Clinical trial NCT04865237
Conditions: Covid19 SARS-CoV Infection Corona Virus Infection Coronavirus COVID-19
Sponsor: Imperial College London
Start date: 2021-03-06; Completion date: 2022-07-11
Enrollment: 36 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a dose optimisation study in healthy adults aged 18-30 who will be experimentally inoculated with SARS-CoV-2. The aim is to cause PCR-confirmed upper respiratory infection in the majority of challenged individuals with minimal or no illness, providing data on the course of COVID-19 and the immune response to SARS-CoV-2 infection. This will establish an optimised dose and study design that will then be used to evaluate the efficacy of treatment and vaccine candidates plus level and duration of immune protection in follow-on trials.

Detailed description:

Arms: arm 1: Dose Level 1: SARS-CoV-2, intranasally (10\^1 TCID50 dose) arm 2: Dose Level 2: SARS-CoV-2, intranasally (10\^2 TCID50 dose) arm 3: Dose Level 3: SARS-CoV-2, intranasally (10\^3 TCID50 dose)
Interventions: intervention 1: SARS-CoV-2 Virus 1x10^1 TCID50 intervention 2: Remdesivir intervention 3: SARS-CoV-2 Virus 1x10^2 TCID50 intervention 4: SARS-CoV-2 Virus 1x10^3 TCID50
Intervention descriptions: intervention 1: SARS-CoV-2, intranasally, (1x10\^1 TCID50) intervention 2: VEKLURY™ intervention 3: SARS-CoV-2, intranasally, (1x10\^2 TCID50) intervention 4: SARS-CoV-2, intranasally, (1x10\^3 TCID50)

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
1 
 
 CLINICAL STUDY PROTOCOL 
 
A dose finding human experimental infection study in healthy subjects using a GMP-
produced SARS-COV-2 wild type strain (SARS-CoV-2 Characterisation Study) 
 
Version and Date of Protocol: 
Final V 7.0 _09Nov2021 
Sponsor Protocol Number: 
20IC6437 
hVIVO Protocol Number: 
HVO-vCS-003 
Sponsor: 
Imperial College London 
Room 221, Level 2, Medical School Building 
Norfolk Place, London W2 1PG 
 
Funder 
UK Vaccine Taskforce, Department of Business, 
Energy and Industrial Strategy. 
IRAS ID: 
292098 
REC Reference: 
20/UK/0002 
 
 
Confidentiality and Protections Statement: 
This document contains confidential information and must not be disclosed to anyone other 
than the study staff and members of the Independent Ethics Committee/Institutional Review 
Board or Competent Authorities. The information in this document cannot be used for any 
purpose other than the conduct or evaluation of the clinical investigation without the prior 
written consent of hVIVO and Imperial College London. 
Personal data included in the protocol is subject to General Data Protection Regulation 
(GDPR:  EU 2016/679) considerations and protections. 
 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
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: 
 
 
 
 
 
 
 
 
 
 
15 Nov 2021 
Ruth Nicholson 
Head of Research Governance and Integrity  
 
Date (DD MMM YYYY) 
 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
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. 
 
Chief Investigator (CI) Signatory:  
Name  
(typed or printed): 
Dr Christopher Chiu 
 
Institution and 
Address: 
Imperial College London 
Hammersmith Campus,  
London,  
W12 0NN 
 
 
Signature:
 
Date: 
15 Nov 2021 
 
 
 
(DD MMM YYYY) 
 
 
 
 




CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
5 
 
Study Personnel Contact Information  
CONTACT 
DETAILS 
Sponsor 
Research Governance and Integrity Team 
Imperial College London  
Room 215, Level 2, Medical School Building, Norfolk Place 
London, W2 1PG 
Phone: 0207 594 9480 
http://www3.imperial.ac.uk/clinicalresearchgovernanceoffice
Sponsor’s Representative 
Keith Boland  
Room 221, Level 2, Medical School Building, Norfolk Place 
London W2 1PG 
Phone: 020 759 49480 
Email: k.boland@imperial.ac.uk  
Chief Investigator (CI)  
Dr Christopher Chiu  
Imperial College London 
Hammersmith Campus, London, W12 0NN 
Phone: 020 8383 2301 
Email: c.chiu@imperial.ac.uk  
Sponsor’s Medical Monitor 
Dr Christopher Chiu  
Imperial College London 
Hammersmith Campus, London, W12 0NN 
Phone: 020 8383 2301 
Email: c.chiu@imperial.ac.uk 
Principal investigator (PI) – 
QMB and Quarantine Site 
(including Follow Up Visits) 
Mariya Kalinova 
hVIVO 
Queen Mary BioEnterprises (QMB) Innovation Centre, 
London  
E1 2AX 
Email: m.kalinova@hvivo.com 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
6 
 
Study Sites 
Royal Free Hospital, London 
hVIVO, Queen Mary BioEnterprises Innovation Centre 
 
 
Key Protocol & Research Contributors 
Professor Robert Read,  
University 
Hospital 
Southampton 
NHS 
Foundation Trust, Southampton SO16 6YD  
Email: R.C.Read@soton.ac.uk  
Professor Peter JM Openshaw,  
Professor 
of 
Experimental 
Medicine, 
National Heart and Lung Institute, Imperial 
College London, London,  
Email: p.openshaw@imperial.ac.uk 
Mark Baillet,  
Managing Director, S-cubed Biometrics, 99 
Park Drive, Milton Park, Abingdon OX14 
4RY, UK  
Email: mb@s-cubed.co.uk  
Professor Malcolm G Semple,  
Professor of Outbreak Medicine and Child 
Health, University of Liverpool, Liverpool, UK 
Email: M.G.Semple@liverpool.ac.uk 
Professor Wendy Barclay,  
Professor 
of 
Virology, 
Department 
of 
Infectious 
Disease, 
Imperial 
College 
London, 
UK 
Email: 
w.barclay@imperial.ac.uk 
Professor William G. Rapeport,  
Visiting Professor, National Heart and Lung 
Institute, Imperial College London SW7 2AZ 
Email: w.rapeport@imperial.ac.uk 
Dr Andrew Catchpole,  
Chief Scientific Officer, hVIVO, Queen Mary 
BioEnterprises Innovation Centre, London 
E1 2AX  
Email: a.catchpole@hvivo.com  
Alex Mann,  
Director of Clinical Science, hVIVO, Queen 
Mary BioEnterprises Innovation Centre, 
London E1 2AX  
Email: a.mann@hvivo.com 
Martin Johnson,  
Chief Medical Officer, hVIVO, Queen Mary 
BioEnterprises Innovation Centre, London 
E1 2AX  
Email: m.johnson@hvivo.com  
Dr Anthony S. Gilbert 
Pharmaceutical Physician 
 
Email: anthony@gilbertgroup.org 
Dr Stephen Harden,  
Consultant Radiologist, University Hospital 
Southampton, Southampton SO16 6YD  
Professor Tom Wilkinson,  
University 
Hospital 
Southampton 
NHS 
Foundation Trust, Southampton SO16 6YD  


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
7 
 
Email: Stephen.Harden@uhs.nhs.uk  
Email: t.wilkinson@soton.ac.uk   
Professor Robert S Heyderman,  
Professor of Infectious Diseases, UCL 
Division of Infection and Immunity, The 
Rayne Building, 5 University Street, London, 
WC1E 6EJ 
Email: r.heyderman@ucl.ac.uk  
 
 
 
Funder 
This study is funded by the UK Vaccine Taskforce, Department of Business, Energy and 
Industrial Strategy.  
This protocol describes the SARS-CoV-2 Characterisation Study and provides information 
about procedures for entering participants. The protocol should not be used as a guide for the 
treatment of other participants; every care was taken in its drafting, but corrections or 
amendments may be necessary. All amendments and changes will be discussed and agreed 
with all parties, relevant approvals obtained and implemented at the recruiting site.  
Problems relating to this trial should be referred, in the first instance, to hVIVO Services Ltd., 
as a delegate of the sponsor.  
The study will adhere to the principles outlined in the UK policy framework for health and social 
care (V3.3 07/11/17). This trial will adhere to the principles outlined in the Medicines for Human 
Use (Clinical Trials) Regulations 2004 (SI 2004/1031), amended regulations (SI 2006/1928) 
and the International Conference on Harmonisation Good Clinical Practice (ICH GCP) 
guidelines. It will be conducted in compliance with the protocol, the Data Protection Act and 
other regulatory requirements as appropriate.  
 
