploratory purposes (remaining epithelial lining fluid may be stored for exploratory purposes).
8.16.1.
Respiratory Pathogen Screen
On entry to quarantine, nasal samples will be collected and screened for the presence of respiratory 
pathogens, including SARS-CoV-2 virus, by multiplexed PCR-based methodology. A positive result from
this pathogen screen could potentially contraindicate a participant’s participation in the study. The 
methodology to be used to conduct the respiratory virus screen will be documented in the AP. Additional 

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
65
test may be conducted if the results from the first test are invalid to support study eligibility prior to virus 
inoculation, or if a community acquired infection is suspected during quarantine.
A nasal sample might also be collected prior to vaccination on Day -28 to determine the presence of the 
SARS-CoV-2 virus.
Any additional screening tests will be conducted at the discretion of the PI.
8.16.2.
Rapid Viral Antigen Test
A rapid diagnostic test (e.g. RVAT) will be used to determine the presence of RSV in a nasal sample taken 
prior to discharge from the Quarantine Unit on Day 12. (and subsequent days if, at the discretion of the PI,
an extended quarantine stay is required due to test result and/or the presence of clinical symptoms) A PCR 
screening test may be used as an alternative test for this purpose.
8.16.3.
Viral Load
Viral load will be determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR)
and viral culture assays to investigate the following parameters:
x
viral dynamics (e.g. AUC, duration, peak, time to peak)
x
infectivity status and rate
x
symptomatic infectivity status and rate
8.16.4.
Biomarkers
The nasal sample and/or nasal wick (Class 1 Device) procedure may be used to collect samples of epithelial 
lining fluid (ELF) for:
x
Antibody binding and neutralisation assays
x
Proteomics (e.g. cytokines and chemokines)
x
RSV quantification
x
Transcriptomics
x
Exploratory purposes (remaining epithelial lining fluid may be stored for exploratory purposes).
8.17.
Recording of Adverse Events and Serious Adverse Events
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 and hVIVO’s SOPs, and also for 
ensuring that the medical management (including follow up) of AEs, SAEs and, where appropriate, 
pregnancy symptoms/complications is provided by competent Investigator Site staff.
The Sponsor of the study will also perform an evaluation of seriousness, causality and expectedness of all 
SAEs. 
The definitions of an AE or 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 10.3

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
66
8.17.1.
Time Period and Frequency for Collecting AE and SAE Information
All AEs/SAEs will be collected from the signing of the ICF until the last Follow-up Visit at the time points 
specified in the SoA (Section 1.3).
Investigators are not obligated to actively seek AE or SAE after conclusion of the study participation.
However, if the investigator learns of any SAE, including a death, 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 investigator must promptly notify the sponsor.
8.17.2.
Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures for 
completing and transmitting SAE reports are provided in Appendix 10.3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about AE occurrences.
8.17.2.1. Solicited AEs
Solicited AEs are pre-defined events for which participants are specifically questioned and which are noted 
by participants in their diaries (Section 8.11.1). Information related to solicited events as defined in Appendix 
10.3 will be recorded by participants in a diary after vaccination. Each participant will be provided with a 
diary and instructions on how to complete the diary. There will be a minimum 30-minute post vaccination 
assessment of solicited events by the Investigator. The participant diary information will be transcribed by 
the study personnel in the appropriate eCRF pages. Participants will be asked to take a daily temperature 
measurement and to note in the diary occurrences of symptoms beginning on the evening of the study
vaccine dosing day (on Study Day -28) and daily for the total of 7 days post-vaccination. Local reactions 
reported via the VDC are redness, swelling, and pain at the injection site. Systemic events reported via the 
VDC are fever, fatigue, headache, vomiting, nausea, diarrhea, muscle pain, and joint pain.
For all ongoing systemic events 7 days post vaccination, the stop date will be recorded in the CRF.
8.17.2.2. Unsolicited AEs
Unsolicited AEs are all AEs for which participants are not specifically questioned in the participant diary. 
Unsolicited AEs monitoring will begin after vaccination on the Vaccination (Study Day -28) Visit and will 
continue through 30 days post vaccination. Any unsolicited AEs that occurs after 30 days post-vaccination 
through to study completion will be recorded by the Investigator and included in the study database. 
Adverse events will be followed by the Investigator as specified in Section 8.17.3.
8.17.2.3. Medically Attended AEs
A medically attended adverse event (MAE) is an adverse event, whether considered related to the 
investigational vaccine or not, that led to the participant seeking evaluation by a healthcare provider. MAEs 
will be assessed between study day -28 and study Day +155 (6 months post-vaccination follow up), through 
self-report by participant and by query by the Investigator/designee at study visits and in any protocol
specified telephone outreach.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
67
8.17.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All AEs/SAEs, will be followed until resolution, stabilisation, the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). Further information 
on follow-up procedures is provided in Appendix 10.3.
8.17.4.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal obligations and 
ethical responsibilities towards the safety of participants and the safety of a study intervention under clinical 
investigation are met.
The following reporting process will be followed:
-
PI will send SAE/pregnancy forms to the Sponsor’s PV within 24 hours of becoming aware of the 
event 
-
Sponsor’s PV will assess expectedness to determine if the SAE requires expedited reporting  
-
Sponsor’s PV will send query to the PI if additional information is needed 
-
Sponsor’s PV will report the case to the Medicines and Healthcare Regulatory Agency (MHRA)
via the EudraVigilance Database Management System EVWEB (or alternatively using MHRA 
eSUSAR tool) 
-
PI will report SUSAR and other relevant safety information to the Ethics Committee in accordance 
with REC guidelines.  
The Sponsor has a legal responsibility to notify both the local regulatory authority and other regulatory 
agencies about the safety of a study intervention under clinical investigation. The Sponsor will comply with 
country-specific regulatory requirements relating to safety reporting to the regulatory authority, Research
Ethics Committee (REC) and investigators.
The Sponsor is responsible for assessing SUSARs, unblinding potential SUSARs, and reporting SUSARs 
to the MHRA and REC. The Sponsor shall ensure that all relevant information about a SUSAR that occurs 
during the course of a clinical trial in the UK and is fatal or life threatening, is reported as soon as possible 
to the MHRA and the REC. This needs to be done within 7 calendar days after the Sponsor became aware 
of the event. Any additional relevant information should be sent within 8 calendar days of the first report 
being sent.
The Sponsor shall ensure that a SUSAR which is not fatal or life-threatening is reported as soon as possible
and in any event within 15 calendar days after the Sponsor became aware of the event.
In accordance with ICH GCP guidelines, the Sponsor will also inform the Investigator of findings that could
affect adversely the safety of participants and/or impact the conduct of the trial. Annual safety reporting to 
the national Competent Authority (MHRA) and the Ethics Committee will be in agreement with ICH guideline
E2F ͆Note for guidance on Development Safety Update Reports (DSUR)͇.
In addition, any other safety issue which may alter the current benefit̽risk assessment of the IMP will be
reported by the Sponsor (or delegate) on an expedited basis to Competent Authorities, Ethics Committees
and the Investigator.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
68
The detailed procedure of the SAE/SUSAR reporting will be described in a Pharmacovigilance Management
Plan that will be finalised before the start of the study to exactly define the different tasks of the Investigator, 
Sponsor and Sponsor’s Pharmacovigilance vendor. 
An investigator who receives an investigator safety report describing a SAE or other specific safety 
information (e.g., summary or listing of SAEs/SUSARs) from the sponsor will review and will notify the REC,
if appropriate according to local requirements.
Further information on regulatory reporting requirements is provided in Appendix 10.3.
8.17.5.
Pregnancy
Details of all pregnancies in female participants and, if indicated, female partners of male participants will 
be collected from study specific informed consent and until the last study assessment as outlined in the 
SoA. If a pregnancy is reported, the Investigator should inform the sponsor within 24 hours of learning of 
the pregnancy and should follow the procedures outlined in  Appendix 10.3.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, foetal death, stillbirth, congenital anomalies, 
ectopic pregnancy) are considered SAEs.
8.18.
Treatment of Overdose
For this study, any dose of any drug administered as part of the study greater than the dose prescribed by 
the protocol will be considered an overdose.
In the event of an overdose. the Investigator should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for any AE/SAE and laboratory abnormalities associated with 
overdose and participants will be clinically followed up until the AE has resolved.
3.
Document the quantity of the excess dose as well as the duration of the overdose in the CRF.
The Sponsor is responsible for notifying the MHRA and REC of the potential serious breach within 7 days 
of becoming aware of it.
8.19.
Biomarkers
Biomarkers may be evaluated from blood and nasal samples, as detailed in Section 8.15.3 and 8.16
respectively.
Samples may be used for exploratory biomarker research related to 
x
immunity and susceptibility to RSV infection 
x
RSV vaccine responses
x
Immune response to RSV infection
8.20.
Immunogenicity Assessments
Samples will be taken and assessed for immunological endpoints as detailed in Section 8.15.3 and 8.16
respectively. Samples may also be retained for future usage as described in Section 10.1.4.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
69
9.
Statistical Considerations
9.1.
Statistical Hypotheses
S-cubed will perform the statistical analysis for the study. Full details of the planned statistical analysis will 
be presented in the Statistical Analysis Plan (SAP). Any deviations from the SAP will be documented in the 
Clinical Study Report (CSR).
9.2.
Sample Size Determination
The statistical powering selected for this study is estimated to be sufficient for the primary objective and the 
primary endpoint family. The primary endpoint family consists of 3 endpoints listed below with their 
associated sample size estimates. As an exploratory proof of concept study, no adjustment for Type I error 
is planned in regard to the primary endpoint family. The sample size of 62 participants (31 in each group) 
will allow:
x
Detection of a 70% relative reduction in the PCR-AUC virology with RSVpreF assuming a 96%CV in 
the control arm. The power for this endpoint is for 80% using a two-sided type-I error rate of 5%. The 
PCR-AUC data is based on log transformed PCR data.
x
Detection of a 60% relative reduction in the symptomatic-infection rate with RSVpreF assuming a 
59.26% rate in the control group (i.e. a rate of 23.7% in the RSVpreF group). The power for this endpoint 
is 80% using a two-sided type-I error rate of 5%. Symptomatic-infection is defined as:
o
Lab confirmed infection (two detectable (≥ Lower Limit of Detection LLOD) RT-PCR 
measurements (reported on 2 or more consecutive days), starting two days post-viral challenge 
(Day +2) up to discharge from quarantine), and
o
Either one or more positive clinical symptoms of any grade from two different categories in the 
symptom scoring system (Upper Respiratory, Lower Respiratory, Systemic), or one Grade 2 
symptom from any category
x
Detection of an 80% relative reduction in the total symptoms with RSVpreF assuming a 113.55% 
common CV. The power for this endpoint is at least 80% using a one sided type-I error rate of 5%.
The sample sizes indicate the number of vaccinated participants to be inoculated with the challenge virus 
per treatment group, more will be vaccinated in order to achieve the inoculation numbers. Therefore, up to 
72 participants will be enrolled and vaccinated with the study vaccine, with 62 participants challenged with 
the study virus
9.3.
Populations for Analyses
The following populations are defined:
Population
Description
ITTc (Intent-to-Treat-
Challenge) Analysis Set
All participants randomly assigned to study intervention and who take a 
dose of study vaccine / placebo and were given viral challenge.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
70
Per Protocol (PP) Analysis 
Set
All participants randomly assigned to study intervention and who take a 
dose of study vaccine / placebo, are given viral challenge, have no 
major protocol deviations, and who complete quarantine (Day 12).
Safety Analysis Set
All participants randomly assigned to study intervention and who take a
dose of study intervention (study vaccine / placebo), regardless of 
whether they received the challenge virus or not. Participants will be 
analysed according to the intervention they actually received.
The primary analysis will be on the ITTc Analysis Set. Analysis using the PP Analysis Set will be secondary. 
The safety evaluation will be performed on the Safety Analysis Set.
Membership of subjects in each analysis set will be determined at a planned blinded data review meeting 
(BDRM), prior to the any analysis and database lock.
9.4.
Statistical Analysis
9.4.1.
Sequence of Analysis
Two analyses will be conducted: the primary analysis after all participants have reached the Day 28 follow 
up, and a follow-up analysis at the end of the 6 months follow-up.
x
The primary analysis will be performed when efficacy and safety clean data up to and including the 
study Day 28 visit are available from all participants. Before this analysis, the blinded data review will 
be conducted, the final SAP will be signed, and a formal database lock will take place. The list of study 
personnel with access to the result will be appropriately documented prior to unblinding. Appropriately 
defined study personnel will remain blinded (i.e., will not have access to the individual participant 
treatment assignment) until end of follow-up and final database lock. No individual listings mentioning 
individual participant treatment assignment will be released to the remaining study personnel until End 
of Study (EOS) and the Investigator will not have access to the treatment allocation up to study end 
and final database lock. The main analysis will be considered as final for key efficacy endpoints.
x
The final EOS analysis will be performed when all endpoint data (safety and efficacy) up to study follow-
up end (Month 6) are available and locked. All tertiary endpoints available at that time may also be 
analysed in this step. An integrated CSR containing all data will be written and made available to the 
sponsor and the Investigator. Individual listings will only be provided at this stage.
The SAP will provide a detailed description of the analyses that will be computed at the time of each 
analysis.
The final CSR will contain at least the final analyses of endpoints. If the data for tertiary endpoints become 
available at a later stage, (an) additional analysis/analyses may be performed. These analyses may be 
documented separately to the CSR and may be made available to the Sponsor and Investigators at that 
time.
9.5.
Statistical Analysis Plan
Data will be analysed and reported using SAS® version 9.4 or later. 