 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
8 
 
Protocol History  
Document 
Date 
Amendment Type 
COVHIC001 Initial Clinical Trial 
Protocol (v3.0) 
08Feb2021 
Not applicable. First Version. 
COVHIC001 
Clinical 
Trial 
Protocol (v4.0) 
24Feb2021 
NSA1 
COVHIC001 
Clinical 
Trial 
Protocol (v5.0) 
11Mar2021 
SA2 
COVHIC001 
Clinical 
Trial 
Protocol (v6.0) 
20May2021 
SA3 
COVHIC001 
Clinical 
Trial 
Protocol (v7.0) 
09Nov2021 
SA4 
Amendment: NSA 1 24Feb2021 
Overall Rationale for the Amendment: 
Page # and 
Section Name 
Description of Change 
Brief Rationale 
Throughout 
Incorrect section 0 link updated 
Administrative correction 
p24-32 SoA 
Superscript w updated and added to 
GAD-7 and PHQ-9 questionnaire rows 
Clarification 
p24-32 SoA 
Superscript v updated around cognitive 
testing timings 
Clarification 
p24-32 SoA 
Superscript j updated 
Clarification 
p24-32 SoA 
BD/TDS/QDS updated 
Clarification 
p24-32 SoA 
Added arrows to clarify that SAE and 
con med recording will take place from 
screening through to follow up 
Clarification 
p24-32 SoA 
Blood serum updated to blood plasma 
markers 
Administrative correction 
p24-32 SoA 
Blood CPT - PBMCs & Plasma replaced 
with Blood Lithium Heparin – PBMCs, 
other blood cells, +/- plasma 
Administrative correction 
p24-32 SoA 
Nasopharyngeal Transwab for cells for 
RNA - Nasopharyngeal replaced with 
mid-turbinate 
Administrative correction 
p24-32 SoA 
DNA Paxgene removed 
Administrative correction 
p58, Risk 
determination 
Nasosorption strip - 2 minutes corrected 
to 1 minute 
Administrative correction 
p57, Risk 
assessment 
Incorrect title removed 
Administrative correction 
p71, 92, 118, 
figure 1 
Deleted figure from caption 
Administrative correction 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
9 
 
Page # and 
Section Name 
Description of Change 
Brief Rationale 
p73 Follow up 
phase 
Added telephone calls every 2-3 days 
between discharge from Q and first 
follow up visit already in soa 
Clarification 
p75 Inclusion 
Criteria 
Criterion 4 – Numbering corrected. 4 
weeks corrected to 2 weeks for 
contraception and “first dose” corrected 
to “inoculation” 
Administrative correction 
and clarification  
p75 Inclusion 
Criteria 
Criterion 4 – corrected to 2 weeks for 
contraception and “first dose” corrected 
to “inoculation” 
Clarification  
p75, 126,135 
References to IMP – replaced with 
“study virus or Remdesivir.” Or 
“Remdesivir” as applicable. 
Administrative correction 
p77 Exclusion 
Criteria 
Criterion 10 – g corrected to kg 
Administrative correction 
p79 Exclusion 
Criteria 
Criterion 18 – Asterix removed 
Administrative correction 
p96, criteria for 
escalation 
Physician replaced with clinician 
Clarification 
P98, p153 ECG 
parameters 
QTcB and QTcF added back in following 
confirmation that RFH machines can 
provide this readout 
Administrative correction 
p99, Radiology 
Wording updated for clarity 
Clarification 
p100, 
Echocardiogram
removed in the quarantine unit at the 
participants’ bedside 
Administrative correction 
p100 
Spirometry 
Wording around FEF25-75 included 
This will be an exploratory 
measurement, not included 
in eligibility assessments. 
p104 
Incorrect reference to PK removed 
Administrative correction 
p107 
Respiratory pathogen screen – 
nasopharyngeal updated to mid 
turbinate 
Administrative correction 
p108 Mask 
wearing 
sampling 
Corrected to day -1 (previously – was 
omitted in error) 
Administrative correction 
p129, Table 12 
HbA1c clarified as only required on 
admission 
Clarification 
p141 
Broken table reference corrected 
Administrative correction 
p141, Table 17 
PV reporting details included 
Clarification 
 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
10 
 