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
71
Primary and secondary efficacy endpoints will be descriptively summarised. Continuous variables will be 
summarised using a number of observations, mean (and/or geometric mean, where applicable), standard 
deviation, standard error, median, lower quartile, upper quartile, minimum and maximum values. 
Categorical variables will be summarised using proportions (counts and percentages). 
Statistical analyses for the primary endpoint will be performed using appropriate one or two-sided 
hypothesis tests at the 5% significance level, with further details in the SAP. The t-test will be used to 
compare means between groups (and/or an appropriate alternative test, e.g. Wilcoxon Rank-Sum test, if 
the t-test assumptions are not satisfied). Methods for checking statistical model assumptions will be 
described in the SAP. Dichotomous data will be tested using a chi-squared test. No adjustment for the type 
I error is planned, as this is an early stage exploratory study.
The detailed SAP will be developed by S-cubed and approved by the Sponsor prior to any look at unblinded 
data. The SAP will give a more detailed description of the report presentations to be produced for the study 
expanding on the protocol specified analysis. Any deviation(s) from the original statistical plan should be 
described and justified in an amendment to the protocol and/or SAP as appropriate and referenced also in 
the final clinical study report (CSR). The SAP will describe and account for the occurrence of and extent of 
missing data, and its possible impact on the study analysis. All baseline assessments will be described in 
the SAP.
Further post-hoc evaluations of any exploratory endpoints may be conducted and reported separately. 
9.6.
General Considerations
9.6.1.
Participant Accountability
The number of participants receiving RSVpreF or placebo, receiving Challenge Virus, withdrawing from 
study (also split by reason for withdrawal), and completing the study, and the numbers in each analysis set, 
will be summarised.
9.6.2.
Protocol Deviations
Participants data will be reviewed for major protocol deviations prior to main analysis database lock at a 
planned blinded data review meeting (BDRM), and decisions will be documented within the meeting 
minutes. At this meeting, participants will be reviewed for their inclusion/exclusion from the analysis sets.
9.6.3.
Demographic and Baseline Characteristics
Descriptive statistics of demographics (age, sex, height, weight, BMI, and ethnicity) will be presented by 
treatment group and across all participants. Medical history information will be listed. Other baseline 
characteristics will be defined in the SAP.
9.6.4.
Compliance to Study Treatment
Compliance with study vaccine will be computed for each group as proportion of subjects received vaccine 
as randomised.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
72
9.6.5.
Primary Efficacy Analysis
The primary efficacy analysis of the primary endpoint family (as specified below) will be performed on the 
ITTc Analysis Set.
x
The AUC for RSV-A Memphis 37b viral load measured in nasal samples by RT-qPCR, as determined 
by qRT-PCR on nasal samples collected twice daily starting two days post-viral challenge (Day +2) up 
to discharge from quarantine, will be summarised and RSVpreF compared to placebo via a t-test or 
Wilcoxon Rank-Sum test as appropriate.
x
Symptomatic RSV infections will be summarised and RSVpreF compared to placebo using a chi-
squared test. RT-PCR-confirmed symptomatic RSV infection, defined as:
o
RT-PCR-confirmed RSV infection (two detectable qRT-PCR measurements (reported on 2 or 
more consecutive days), starting two days post-viral challenge (Day +2) up to discharge from 
quarantine.), AND
o
Either one or more positive clinical symptoms of any grade from two different categories in the 
symptom scoring system (Upper Respiratory, Lower Respiratory, Systemic), or one Grade 2 
symptom from any category.
x
Sum total symptoms, as measured by graded symptom scoring system collected three times daily 
starting one days post-viral challenge (Day +1) up to discharge from quarantine, will be summarised 
and RSVpreF compared to placebo using a t-test or Wilcoxon Rank-Sum test as appropriate.
The primary efficacy analysis will be supported by sensitivity analyses and these will be specified in the 
SAP.
9.6.6.
Secondary Efficacy Analysis
Secondary endpoints as described in Section 3 will be summarised by treatment group and analysed per 
Section 9.5 as appropriate. 
9.6.7.
Tertiary/exploratory Analysis
Except if otherwise specified, no formal statistical testing will be conducted for tertiary endpoints described 
in Section 3. Only the descriptive statistics will be computed. These analyses will be described in the SAP.
9.6.8.
Safety Analyse(s)
Safety data will be summarised descriptively.
AEs will be coded using the most current version of the Medical Dictionary for Regulatory Activities 
(MedDRA) and summarised by system organ class, preferred term, and treatment group for the number of 
AEs reported and the number and percentage of participants reporting each AE.
Solicited local and systemic AEs and unsolicited AEs will be summarised descriptively. 
A by-participant AE data listing including onset and resolution dates, verbatim term, preferred term, blinded 
treatment, severity, relationship to treatment, action taken, and outcome will be provided.
Other safety endpoints will be presented by treatment group includes laboratory evaluations (biochemistry, 
haematology, coagulation (if required), cardiac enzymes and urine analysis), vital signs assessments, 
physical examinations, 12-lead ECG and Spirometry. Additionally, physical examinations will be listed.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
73
9.6.9.
Other Analyse(s) 
Certain pre-specified primary and secondary analysis (as documented in the SAP) will also be performed 
for the “Lab-confirmed infected” subgroup. The subgroup is defined as those participants that fulfil the 
following criteria:
x
RT-PCR-confirmed quantifiable infection (two quantifiable RT-PCR measurements (reported on 2 
or more consecutive days), starting two days post-viral challenge (Day +2) up to discharge from 
quarantine)
9.7.
Interim Analyses 
No interim analysis (i.e. an analysis of early trial data, before enrolment is completed, to detect trends that 
might warrant modification of the protocol, change in data being collected or trial termination) is planned for 
the study. A sequence of two analyses (primary analyses after the study Day 28 visit, and an EOS analysis 
after last participant last scheduled visit) is planned and described in Section 9.4.1.
The infection rate in the placebo group will be monitored on an ongoing basis by an unblinded statistician 
who does not have any other study function to confirm the powering assumptions (i.e. infection rate) within 
the Placebo group and ensure sufficient infection rate has occurred. If the infection rate is lower than 
anticipated, additional participants (up to 5 per treatment group) may be enrolled if needed to ensure the 
study is not underpowered.
The unblinded statistician will also monitor participant drop out between vaccination and inoculation to 
confirm that the number of participants inoculated in each treatment group is balance and 31 evaluable 
participants in each treatment group is achieved when the study is complete.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
74
10.
Supporting Documentation and Operational Considerations
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:
o
Consensus ethical principles derived from international guidelines including the Declaration of 
Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International 
Ethical Guidelines
o
Applicable ICH Good Clinical Practice (GCP) Guidelines
o
Applicable laws and regulations
In addition to regulatory submission, the protocol, protocol amendments, ICF, Investigator Brochure, and 
other relevant documents (e.g., advertisements) must be submitted to a REC by the Investigator and 
reviewed and approved by the REC before the study is initiated.
Substantial amendments to the protocol will require Regulatory Authority approval prior to implementation. 
Any amendments to the protocol will require REC approval before implementation of changes made to the 
study design, except for changes necessary to eliminate an immediate hazard to study participants.
The Investigator will be responsible for the following:
o
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
o
Notifying the REC of SAEs or other significant safety findings as required by REC procedures
o
Providing oversight of the conduct of the study at the site and adherence to requirements of ICH 
guidelines, the REC, European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
10.1.2.
Financial Disclosure
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial information 
as requested to allow the Sponsor to submit complete and accurate financial certification or disclosure 
statements to the appropriate regulatory authorities. Investigators are responsible for providing information 
on financial interests during the course of the study.
10.1.3.
Informed Consent Process
The Investigator will obtain a signed ICF from each participant before any study specific procedures are 
performed.
When historical screening data collected through the hVIVO generic screening process is used for 
screening, the study specific ICF will be obtained at vaccination visit (D-28 ±3 days) from each participant
before any study specific procedures are performed.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
75
Potential participants will typically be sent a copy of the ICF when their Screening Visit/Quarantine 
admission visit (as applicable) is arranged and at least a day prior to the visit, and will be encouraged to 
read it prior to their appointment. Upon arrival at the vaccination visit, the ICF is discussed by the 
Investigator, and they 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 Investigator will be 
responsible for ensuring that the participant understands the information contained in the ICF. Once the 
Investigator has confirmed that the participant has understood the study, including the benefits and risks of 
participation, the participant and the Investigator can sign and date the ICF. 
The ICF must be signed and dated by the participant and countersigned by the Investigator (whoever 
conducted the consent discussion). A copy of the 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 ICF.
The ICF will contain a separate section that addresses the use of samples for future research. The 
investigator or authorised designee will explain to each participant the objectives of the exploratory 
research. Participants will be told that they are free to refuse to participate and may withdraw their consent 
at any time and for any reason. 
A separate 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.
10.1.4.
Storage of Samples for Future Research
Samples collected in this study may be stored for up to 25 years (or according to local regulations) for future 
research. The research may begin at any time during the study or the post-study storage period. Any 
movement and storage of samples will be in accordance with the Human Tissue Act 2004 and other relevant 
laws
Stored samples will be coded throughout the sample storage and analysis process and will not be labeled 
with personal identifiers. Participants may withdraw their consent for their samples to be stored for future 
research.
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’s collaborators 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 as 
well as the Sponsor collaborators and subcontractors in accordance with local data protection law. The 
level of disclosure must also be explained to the participant in ICF.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
76
The participant must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate REC members, 
and by inspectors from regulatory authorities.
10.1.6.
Dissemination of Clinical Study Data
The key design elements of this Protocol will be posted on publicly accessible registers, such as 
ClinicalTrials.gov. Where required, protocol summaries will also be posted on national or regional clinical 
trial registers or databases (e.g., EudraCT database) in compliance with the applicable regulations.
It is the Sponsor’s (or Sponsor delegate) responsibility to send the Clinical Trial Summary Report to the 
REC and Medicines and Healthcare Regulatory Agency (MHRA) (if required) within 1 year of the end of the 
trial. In addition, the Sponsor or Sponsor delegate is responsible for entering appropriate data into the 
EudraCT results database within 1 year of the end of the trial. 
The PI/Investigator shall provide assurance to participants that their confidentiality will be maintained hVIVO 
have a legal obligation to protect at all times the confidentiality of participant personal data from the point 
of capture, through processing, dissemination in line with consent from the participant and to its final 
disposition.
10.1.7.
Data Quality Assurance
Participant data will be collected at site using paper source casebooks which will then be data entered into 
the electronic case report form (eCRF) database unless transmitted to the sponsor or designee 
electronically (e.g., laboratory data). The Investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF
The Investigator must maintain accurate documentation (source data) that supports the information entered 
in the CRF. This can be paper source and/or eSource.
The Investigator must permit study-related monitoring, audits, REC review, and regulatory agency 
inspections and provide direct access to source data documents. Monitoring details describing strategy 
(e.g., risk-based initiatives in operations and quality such as Risk Management and Mitigation Strategies 
and Analytical Risk-Based Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (remote or on-site monitoring) are provided in the
Monitoring Plan.
Study monitors will perform ongoing source data verification to confirm that data entered into the CRF by 
authorized site personnel are accurate, complete, and verifiable from source documents; that the safety 
and rights of participants are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all applicable regulatory 
requirements.
Records and documents, including signed ICFs, pertaining to the conduct of this study must be retained by 
the Investigator during the retention period as agreed with the sponsor and as required by local regulations 
or institutional policies. 

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
77
10.1.8.
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.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The Investigator may need 
to request previous medical records or transfer records, depending on the study. Also, current medical 
records must be available.
Definition of what constitutes source data for the study can be found in the Source Data Agreement.
10.1.9.
Study Discontinuation
The Sponsor reserves the right to temporarily suspend or discontinue the study for any reason at any time.
In addition, the study may be stopped at any time if, in the opinion of the PI, the safety data suggest that 
the medical safety of participants is being compromised.
If the study is suspended or terminated for safety reason(s), the Sponsor will promptly inform the PI, and 
will also inform the regulatory authorities of the suspension or termination of the study and the reason(s) 
for the action.
The PI/Investigator is responsible for promptly informing the REC and providing the reason(s) for the 
suspension or termination of the study.
If the study is prematurely terminated, all study data must be returned to the Sponsor and the Sponsor’s 
collaborators. In addition, the site must conduct final disposition of all unused IMPs in accordance with the 
Sponsor and the Sponsor’s collaborators. procedures for the study.
Termination of the clinical trial may also be initiated by the MHRA or the REC.
10.1.10.
Publication Policy
By signing the study protocol, the PI agrees that the results of this study may be used for the purposes of 
national and international registration, publication, and information for medical and pharmaceutical 
professionals by the Sponsor and the Sponsor’s collaborators.
If necessary, the authorities will be notified of the PI's name, address, qualifications, and extent of 
involvement. In order to allow the use of the information derived from this clinical study, the PI understands 
that he/she has an obligation to provide complete test results and all data developed during this study to 
the Sponsor.
If the study is to be published, the Sponsor and the Sponsor’s collaborators may jointly prepare and co-
author manuscript(s) that could result from the clinical trial in accordance with the relevant contracts.
Confirmation of study specific arrangements between Sponsor and Sponsor’s collaborators can be found 
in the clinical study agreement.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
78
10.2.
Appendix 2: Clinical Laboratory Tests
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 5 of the 
protocol.
Additional tests may be performed at any time during the study as determined necessary by the Investigator 
or required by local regulations.
Table 5 Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count.
White blood cell (WBC) count (absolute)
WBC differential:
Neutrophils
Lymphocyte
Monocytes
Eosinophils
Basophils
Red blood cell (RBC) count
Reticulocyte count (% and absolute)
Haemoglobin
Haematocrit
Mean corpuscular volume (MCV)
Mean corpuscular haemoglobin (MCH)
MCH concentration (MCHC).
Coagulation
Prothrombin time (PT)
Activated Partial Thromboplastin Time (APTT)
Biochemistry
Sodium
Potassium
Glucose (random)
Albumin
Chloride
Bicarbonate
Calcium
Uric acid
Total protein
Creatinine
Total, direct, and indirect bilirubin
Inorganic phosphate
Blood urea nitrogen
C-reactive protein (CRP)
Gamma glutamyl transferase (GGT)
Alkaline phosphatase (ALP)
Alanine transaminase (ALT)
Lactate dehydrogenase