Amendment SA 2 11Mar2021 
Overall Rationale for the Amendment: 
Page # and 
Section Name 
Description of Change 
Brief Rationale 
Throughout 
document 
Minor typographical and formatting 
corrections 
Correction of administrative 
error 
p28, p33 and p 
106 
Update to frequency of UPSET smell 
tests, update to footnote u, update to 
text around UPSIT smell test 
Clarification/Correction of 
administrative error 
p33 SoA 
Update to footnote o 
Clarification/Correction of 
administrative error 
p30 SoA 
Mask wearing removed from day 0 
Clarification/Correction of 
administrative error 
p74, Follow up 
phase 
Addition of day 270 (previously omitted 
in error) 
Clarification/Correction of 
administrative error 
p75, Inclusion 
criterion 4 
Clarification about timing of 
contraception regarding Remdesivir and 
study virus. 
Clarification/Correction of 
administrative error 
p76, Inclusion 
criterion 5 
Addition of “if applicable” regarding 
rescue medication 
Clarification/Correction of 
administrative error 
p79, Exclusion 
criterion 12 
Corrected parentheses 
Clarification/Correction of 
administrative error 
p110 Discharge 
Criteria 
Removal of reference to home visits 
Clarification/Correction of 
administrative error 
p110 Discharge 
Criteria 
Update to wording to clarify home 
testing 
Clarification/Correction of 
administrative error 
p132 Appendix 
3 
Updates and amendments to table to 
reflect laboratory AE values 
Clarification/Correction of 
administrative error 
p140 Vital signs 
Updates to Bradycardia grading 
Clarification/Correction of 
administrative error 
 
 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
11 
 
Amendment SA 3 20May2021 
Overall Rationale for the Amendment: 
Page # and 
Section Name 
Description of Change 
Brief Rationale 
p.18 Protocol 
Synopsis 
Change to anti-viral treatment wording - 
pre-emptive treatment with Remdesivir 
or Early Rescue with REGEN-COV or 
no pre-emptive or rescue treatment. 
 
Change to wording following 
DSMB meeting 19Apr2021 
p.19 
Change to wording on Discharge 
Criterion. Subjects will remain in the 
quarantine unit until these criteria are 
met. 
 
Two consecutive swabs with qPCR Ct 
>33.5 AND negative culture. 
 
Lateral flow tests may be used in place 
of culture, if culture data is not available. 
 
A qualitative PCR may be used in place 
of quantitative PCR, if the latter is not 
available. 
 
At the PI’s discretion, if protracted 
quarantine is deemed to be causing 
harm to the participant’s mental or 
physical health and no viable virus is 
detected by culture or a lateral flow test 
is negative. 
 
For non-infected subjects: 
 
2 consecutive swabs with undetectable 
virus by PCR only prior to discharge  
Change to wording following 
DSMB meeting 19Apr2021 
p.19 
Subjects will remain in the quarantine 
unit for a minimum of 14 Days from 
inoculation. 
Clarification 
p.21 
Change to wording on Sample Size to 
include ‘and treatment regimen’ and ‘up 
to a total of 90 subjects overall’ 
Clarification 
p.23 SoA 
Vital signs, Temperature, Diary Card, 
added (X) to D-2 assessment. 
Clarification 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
12 
 