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
79
Laboratory 
Assessments
Parameters
Aspartate transaminase (AST)
Urea.
Thyroid function
Thyroid Stimulating Hormone (TSH) at screening only
Thyroxine at screening only
Cardiac enzymes
Creatine Kinase (CK)
Troponin (T)
Routine urinalysis
Colour
Specific gravity
Appearance
pH
Presence of blood, glucose, leukocytes, ketones, nitrites, proteins, 
urobilinogen, bilirubin by dipstick
Microscopy, culture and sensitivity examination (If the dipstick 
yields clinically significant abnormal results)
Other 
screening/eligibility 
tests
Follicle stimulating hormone (FSH)*
β-human chorionic gonadotrophin (β-hCG)
Glycated haemoglobin (HbA1c)
Thyroid function test [thyroid stimulating hormone (TSH), free 
thyroxine (T4)]
Antibodies against HIV-1 and HIV-2
Hepatitis A immunoglobulin M (HepA)
Hepatitis B surface antigen (HBsAg)
Hepatitis C antibodies (HepC)
Immunoglobulin A (IgA) antibodies
*Only for post-menopausal women
Investigators must document their review of each laboratory safety report.
Laboratory results that could unblind the study will not be reported to investigator sites or other blinded
personnel until the study has been unblinded, unless in the case of an emergency unblinding (Section 
6.3).

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
80
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.3.1.
Adverse Event
AE Definition
An AE is defined as any untoward medical occurrence in participants. An AE can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of an investigational medicinal product, whether or not considered 
related to the investigational medicinal product, or for the purposes of Human Viral Challenge studies,
the Challenge Virus.
Events Meeting the AE Definition
x
Exacerbation of a pre-existing illness.
x
Increase in frequency or severity of a pre-existing episodic condition.
x
A condition detected or diagnosed after IMP or inoculum administration even though it may have 
been present prior to the start of the study.
x
A complication that occurs during a hospitalisation.
x
A clinically significant change in laboratory parameter.
Events NOT Meeting the AE Definition
x
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion); the 
condition that leads to the procedure is an AE.
x
Pre-existing disease or conditions present or detected prior to start of IMP or Challenge Virus 
inoculation administration that does not worsen (including screening findings such as abnormal 
laboratory results).
x
Hospitalisation for elective surgery, social and/or convenience admissions provided they are 
arranged before the start of IMP administration.
x
Over-administration of either the challenge virus, IMP or concomitant medication without any 
signs or symptoms.
x
An uncomplicated pregnancy or an induced elective abortion to terminate a pregnancy without 
medical reason.
x
Typical/expected viral symptoms on symptom diary cards
x
Procedural related events may be noted during the study whilst conducting nasal sampling 
(collection of nasal wash samples or nasopharyngeal swabs), specifically:
o
Nasal discomfort/irritation

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
81
o
Nasal abrasions
o
Nasal epistaxis
o
Sneezing
o
Watery eyes
When mild in nature and as expected in the opinion of the PI or Delegated Physician, these 
events will not be reported as adverse events.
10.3.2.
Adverse Drug Reaction
An adverse drug reaction (ADR) is any untoward and unintended response in a participant to an IMP which 
is related to any dose administered to that participant.
‘Response’ in this context means that a causal relationship between a medicinal product and an AE is at 
least a reasonable possibility.
All AEs assessed by either the reporting Investigator or the Sponsor as having a reasonable causal 
relationship to a medicinal product qualify as ADRs. The expression ‘reasonable causal relationship’ means 
to convey in general that there is evidence or argument to suggest a causal relationship.
10.3.3.
Unexpected Adverse (Drug) Reaction
An “Unexpected Adverse (Drug) Reaction” means an adverse reaction, the nature and severity of which is 
not consistent with the information about the medicinal product in question set out:
(a) In the case of a product with a marketing authorisation, in the Summary of Product Characteristics for 
that product,
(b) In the case of any other investigational medicinal product, in the Investigator’s Brochure relating to the 
trial in question’.
10.3.4.
Serious Adverse Event
SAE Definition 
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the participant was at 
risk of death at the time of the event. It does not refer to an event, which hypothetically might have 
caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
x
In general, hospitalisation signifies that the participant has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalization are AEs. If a complication prolongs 

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
82
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether “hospitalisation” occurred or was necessary, the AE should be considered serious.
x
Hospitalisation for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity
x
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions.
x
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental 
trauma (e.g., sprained ankle) which may interfere with or prevent everyday life functions but do 
not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Is an important medical event:
x
Important medical events’ - some medical events may jeopardise the participant or may require 
an intervention to prevent one of the above characteristics/consequences. Such events should 
also be considered as ‘serious’ in accordance with the above definition. 
x
Medical judgement should be exercised in deciding whether an adverse event/reaction is 
serious. Important adverse events/reactions that are not immediately life threatening or do not 
result in death or hospitalisation, but may jeopardise the participant or may require intervention 
to prevent one of the other outcomes listed in the definition above occurring, should also be 
considered serious. Details of the SAE must be provided.
10.3.5.
Suspected Unexpected Serious Adverse Reaction
A suspected unexpected serious adverse reaction (SUSAR) is ‘a serious adverse reaction, the nature and 
severity* of which is not consistent with the information about the medicinal product in question, as defined 
in the Investigator’s Brochure relating to the trial in question.
Medical events will be assessed for expectedness against the Reference Safety Information (RSI) section 
of the IB or equivalent, and any available IB addendum. Any changes to the RSI will be deemed as a 
change to the risk/benefit profile and will require a substantial amendment to be submitted to the MHRA. 
This amendment must be approved before the changes are implemented in the study.
*The term ‘severity’ is used here to describe the intensity of a specific event. This is not the same as ‘serious’ 
which is based on participant/event outcome or action criteria.
10.3.6.
Recording, Assessment and Follow-up of AE and/or SAE
10.3.6.1. AE and SAE Recording 
All AEs and SAEs will be collected from the time of written informed consent until study completion/final 
study contact or until the resolution of the AE. AEs will be fully recorded in the source documents as they 

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
83
are reported, whether spontaneously volunteered by a participant or in response to questioning about 
wellbeing at each face to face study visit and during telephone calls. Enquiries about AEs should cover the 
period between the previous and current visit.The following are examples of open ended, non-leading 
questions that may be used to obtain this information: 
x
How are you feeling?
x
Have you had any medical problems since your last visit/assessment? 
x
Have you taken any new medicines, other than those given to you in this study, since your last 
visit/assessment?
Following the reporting of AEs and concomitant medication, the Investigator should assess the participant’s 
eligibility to continue in the study. 
The PI will record all relevant information regarding an AE/SAE in the source documents and evaluate AEs 
using the following guidelines: 
x
Description of events (if the event consists of a cluster of signs and symptoms, a diagnosis 
should be recorded)
x
Seriousness
x
Severity (or grade)
x
Onset date and time
x
Frequency
x
Date and time of resolution (or ‘continuing’ if unresolved)
x
Action taken 
x
Concomitant medication
x
Clinical outcome
x
Relationship
or 
causality 
(IMP/Challenge 
Virus/ 
study 
procedures/ 
concomitant 
medication/other).
Any clinically significant abnormal laboratory result, vital sign or other measure will be followed until it 
returns to normal or baseline values, stabilises, or is judged by the Investigator to be no longer clinically 
significant. 
If an AE is not resolved at the end of the study, the AE should be followed until it has resolved or (in the 
case of pregnancy) the pregnancy has been terminated (including spontaneous abortion), resulted in a 
birth, or a decision has been made by the Sponsor that no further follow-up is required.
Even if the AE or SAE is assessed by the PI as not reasonably attributable to the challenge virus, its 
occurrence must be fully documented in the source notes
10.3.6.2. Assessment
Description