Page # and 
Section Name 
Description of Change 
Brief Rationale 
p.24 SoA 
HIV, Hepatitis A B & C added (X) to 
Day-2/-1 
Clarification 
p.25 SoA 
Added wording – Mid Turbinate or 
nasopharyngeal swab for cells for RNA 
(g) 
Administrative change to 
wording 
p.25 & p.26 SoA
Mask Wearing and Environmental 
Sampling added (X) at Extended stay 
Clarification 
p.25 & p.29 SoA
Added wording to clarify Chest X-Ray 
and ECHO will not be repeated if a 
subject is reinvited to a future 
Admission/Quarantine. 
Clarification 
p.27 
Updated wording to reflect current 
National Vaccine Program roll-out – 
removal of ‘vaccines in the near future’.  
Administrative correction 
p.27 
Addition of wording to clarify Regeneron 
– ‘Pre-clinical and clinical experience 
with REGEN-COV (Regeneron 
Monoclonal Antibody cocktail) for 
COVID-19.  Background and reference 
to previous clinical studies. 
Additional of wording for 
clarification. 
p.29 SoA & 
p.109 
Change to timing of Mask Wearing from 
‘up 60 minutes’ to ‘between 60 – 90 
minutes’. 
Additional wording for 
clarification and accuracy of 
assessment requirement. 
p.51 
Updated replacement of Gilead 
Remdesivir Fact Sheet.
Update. 
p.67 
Clarification on Screening activities in 
the Screening Protocol up to the time of 
signing the consent for the main study 
protocol (between D-90 to Day -2). 
Clarification. 
p.69 
Additional wording to reference Royal 
Free Hospital elective admission 
procedure.
Clarification. 
p.69 
Quarantine Phase – adjustment to 
wording ‘subjects will stay overnight for 
a period of at least 16 days’.  
Clarification. 
p.71 & p.72 
Inclusion criterion, Item 4 & 5 – 
adjustment to wording on contraception 
for both male and female participants to 
add willing to use contraception ‘until 6 
months after receipt of final dose of 
study virus or intervention treatment’.
Clarification. 
p.72 
QCOVID removal of QCOVID tool as an 
Inclusion Criterion but remains in the 
study and ICF. 
Change to Inclusion 
Criterion. 
p.79-81 
Section 4 – Study Intervention – addition 
of REGEN-COV information. 
Clarification. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
13 
 
Page # and 
Section Name 
Description of Change 
Brief Rationale 
p.88 & p.89 
Update to Dose Escalation, De-
escalation and Confirmation Figure 4. 
Clarification. 
p. 93  
Criteria for Clinical Evaluation of 
Participant – re-wording of sentence to 
accurately reflect procedure and 
inclusion of the RFH Patient 
Assessment and Response Team 
(PARRT).  
Clarification. 
p.106 – p.109 
Re-wording of SARS-CoV-2 Discharge 
Process. 
Clarification. 
p.108 
Environmental and Mask Wearing 
sampling – re-wording. 
Clarification. 
p.111 
Addition of wording - Reporting of 
Events related to REGEN-COV – 
addition of wording to reference SAEs / 
AEs and Grading.  
Clarification. 
p.21 & p.117 
Sample Size – change to wording to 
include ‘dose-level and treatment 
regimen’ and ‘up to 90 subjects overall’ 
Administrative correction. 
p.123 
Additional wording to cover 
reimbursement of extended stays in the 
quarantine unit, beyond the Day 14 
post-inoculation quarantine period. 
Administrative change. 
p.129 
Additional wording – HbA1c (only 
required at screening). 
Clarification. 
p.138 
Rewording to add ‘PI/Investigator will 
use his/her clinical judgement to assign 
severity grades above Grade 1, based 
on evaluation of clinical signs and 
symptoms’. 
Administrative correction 
 
Administrative Changes  
 
Throughout  
Section Numbering  
Administrative correction for 
clarification 
Throughout  
Format, Tables, Figures, Document 
Alignment. 
Administrative correction for 
clarification 
Throughout  
Re-wording for clarity that does not 
change the protocol. 
Administrative correction for 
clarification 
Throughout  
Minor typographical errors. 
Administrative correction 
p.6 
Updated RGIT website. 
Administrative correction 
 
 
 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
14 
 
Amendment SA 4 09Nov2021 
 
Overall Rationale for the Amendment: 
Page # and 
Section Name 
Description of Change 
Brief Rationale 
Investigator 
Agreement (p. 
4) 
Change in Principal Investigator (PI) to 
remove Dr Ben Killingley and transfer 
responsibilities to Dr Mariya Kalinova 
Change in PI 
Cover page (p. 
1) and protocol 
history (p. 8)  
- Addition of summary of changes 
tables 
- Removal of EudraCT number 
Administrative corrections 
Section 5.18 
(p.106) and 
SoA (p.28)  
‘Mid-turbinate or nasopharyngeal’ 
amended to ‘Mid-turbinate and/or 
nasopharyngeal’  
Update to reflect a non-
substantial change 
implemented  
Throughout 
Minor administrative corrections 
Administrative correction 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
15 
 
 
 
 
List of figures 
Figure 1 SARS-CoV-2 viral load in naturally infected patients by qPCR and culture. .......................... 37 
Figure 2 Outcomes of 20,133 hospitalised COVID-19 patients by age ................................................ 44 
Figure 3 Frequency of individuals with the most common COVID-19 associated symptoms by 
duration. ................................................................................................................................................ 48 
Figure 4 Group and Dose Escalation Scheme...................................................................................... 89 
 
List of Tables 
Table 1 Schedule of Activities ............................................................................................................... 25 
Table 2 Key notes for SoA .................................................................................................................... 29 
Table 3 Frequency of COVID-19 related symptoms in healthy 18-30 year olds with PCR-confirmed 
infection ................................................................................................................................................. 46 
Table 4 Duration of COVID-19 related symptoms in healthy 18-30 year olds with PCR-confirmed 
infection. ................................................................................................................................................ 47 
Table 5 Representative risk assessments using QCOVID ................................................................... 50 
Table 6: Risk Assessment ..................................................................................................................... 58 
Table 7 - Study Interventions ................................................................................................................ 80 
Table 8: Permitted medications and restrictions ................................................................................... 87 
Table 9 Prohibited Medications ............................................................................................................. 88 
Table 10 Study Stopping Rules ............................................................................................................ 96 
Table 11 List of symptoms recorded by subjects ................................................................................ 103 
Table 12 Protocol-Required Safety Laboratory Assessments ............................................................ 129 
Table 13 Classification of Adverse Event Severity ............................................................................. 138 
Table 14 Severity grading criteria for physical observations .............................................................. 140 
Table 15 Classification of Adverse Event Relationship ...................................................................... 142 
Table 16 Classification of Adverse Event Outcome ............................................................................ 143 
Table 17 Contact Details for Reporting SAEs ..................................................................................... 144 
 