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
84
If the event consists of a cluster of signs and symptoms, a diagnosis should be recorded (e.g. 
gastroenteritis) rather than each sign and symptom. 
Onset and end
The dates and times of the onset and end of the event should be recorded. 
Assessment 
Challenge Virus Symptoms
The Investigator will assess and review Challenge Virus related symptoms recorded in participants’ 
hVIVO Symptom Diary Cards. Symptoms greater than Grade 0 will be expected and presumed to 
represent virus infection consequent to Viral Challenge, and will not be additionally captured as AEs 
unless they meet the definition of an AE, and are deemed to be clinically significant (in the opinion of 
the Investigator) to be classed as AEs.
Following Viral Challenge all unexpected (in the opinion of the Investigator) symptoms post inoculation 
will be captured as AEs, along with all other occurrences that meet the criteria for an AE.
Physical Examination
Any clinically significant change in complete physical examination findings during the study will be 
documented as an AE.
Directed Physical Examination
Following Viral Challenge, upper and lower respiratory symptoms (nasal discharge, otitis, pharyngitis, 
sinus tenderness, new wheezes, rales and rhonchi) will be expected and presumed to represent virus 
infection consequent to Viral Challenge, and will not be additionally captured as AEs unless they meet
the definition of an AE, and are deemed to be clinically significant (in the opinion of the Investigator) to 
be classed as AEs.
Vital Signs
Deterioration in a vital sign (compared to baseline) should only be reported as an AE if the deterioration 
fulfils the criteria for an AE. If deterioration in a vital sign is associated with clinical signs and 
symptoms, the sign or symptom will be reported as an AE and the associated vital sign will be 
considered as additional information.
Temperature
Following Viral Challenge, pyrexia will be expected and presumed to represent virus infection 
consequent to Viral Challenge, and will not be additionally captured as an AE unless it meets the 
definition of an AE, and is deemed to be clinically significant (in the opinion of the Investigator) to be 
classed as an AE.
Following Viral Challenge all unexpected (in the opinion of the Investigator) pyrexia post inoculation will 
be captured as an AE, along with all other occurrences that meet the criteria for an AE.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
85
Spirometry
A 15% drop in a spirometry value (compared to baseline) confirmed by a repeat on the same day, will 
be a Grade 1 (mild) AE. The PI/Investigator will use his/her clinical judgement to assign severity grades 
above Grade 1, based on evaluation of clinical signs and symptoms. If the repeated value has returned 
to normal an AE will not be raised.
Laboratory Values
Deterioration in a laboratory value (compared to baseline) should only be reported as an AE if the 
deterioration fulfils the criteria for an AE. If deterioration in a laboratory result is associated with clinical 
signs and symptoms, the sign or symptom will be reported as an AE and the associated laboratory 
result will be considered as additional information.
The Investigator and/or SMM will judge whether abnormal laboratory values are clinically significant or 
not clinically significant, and record this in the source document. This entry should be signed and dated 
by the relevant Investigator. Laboratory abnormalities detected at screening will be considered as part 
of the medical history and will not be reported as AEs
Challenge Virus associated laboratory abnormalities (e.g.: elevated ALT, AST or GGT; decreased 
neutrophils) may be recorded as AEs (at the discretion of the Investigator).
10.3.6.3. Assessment of Intensity
The term ’severe’ is often used to describe the intensity (severity) of a specific event. This is not the same 
as ‘serious’ which is based on participant/event outcome or action criteria.
The Investigator will use the FDA toxicity scale [“FDA Guidance for Industry: Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, September 2007.”]
as a reference when collecting, reporting and clarifying database queries of AEs, SAEs and ARs.
The severity of an AE that does not appear in the FDA toxicity scale should be determined according to the 
definitions in Table 6.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
86
Table 6 Classification of Adverse Events Severity
Grade
Classification
Definition
Grade 1
Mild
Mild level of discomfort, and does not interfere with regular activities
Grade 2
Moderate
Moderate level of discomfort and significantly interferes with regular 
activities
Grade 3
Severe
Significant level of discomfort and prevents regular activities
Grade 4
Life-threatening 
Extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalisation or 
hospice care probable
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as described in the 
definition of an SAE, NOT when it is rated as severe.
10.3.6.4. Frequency
The frequency of the AE should be categorised as one of the following:
x
Single
x
Intermittent
x
Continuous
10.3.6.5. Assessment of Causality
x
The Investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.
x
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or arguments 
to suggest a causal relationship, rather than a relationship cannot be ruled out.
x
The Investigator will use clinical judgment to determine the relationship.
x
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to study intervention administration will be considered 
and investigated.
x
The Investigator will also consult the Investigator’s Brochure (IB) and/or Product Information, for 
marketed products, in his/her assessment.
x
For each AE/SAE, the Investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality.
x
There may be situations in which an SAE has occurred and the Investigator has minimal information 
to include in the initial report to Sponsor’s Pharmacovigilance provider. However, it is very important 
that the Investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to Sponsor’s Pharmacovigilance provider.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
87
x
The Investigator may change his/her opinion of causality in light of follow-up information and send 
a SAE follow-up report with the updated causality assessment.
x
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
x
The relationship of an AE to the IMP will be categorised as shown in Table 7:
Table 7 Classification if Adverse Events Relationship
Classification
Definition
Not related
The AE is related to an aetiology other than the IMP (the alternative 
aetiology must be documented in the participant’s medical record).
Unlikely to be related
The AE is unlikely to be related to the IMP and likely to be related to 
factors other than IMP.
Possibly related
There is an association between the AE and the administration of the 
IMP, and there is a plausible mechanism for the AE to be related to the 
IMP, but there may also be alternative aetiology, such as characteristics 
of the participant’s clinical status or underlying disease.
Probably related
A reasonable temporal sequence of the AE and the IMP administration 
exists and, based upon the known pharmacological action of the drug, 
known or previously reported adverse reactions to the drug or class of 
drugs, or judgment based on the Investigator’s clinical experience, the 
association of the AE with the IMP seems likely.
Definitely related
A definite causal relationship exists between the AE and the 
administration of the IMP, and other conditions do not appear to explain 
the AE.
Unless an AE is ‘definitely related’ to the IMP, a causal relationship to one of the following should be 
considered, and full details provided on the AE reporting form as appropriate.
x
Challenge Virus
x
Study procedures
x
Concomitant medication
x
Other
10.3.6.6. Action Taken
The Investigator should ensure that adequate medical care is provided to participants for any AEs, including 
clinically significant laboratory values related to the IMP. In addition, the Investigator will describe whether 
any treatment was given for the AE.
The Investigator will classify the action taken with regard to the AE. The action taken should be classified 
according to the following categories and full details provided as appropriate:

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
88
x
None
x
Non-drug therapy given
x
Concomitant medication taken
x
IMP dose not changed
x
IMP dose adjusted
x
IMP administration temporarily interrupted
x
IMP administration permanently discontinued
x
Participant withdrawn
x
Participant hospitalised
x
Other
10.3.6.7. Outcome
An AE should be followed until the Investigator has determined and recorded the outcome or an 
alternative explanation. The outcome should be classified according to the categories shown in Table 8.
Table 8 Classification of Adverse Events Outcome
Classification
Definition
Resolved
Resolution of the AE with no residual signs or symptoms
Resolved with sequelae
Resolution of the AE with residual signs or symptoms
Ongoing
Either incomplete improvement or no improvement of the AE, 
such that it remains on-going
Fatal
Outcome of the AE was death. ‘Fatal’ should be used when 
death was at least possibly related to the AE.
Unknown (e.g. Lost to follow-up)
Outcome of the AE is not known (e.g. the participant is lost to 
follow-up).
10.3.6.8. Follow-up
All AEs and SAEs must be followed-up by the Investigator, or where appropriate, be referred to the 
Participant’s GP or other healthcare professional for follow-up until they are:
x
Resolved (return to normal or baseline values), or
x
Stabilised, or
x
Judged by the PI/Investigator to be no longer clinically significant, or
x
An alternative explanation has been provided.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
89
Additional measurements and/or evaluations may be necessary to investigate the nature and/or causality 
of an AE or SAE. This may include additional laboratory tests, diagnostic procedures, or consultation with 
other healthcare professionals. If the participant dies, any post-mortem findings (including histopathology) 
will be provided to the Sponsor if possible.
10.3.7.
Reporting of SAEs
SAEs must be documented and reported as per hVIVO’s SOPs. 
Prompt notification of SAEs by the Investigator to the Sponsor is essential so that the Sponsor can meet 
its regulatory and REC reporting obligations for the study. If the Investigator does not have all of the 
details regarding the SAE he/she will not wait until this information becomes available before making the 
initial report to Sponsor. Contact details are detailed in Table 10.5.
x
Notification should be made:
x
By telephone as soon as possible and within 24 hours of the Investigator being made aware of the 
event.
x
In a detailed written report within 24 hours of the Investigator becoming aware of the event.
All reports should be directed to the SMM. The Investigator at the site is responsible for ensuring that a 
member of the Sponsor study team is made aware of any SAE reports that have been transmitted. The 
SAE reporting contact details will be included in the local study contact list document and the
Pharmacovigilance/ Safety Management Plan.
In addition, any AE resulting in permanent study discontinuation for a participant, even if not serious and 
regardless of expectedness or causality, must be reported by telephone, email or fax to the Sponsor within 
7 calendar days of the PI or any other site personnel’s knowledge of the event. 
The SAE form, AE record and relevant concomitant medication record should be faxed/emailed to the 
Sponsor within 24 hours of the Investigator or any site personnel’s knowledge of a SAE. An updated SAE 
report form should be forwarded to the Sponsor within 24 hours of receipt of the new/updated information 
as relevant. 
Information relating to the participant’s subsequent medical progress must be submitted to the Sponsor as 
available, until the SAE has subsided or, in the case of permanent impairment, until it stabilises and the 
overall clinical outcome has been ascertained. 
The Investigator will also provide additional information, including a copy of the following documents (where 
applicable):
x
Copies of test results, as available 
x
Hospital discharge summary (as soon as it is available to the PI)
x
Autopsy report (as soon as it is available to the PI).
The Investigator must report SAEs/SUSARs to the relevant REC in accordance with applicable regulatory 
requirements and within the relevant timelines.
The REC will be sent annual safety updates in order to facilitate their continuing review of the study.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
90
10.3.8.
Reporting of SUSARs
The Sponsor is responsible for assessing SUSARs, unblinding potential SUSARs, and reporting SUSARs 
to the MHRA and REC. 
The Sponsor shall ensure that all relevant information about a SUSAR that occurs during the course of a 
clinical trial in the UK and is fatal or life threatening, is reported as soon as possible to the MHRA and the
REC. This needs to be done within 7 calendar days after the Sponsor became aware of the event. Any 
additional relevant information should be sent within 8 days of the first report being sent.
The Sponsor shall ensure that a SUSAR which is not fatal or life-threatening is reported as soon as possible 
and in any event within 15 calendar days after the Sponsor became aware of the event.
10.3.9.
Adverse Reactions to non-IMPs
Any AEs and SAEs which are related to/caused by a concomitant medication or Challenge agent, should 
not be classed as ARs, SARs, or SUSARs (ARs, SARs, SUSARs relate only to IMP by definition). However, 
an SAE caused by a non-IMP would need to be reported to the MHRA/REC for the appropriate action to 
be taken.
10.3.10.
Post-study AEs and SAEs
All SAEs that occur during the study from ICF signature until last participant last scheduled visit must be 
reported by the Investigator to the SMM as soon as possible, in accordance with hVIVO’s SOPs, and at the 
latest within 24 hours of becoming aware of the event.
All SAEs that have not resolved by the end of the study, or that have not resolved upon discontinuation of
the participant’s participation in the study, must be followed-up until the event is considered resolved, until 
the participant is lost during follow-up, or until the PI in conjunction with the Sponsor deem the event stable 
and a decision for no further follow-up has been taken
10.3.11.
Pregnancy
If a female participant or partner of a male participant becomes pregnant during the course of the study,
this must be reported by the Investigator to the SMM and Study Monitor by telephone as soon as possible, 
in accordance with hVIVO’s SOPs, and at the latest within 24 hours of becoming aware of the event. 
Following the telephone notification, the Investigator must fully and accurately complete the appropriate 
pregnancy reporting form, which must be e-mailed to the SMM and the Study Monitor at the latest within 
24 hours of becoming aware of the pregnancy. 
Participants will be advised to contact their GP or a specialist, as appropriate. 
Consent for follow-up of the pregnancy and pregnancy outcome will be sought from the pregnant study 
participant or the pregnant partner of the male study participant as applicable. Consent for follow-up will be 
documented on an hVIVO Pregnancy Follow-up ICF. 
Provided that the appropriate consent is in place, information related to the pregnancy will be collected as 
per hVIVO’s SOPs and the Sponsor’s requirements. The completed reporting form(s) will be sent to the 
Sponsor for review and assessment, and subsequent reporting as required.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
91
x
A complete evaluation will be documented in the source data to permit transfer to the clinical 
database. 
x
The emergency code break envelopes will be requested (Section 6.3) to break the blind for the 
appropriate study participant to ensure that further care can be based on the actual identity of the 
study treatment that the participant received.
x
hVIVO will maintain contact with the participant for a protracted period of time, but certainly until 
after the birth, in order to assess for outcomes that may be reportable as related AEs, and for 
reporting to the Sponsor as appropriate. 
x
hVIVO in consultation with the participant will keep the participant’s GP informed. 
x
All cases of foetal drug exposure via the parent as a study participant will be reported to the Sponsor 
and the REC.
10.3.12.
Reactogenicity Data 
Reactogenicity data are solicited AEs collected using the VDC, starting on the day of vaccination through 
7 days post vaccination. The reactogenicity data will include local reactions (redness, swelling, and pain at 
the injection site) and systemic events (fever, fatigue, headache, vomiting, nausea, diarrhea, muscle pain, 
and joint pain).
10.3.12.1.Local Reactions
Local reactions reported in the VDC are redness, swelling, and pain at the injection site.
x
Presence of Local Reactions (Proportion of Participants Reporting)
The participants will record the presence or absence of pain at the injection site in the diary as “Mild,” 
“Moderate,” “Severe,” or “None.” Redness and swelling will be measured in cm or measuring device units 
(range: 1 to 21 and 21+) and then categorised as mild, moderate, or severe based on the grading scale in 
Table 9. Measuring device units can be converted to centimeters according to the following scale: 1 
measuring device unit = 0.5 cm. A participant with a severe (Grade 3 or above) local reaction will be 
prompted to contact the investigator to assess if an unscheduled visit is required to assess the reaction.
Table 9 Grading Scale for Local Reactions
Mild 
Grade 1
Moderate
Grade 2
Severe
Grade 3
Grade 4
Redness
>2.0 cm to 
5.0 cm (5 to
10 measuring 
device units)
>5.0 cm to 
10.0 cm (11 to 
20 measuring 
device units)
>10 cm 
(>20 measuring 
device units)
Necrosis or exfoliative 
dermatitis
Swelling
>2.0 cm to 
5.0 cm (5 to
10 measuring 
device units)
>5.0 cm to 
10.0 cm (11 to 
20 measuring 
device units)
>10 cm 
(>20 measuring 
device units)
Necrosis
Pain (at the 
injection site)
Does not 
interfere with 
activity
Interferes with 
activity
Prevents daily 
activity
Emergency room visit or 
hospitalisation for severe pain 
at the injection site

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
92
Only an investigator is able to classify a participant’s local reaction as Grade 4, after clinical evaluation of 
the participant or documentation from another medically qualified source (eg, emergency room or hospital 
record) or, in the case of pain at the injection site only, contact with the participant. If a participant 
experiences a Grade 4 local reaction, the investigator must immediately notify the SMM. Grade 4 reactions 
will be recorded as an AE on the CRF.
The presence or absence of each local reaction on a given day is defined as follows:
= “Missing,” if the value is missing on a given day;
= “Yes,” if the participant reports the reaction as “Yes” for redness or swelling (with a diameter of 
more than 2.0 cm) or “Mild,” “Moderate,” “Severe,” or “Grade 4” for pain at the injection site on a 
given day;
= “No,” if the participant reports the reaction as “No” for redness or swelling or “None” for pain at 
the injection site on a given day.
For each local reaction, the derivation of whether or not the specific reaction occurred on “any day (Day 1-
7)” will be made. The derivation of this variable is given in Table 10 below.
Table 10 Derived Variables for Each Local Reaction
Variablea
Yes (1)
No (0)
Missing (.)
Any day 
(Day 1-7)
Participant reports the 
reaction as “Yes” on any day 
from Day 1 through Day 7.
Participant reports the 
reaction as “No” on all 7 
days or as a combination of 
“No” and missing on all 7 
days.
Participant reports the 
reaction as missing on all 
7 days.
a. The variable will be defined for each of the 3 local reactions.
For “any local reaction” on any day, a similar definition can be applied, as given in Table 11 below.
Table 11 Derived Variables for Any Local Reaction
Variable
Yes (1)
No (0)
Missing (.)
Any day 
(Day 1-7)
Participant reports any 
redness or swelling >2.0 cm
or “Yes” for pain at injection 
site on any day during Days 
1 through 7.
Participant reports redness 
or swelling ≤2.0 cm or pain 
at injection site as “No” on all 
7 days or as a combination 
of above and missing on all 
7 days for all 3 local 
reactions.
Participant reports all of 
the local reactions as 
missing on all 7 days.
x
Maximum Severity for Local Reactions
The maximum severity (highest grading) of each local reaction within 7 days after vaccination will be 
derived. The maximum severity will be derived as follows:
= “Missing,” if values are missing for all days from Days 1 through 7;
= 0, if the participant reports all reactions as “No” or a combination of missing and “No” for all 
days from Days 1 through 7;

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
93
= highest grade (maximum severity) within 7 days after vaccination, if the answer is not “No” for 
at least 1 day.
x
Duration of Each Local Reaction
The duration of each local reaction will be calculated in days as (resolution date of reaction - start date of 
reaction + 1). Resolution of the reaction is the last day on which the reaction is recorded in the VDC or the 
date the reaction ends if it is unresolved during the participant diary-recording period (end date collected 
on the CRF), unless chronicity is established. If there is no known end date, the duration will be considered 
unknown and set to missing.
x
Onset of Local Reaction
The onset day of each local reaction and any local reaction will be derived.
For the onset day of each local reaction, if participants report severity change for the local reaction, the first 
day of initial reporting of that specific local reaction will be counted.
For the onset day of any local reaction, the first day of reporting any severity of any local reaction will be 
counted.
In summary, the following variables will be derived for each local reaction:
1.
Presence or absence of each local reaction on each day (Days 1-7) after vaccination.
2.
Presence or absence of each local reaction on “any day (Day 1-7)” after vaccination.
3.
Presence or absence of any local reaction on “any day (Day 1-7)” after vaccination.
4.
Maximum severity of each local reaction on “any day (Day 1-7)” after vaccination.
5.
Duration of each local reaction after vaccination.
6.
Onset day of each local reaction after vaccination.
7.
Onset day of any local reaction after vaccination
10.3.12.2.Systemic Events
Systemic events reported via the VDC are fever, fatigue, headache, vomiting, nausea, diarrhea, muscle 
pain, and joint pain. For all ongoing systemic events on Day 7, the stop date will be recorded in the 
CRF. Additionally, the participant is to document the presence or absence of systemic events in the VCD
as “Mild,” “Moderate,” “Severe,” or “None.” Participants will assess the severity of each event according to 
Table 5.
Only an investigator is able to classify a participant’s systemic event as Grade 4, after physical evaluation 
of the participant or documentation from another medically qualified source (eg, emergency room or 
hospital record) or contact with the participant. If a participant experiences a Grade 4 systemic event, the 