 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
16 
 
Table of Contents 
Contents 
CLINICAL STUDY PROTOCOL ...................................................................... 1 
Investigator Agreement: ................................................................................... 4 
Protocol History ................................................................................................ 8 
Table of Contents ......................................................................................... 16 
1. 
Protocol Synopsis ....................................................................... 20 
1.1 Protocol Summary .................................................................................... 20 
1.2 Schedules of Activities (SoA) ................................................................... 25 
2. 
Background to Research ............................................................ 32 
2.1 Why is the COVID-19 challenge model so important? ............................ 32 
2.2 Research Strategy ................................................................................... 35 
2.3 Virology of SARS-CoV-2 .......................................................................... 36 
2.4 Virological Correlates of Infection ............................................................ 36 
2.5 Immunology of COVID-19 ........................................................................ 37 
2.6 Clinical outcomes of SARS-CoV-2 infection ............................................ 39 
2.7 Mitigating Risk in Experimental Human SARS-CoV-2 Infection .............. 48 
2.8 Pre-clinical and clinical experience with Remdesivir for COVID-19 ........ 51 
2.9 Pre-clinical and clinical experience with REGEN-COV (Regeneron 
Monoclonal Antibody cocktail) for COVID-19 ................................ 52 
2.10 Human respiratory virus challenge studies in the UK ............................ 53 
2.11 Study Rationale ...................................................................................... 54 
2.12 Research Hypotheses ............................................................................ 56 
2.13 Benefit/Risk Assessment ....................................................................... 57 
2.13.1 Vulnerable persons ............................................................................. 62 
2.13.2 Benefit assessment ............................................................................. 62 
2.13.3 Overall benefit: risk conclusion ........................................................... 62 
2.14 Objectives and Endpoints ...................................................................... 63 
3. 
Study Design ................................................................................ 68 
3.1 Overall Design .......................................................................................... 68 
3.2 Screening Phase ...................................................................................... 68 
3.3 Study Specific Consent ............................................................................ 69 
3.4 Quarantine Phase .................................................................................... 70 
3.5 Follow Up Phase ...................................................................................... 71 
3.6 End of Study Definition............................................................................. 71 
3.7 Study Population ...................................................................................... 71 
3.8 Inclusion Criteria ...................................................................................... 71 
3.9 Exclusion Criteria ..................................................................................... 73 
3.10 Lifestyle Considerations ......................................................................... 79 
3.10.1 Meals and dietary restrictions ............................................................. 79 
3.10.2 Caffeine, alcohol and tobacco ............................................................. 79 
3.10.3 Activity ................................................................................................. 79 
3.11 Screen Failure ........................................................................................ 79 
4. 
Study Intervention(s) ................................................................... 80 
4.1 Summary of Study Intervention(s) Administered ..................................... 80 
4.2 
SARS-CoV-2 Challenge Virus ....................................................... 83 
4.2.1 Provenance of the wild type SARS-CoV-2 challenge virus .................. 83 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
17 
 
4.2.2 Justification for treatment dose and route of administration ................. 83 
4.2.3 Supply and accountability of challenge virus ........................................ 83 
4.2.4 Storage of challenge virus .................................................................... 83 
4.2.5 Preparation and administration of challenge virus ................................ 84 
4.3 Antiviral Treatment (Remdesivir as Pre-emptive Medication) .................. 85 
4.4 Dose Preparation ..................................................................................... 85 
4.5 Early “Rescue” Therapy ........................................................................... 85 
4.6 Dose Preparation ..................................................................................... 86 
4.7 Handling, Storage, and Accountability ..................................................... 86 
4.8 Randomisation and Blinding .................................................................... 87 
4.9 Study Intervention Compliance ................................................................ 87 
4.10 Concomitant and Prior Therapy ............................................................. 87 
4.11 Dose Escalation, De-escalation and Confirmation ................................ 89 
4.12 Temporary Discontinuation/Temporary Delay in Enrolment .................. 96 
4.12 Participant Replacement Strategy ......................................................... 96 
4.13 Stopping Rules ....................................................................................... 96 
5. 
Study Assessments and Procedures ........................................ 98 
5.1 Medical and Medication History ............................................................... 98 
5.2 Demographics .......................................................................................... 98 
5.3 Height, Weight and Body Mass Index (BMI) ............................................ 98 
5.4 Alcohol Breath Testing ............................................................................. 99 
5.5 Physical Examinations ............................................................................. 99 
5.6 Vital Signs ................................................................................................ 99 
5.7 Temperature ........................................................................................... 100 
5.8 Radiology ............................................................................................... 100 
5.9 Echocardiogram ..................................................................................... 101 
5.10 Electrocardiogram ................................................................................ 101 
5.11 Lung Function ...................................................................................... 101 
5.11.1 Spirometry ......................................................................................... 101 
5.11.2 Forced oscillation technique (FOT) ................................................... 102 
5.12 Patient Health Questionnaire (PHQ-9) and Generalised Anxiety Disorder 
(GAD-7) Questionnaire ................................................................ 102 
5.13 Participant Symptom Diary Card – Clinical scores .............................. 102 
5.14 University of Pennsylvania Smell Identification Test (UPSIT) ............. 103 
5.14 Cognitive Testing ................................................................................. 104 
5.15 Urinalysis .............................................................................................. 105 
5.15 Urine Drugs of Abuse and Nicotine Test.............................................. 105 
5.16 Pregnancy Test .................................................................................... 105 
5.17 Blood Samples ..................................................................................... 105 
5.17.1 Safety blood samples ........................................................................ 106 
5.17.2 Immunology and sero-suitability to challenge virus .......................... 106 
5.18 Respiratory Samples ............................................................................ 106 
5.18.1 Viral load ........................................................................................... 106 
5.18.2 Respiratory pathogen screen ............................................................ 107 
5.18.3 SARS-CoV-2 confirmation of infection for intervention treatment .... 107 
5.18.4 SAR-CoV-2 confirmation of infection endpoint analysis ................... 107 
5.18.5 SARS-CoV-2 discharge process ....................................................... 107 
5.18.6 Post-discharge process .................................................................... 108 
5.19 Environmental Sampling ...................................................................... 108 
5.20 Mask wearing sampling........................................................................ 109 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
18 
 