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
94
investigator must immediately notify the sponsor. A Grade 4 event will be recorded as an AE.  The AE 
event will be graded as per Table 12.
Table 12 Grading Scale for Systemic Events
Mild
Grade 1
Moderate
Grade 2
Severe
Grade 3
Grade 4
Fatigue
(= tiredness in 
diaries)
Does not interfere 
with activity
Some interference 
with activity
Prevents daily 
routine activity
Emergency room 
visit or 
hospitalisation for 
severe fatigue 
Headache
Does not interfere 
with activity
Some interference 
with activity
Prevents daily 
routine activity
Emergency room 
visit or 
hospitalisation for 
severe headache 
Vomiting
1 to 2 times in 
24 hours
>2 times 
in 24 hours
Requires 
intravenous 
hydration
Emergency room 
visit 
or hospitalisation 
for severe vomiting
Nausea
Does not interfere 
with activity
Some interference 
with activity
Prevents daily 
routine activity
Emergency room 
visit or 
hospitalisation for 
severe nausea
Diarrhea
2 to 3 loose stools
in 24 hours
4 to 5 loose stools
in 24 hours
6 or more loose 
stools
in 24 hours
Emergency room 
visit
or hospitalisation 
for severe diarrhea
Muscle pain
Does not interfere 
with activity
Some interference 
with activity
Prevents daily 
routine activity
Emergency room 
visit or 
hospitalisation for 
severe muscle 
pain
Joint pain
Does not interfere 
with activity
Some interference 
with activity
Prevents daily 
routine activity
Emergency room 
visit or 
hospitalisation for 
severe joint pain

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
95
The highest temperature for each day for 7 days after vaccination is to be recorded in the VDC. For 
reporting purposes, fever will be analysed using the grading scale in Table 13.
Table 13 Grading Scale for Fever in the VDC
Mild
Grade 1
Moderate
Grade 2
Severe
Grade 3
Grade 4
≥38.0°C to 38.4°C
>38.4°C to 38.9°C
>38.9°C to 40.0°C
>40.0°C
The presence or absence of each systemic event on a given day is defined as follows:
= “Missing,” if the value is missing on a given day;
= “Yes,” if the participant reports a temperature ≥38.0°C for fever or “Mild,” “Moderate,” “Severe,” 
or “Grade 4” for the remaining events on a given day;
= “No,” if the participant reports a temperature <38.0°C for fever or “None” for the remaining events 
on a given day.
For each systemic event, the following variables will be derived:
1.
Presence or absence of each systemic event on each day (Days 1-7) after vaccination.
2.
Presence or absence of each systemic event on “any day (Day 1-7)” after vaccination.
3.
Maximum severity of each systemic event on “any day (Day 1-7)” after vaccination.
4.
Presence or absence of any systemic event on “any day (Day 1-7)” after vaccination.
5.
Duration of each systemic event after vaccination.
6.
Onset day of each systemic event after vaccination.
7.
Onset day of any systemic event after vaccination.
The derivation of these variables is similar to the derivation of the variables for local reactions (Section 
10.3.13)

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
96
10.4.
Appendix 4: Normal Ranges
Vital signs normal ranges 
Vital signs
Lower limit
Higher limit
Units
Tympanic temperature
(above 37.8 classed as 
pyrexia)*
35.5
37.8
oC
Oxygen saturation
Normal is ≥95
%
Respiratory rate
10
20
breaths per minute
Heart rate
40
100
beats per minute
Systolic BP
90
140
mmHg
Diastolic BP
60
90
mmHg
*Tympanic temperature refers to temperatures not recorded as part of the vaccine reactogenicity monitoring 
ECG
ECG Parameters
Lower limit
Higher limit
Units
HR
40
100
bpm
QRS
60
120
ms
PR interval
120
220
ms
QT
320
450
ms
QTc
Normal for females is < 450 
ms
Normal for males is < 430
QTcF
320
450
ms
QTcB
320
450
ms
Spirometry
Spirometry parameters
Lower limit
Higher limit
Units
FEV1 
Normal if ≥ 80% of the predicted value
litres
FEV1/FVC
Normal if ≥70% (≥ 0.7) of the predicted value 
litres 

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
97
No single value should be used in isolation, all spirometry reference ranges require physician 
interpretation of the participant’s overall status to determine their relevance.
10.5.
Appendix 7: Abbreviations
Abbreviation 
Term
AE
Adverse Event
ALP
Alkaline Phosphatase
ALRI
Acute Lower Respiratory Infection
ALT
Alanine Aminotransferase
AP
Analytical Plan
APTT
Activated Partial Thromboplastin Time
AR 
Adverse Reaction
AST
Aspartate Transaminase
ATS
American Thoracic Society 
AUC
Area Under the Curve
BD
Twice Daily
BMI
Body Mass Index
cGMP
Current Good Manufacturing Practices
CK
Creatine Kinase
COPD
Chronic Obstructive Pulmonary Disease
CRF
Case Report Form
CRP
C-reactive Protein
CV
Coefficient of Variance 
CYP450
Cytochrome 450
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram 
ECSC
European Coal and Steel Community 
ELISA
Enzyme-linked Immunosorbent Assay
EU
European Union 
FEV
Forced Expiratory Volume
FSH
Follicle Stimulating Hormone
GAD
Generalised Anxiety Disorder
GCP
Good Clinical Practice
GDPR
General Data Protection Regulation
GP
General Practitioner 
HAV
Hepatitis A
HbA1c
Haemoglobin A1c
HBV
Hepatitis B
HCV
Hepatitis C
HIV
Human Immunodeficiency Virus
HVC
Human Viral Challenge 
ICF
Inform Consent Form
ICH
International Council for Harmonisation
IgA
Immunoglobulin A
IgG
Immunoglobulin G
IM
Intramuscular
IMP
Investigational Medicinal Product
IUD
Intrauterine Device 
LRT
Lower Respiratory Tract
MCH
Mean Corpuscular Haemoglobin
MCHC
Mean Corpuscular Haemoglobin Concentration

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
98
MCV
Mean Corpuscular Volume
MHRA
Medicines and Healthcare products Regulatory Agency
NIMP
Non-Investigational Medicinal Product
NPS
Nasopharyngeal Swab
PBMC
Peripheral Blood Mononuclear Cell
PCR
Polymerase Chain Reaction
PFU
Plaque Forming Unit
PHQ
Patient Health Questionnaire
PI
Principal Investigator
PT
Prothrombin Time
qRT-PCR
Quantitative Reverse Transcriptase-Polymerase Chain Reaction
RBC
Red Blood Cell
REC
Research Ethics Committee
RNA
Ribonucleic acid
RSI
Reference Safety Information 
RSV
Respiratory Syncytial Virus
SAE
Serious Adverse Event
SMM
Sponsor’s Medical Monitor
SoA
Schedule of Activities 
SOP
Standard Operating Procedure 
SUSAR
Suspected Unexpected Adverse Reaction
T
Troponin
TDS
Three Times Daily
TMF
Trial Master File
TSH
Thyroid Stimulating Hormone
TSS
Total Symptoms Score
UK
United Kingdom
URT
Upper Respiratory Tract
WBC
White Blood Cell
β-HCG
β-human chorionic gonadotrophin

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
99
10.6.
Appendix 9: Definitions
10.6.1.
General
TERM
hVIVO Services Limited Definition
Completion (of a participant’s 
participation in the study)
A participant will be considered to have completed the study after 
his/her attendance at the last planned study visit, or the last 
unscheduled visit as applicable.
Baseline       
For safety assessments the nearest assessments completed prior 
to vaccination will be used as the baseline measure, unless stated 
otherwise.
Enrolment (of a participant into 
the study)
A participant will be considered to be `enrolled` into the study 
once he/she has been randomised, dosed, or inoculated 
(whichever occurs first).
Infectious titre
The titre of virus inoculum producing viral infection in a participant.
The term ‘titre’ applies to the quantity or concentration of virus 
inoculum (depending on the units documented).
Quarantine group
A group of participants who are admitted to and are resident in the 
Quarantine Unit for a particular quarantine period (i.e., participants
whose Day 0 and scheduled discharge date are the same).
Quarantine period
The period of time when clinical trial participants are isolated in 
the Quarantine Unit during a HVC study.
Randomisation number
The number allocated to a participant at randomisation.
Participant number
The unique number assigned to a participant on the hVIVO 
participant database, which is used to identify the participant prior 
to randomisation.
Viral Challenge (or Challenge)
The inoculation of a participant with virus inoculum. By definition, 
the day of Viral Challenge is Day 0.
10.6.2.
Study definition of infection and illness
TERM
CRITERIA  
Seroconversion
Not applicable for RSV.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
100
TERM
CRITERIA  
Lower Respiratory Tract Illness 
(LRTI)
Any one of the following signs and/or symptoms on two 
consecutive scheduled assessments, at least one of which must 
feature Grade 2 severity, or if any of the following attain Grade 3 
severity once:
o
Self-reported symptoms: cough, shortness of 
breath, chest tightness and wheeze
o
Physician findings: Abnormal breath sounds 
externally (e.g. stridor, wheezing) and on chest 
auscultation (rhonchi, crepitations or other).
Upper Respiratory Tract Illness 
(URTI)
Any one of the following signs and/or symptoms on two 
consecutive scheduled assessments, at least one of which must 
feature Grade 2 severity, or if any of the following attain Grade 3 
severity once:
Self-reported symptoms: rhinorrhoea (runny nose), nasal 
congestion (stuffy nose), sore throat, sneezing.
Physician findings: nasal discharge, otitis, pharyngitis, sinus 
tenderness.
Systemic Illness
Fulfils the criteria for febrile illness, or fulfils the definition of upper 
respiratory tract illness and/or lower respiratory tract illness 
And
Any one of the following symptoms on two consecutive scheduled 
assessments, at least one of which must feature Grade 2 severity, 
or if any of the following attain Grade 3 severity once
x
malaise
x
headache 
x
muscles and/or joint ache
x
chilliness 
x
feverishness
Febrile Illness
Any occurrence of temperature ≥ 37.9oC
Viral shedding
One or both of the following definitions must be met (between 
Day +2 and discharge from quarantine):
x
At least 2 positive quantifiable detections by viral load 
qPCR assay specific for the challenge virus, reported on 2 
or more consecutive days and from 2 independent samples 
(which can either be the same type of sample or different 
e.g. throat swab and nasal wash or 2 nasal wash samples);
x
One positive detection by viral load qPCR assay, specific 
for the challenge virus, in which an aliquot of the same 
sample has also tested positive in a viral culture assay 
appropriate for detecting the challenge virus.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
101
TERM
CRITERIA  
Laboratory confirmed RSV
infection
Viral shedding definition has been met.

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
102
11.
References
Agius, G., G. Dindinaud, R. J. Biggar, R. Peyre, V. Vaillant, S. Ranger, J. Y. Poupet, M. F. Cisse, and M. 
Castets. 1990. 'An epidemic of respiratory syncytial virus in elderly people: clinical and serological 
findings', J Med Virol, 30: 117-27.
Bont, L., P. A. Checchia, B. Fauroux, J. Figueras-Aloy, P. Manzoni, B. Paes, E. A. Simoes, and X. 
Carbonell-Estrany. 2016. 'Defining the Epidemiology and Burden of Severe Respiratory Syncytial 
Virus Infection Among Infants and Children in Western Countries', Infect Dis Ther, 5: 271-98.
DeVincenzo, J. P., T. Wilkinson, A. Vaishnaw, J. Cehelsky, R. Meyers, S. Nochur, L. Harrison, P. 
Meeking, A. Mann, E. Moane, J. Oxford, R. Pareek, R. Moore, E. Walsh, R. Studholme, P. 
Dorsett, R. Alvarez, and R. Lambkin-Williams. 2010. 'Viral load drives disease in humans 
experimentally infected with respiratory syncytial virus', Am J Respir Crit Care Med, 182: 1305-
14.
DeVincenzo, John, Efi Gymnopoulou, Els De Paepe, Bryan Murray, Arangassery Rosemary Bastian, 
Wouter Haazen, Nicolas Noulin, Christy Comeaux, Esther Heijnen, Kinglsey Eze, Anthony 
Gilbert, Rob Lambkin-Williams, Hanneke Schuitemaker, Benoit Callendret, and Jerald Sadoff. 
2019. '902. A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy of a 
Single Immunization of Ad26.RSV.preF against RSV Infection in a Viral Challenge Model in 
Healthy Adults', Open Forum Infectious Diseases, 6: S27-S28.
Falsey, A. R., C. K. Cunningham, W. H. Barker, R. W. Kouides, J. B. Yuen, M. Menegus, L. B. Weiner, C. 
A. Bonville, and R. F. Betts. 1995. 'Respiratory syncytial virus and influenza A infections in the 
hospitalized elderly', J Infect Dis, 172: 389-94.
Falsey, A. R., P. A. Hennessey, M. A. Formica, C. Cox, and E. E. Walsh. 2005. 'Respiratory syncytial 
virus infection in elderly and high-risk adults', N Engl J Med, 352: 1749-59.
Fleming, D. M., R. J. Taylor, R. L. Lustig, C. Schuck-Paim, F. Haguinet, D. J. Webb, J. Logie, G. Matias, 
and S. Taylor. 2015. 'Modelling estimates of the burden of Respiratory Syncytial virus infection in 
adults and the elderly in the United Kingdom', BMC Infect Dis, 15: 443.
Gilman, M. S., C. A. Castellanos, M. Chen, J. O. Ngwuta, E. Goodwin, S. M. Moin, V. Mas, J. A. Melero, 
P. F. Wright, B. S. Graham, J. S. McLellan, and L. M. Walker. 2016. 'Rapid profiling of RSV 
antibody repertoires from the memory B cells of naturally infected adult donors', Sci Immunol, 1.
Graham, B. S., K. Modjarrad, and J. S. McLellan. 2015. 'Novel antigens for RSV vaccines', Curr Opin 
Immunol, 35: 30-8.
Hall, C. B., G. A. Weinberg, M. K. Iwane, A. K. Blumkin, K. M. Edwards, M. A. Staat, P. Auinger, M. R. 
Griffin, K. A. Poehling, D. Erdman, C. G. Grijalva, Y. Zhu, and P. Szilagyi. 2009. 'The burden of 
respiratory syncytial virus infection in young children', N Engl J Med, 360: 588-98.
Kapikian, A. Z., R. H. Mitchell, R. M. Chanock, R. A. Shvedoff, and C. E. Stewart. 1969. 'An epidemiologic 
study of altered clinical reactivity to respiratory syncytial (RS) virus infection in children previously 
vaccinated with an inactivated RS virus vaccine', Am J Epidemiol, 89: 405-21.
Lambkin-Williams, R., N. Noulin, A. Mann, A. Catchpole, and A. S. Gilbert. 2018. 'The human viral 
challenge model: accelerating the evaluation of respiratory antivirals, vaccines and novel 
diagnostics', Respir Res, 19: 123.
Matias, G., R. Taylor, F. Haguinet, C. Schuck-Paim, R. Lustig, and V. Shinde. 2014. 'Estimates of 
mortality attributable to influenza and RSV in the United States during 1997-2009 by influenza 
type or subtype, age, cause of death, and risk status', Influenza Other Respir Viruses, 8: 507-15.
Miller, M. R., J. Hankinson, V. Brusasco, F. Burgos, R. Casaburi, A. Coates, R. Crapo, P. Enright, C. P. 
van der Grinten, P. Gustafsson, R. Jensen, D. C. Johnson, N. MacIntyre, R. McKay, D. Navajas, 

HVO-CS-005 Protocol Final v3.0
hVIVO template identifier: (G_0687) v3.0
103
O. F. Pedersen, R. Pellegrino, G. Viegi, J. Wanger, and Ats Ers Task Force. 2005. 
'Standardisation of spirometry', Eur Respir J, 26: 319-38.
Moghaddam, A., W. Olszewska, B. Wang, J. S. Tregoning, R. Helson, Q. J. Sattentau, and P. J. 
Openshaw. 2006. 'A potential molecular mechanism for hypersensitivity caused by formalin-
inactivated vaccines', Nat Med, 12: 905-7.
Nair, H., D. J. Nokes, B. D. Gessner, M. Dherani, S. A. Madhi, R. J. Singleton, K. L. O'Brien, A. Roca, P. 
F. Wright, N. Bruce, A. Chandran, E. Theodoratou, A. Sutanto, E. R. Sedyaningsih, M. Ngama, P. 
K. Munywoki, C. Kartasasmita, E. A. Simoes, I. Rudan, M. W. Weber, and H. Campbell. 2010. 
'Global burden of acute lower respiratory infections due to respiratory syncytial virus in young 
children: a systematic review and meta-analysis', Lancet, 375: 1545-55.
Shi, T., E. Balsells, E. Wastnedge, R. Singleton, Z. A. Rasmussen, H. J. Zar, B. A. Rath, S. A. Madhi, S. 
Campbell, L. C. Vaccari, L. R. Bulkow, E. D. Thomas, W. Barnett, C. Hoppe, H. Campbell, and H. 
Nair. 2015. 'Risk factors for respiratory syncytial virus associated with acute lower respiratory 
infection in children under five years: Systematic review and meta-analysis', J Glob Health, 5: 
020416.
Walsh, E. E., and A. R. Falsey. 2012. 'Respiratory syncytial virus infection in adult populations', Infect 
Disord Drug Targets, 12: 98-102.
Zhou, H., W. W. Thompson, C. G. Viboud, C. M. Ringholz, P. Y. Cheng, C. Steiner, G. R. Abedi, L. J. 
Anderson, L. Brammer, and D. K. Shay. 2012. 'Hospitalizations associated with influenza and 
respiratory syncytial virus in the United States, 1993-2008', Clin Infect Dis, 54: 1427-36.