5.21 Exploratory research ............................................................................ 109 
5.22 Optional Exploratory Non-Interventional Study of Wearable Device ... 110 
6. 
Recording of Adverse Events and Serious Adverse Events. 111 
6.1 Time Period and Frequency for Collecting AE and SAE Information .... 111 
6.2 Method of Detecting AEs and SAEs ...................................................... 111 
6.2.1 Follow-up of AEs and SAEs ................................................................ 111 
6.2.2 Regulatory reporting requirements of SAEs ....................................... 111 
6.3 Reporting of events related to REGEN-COV ......................................... 112 
6.3.1 Pregnancy ........................................................................................... 112 
6.3.2 Disease-related events and/or disease related outcomes not qualifying 
as AEs or SAEs ........................................................................... 113 
6.3.3 Treatment of overdose ........................................................................ 113 
6.4 Safety Oversight Procedures ................................................................. 113 
6.4.1 Procedures to be followed in the event of abnormal findings ............. 113 
6.4.2 Ongoing and interim safety reviews .................................................... 113 
6.4.3 Safety holding rules............................................................................. 114 
6.4.4 Group holding rules ............................................................................. 114 
6.5 Data Safety Monitoring Board ................................................................ 115 
6.6 Trial Steering Committee (also known as Medical Oversight Committee)
 ..................................................................................................... 115 
6.7 Human Challenge Steering Committee ................................................. 115 
6.8 Pharmacokinetics ................................................................................... 116 
6.9 Pharmacodynamics ................................................................................ 116 
7. 
Statistical Methods and Planned ............................................. 117 
7.1 Study Analysis Sets ............................................................................... 117 
7.2 Subgroup Analysis ................................................................................. 117 
7.3 Sample Size ........................................................................................... 118 
7.4 Cohort and Dose Escalation .................................................................. 118 
7.5 Interim Statistical Analysis ..................................................................... 119 
7.6 Statistical Analysis Plan ......................................................................... 119 
7.6.1 Subject Accountability ......................................................................... 120 
7.6.2 Protocol deviations .............................................................................. 120 
7.6.3 Demographic and baseline characteristics ......................................... 120 
7.7 Primary Endpoint Analysis ..................................................................... 120 
7.8 Secondary Endpoint Analysis ................................................................ 121 
7.9 Exploratory Endpoints ............................................................................ 121 
7.10 Safety Analysis ..................................................................................... 121 
8. 
Appendices: Supporting Documentation and Operational 
Considerations ........................................................................... 123 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....... 123 
8.1.1 Regulatory and ethical considerations ................................................ 123 
8.1.2 Financial disclosure ............................................................................. 123 
8.1.3 Funding ............................................................................................... 124 
8.1.4 Informed Consent Process ................................................................. 124 
8.1.5 Confidentiality ...................................................................................... 125 
8.1.6 Data protection .................................................................................... 125 
8.1.7 Indemnity ............................................................................................. 125 
8.1.8 Sponsor ............................................................................................... 125 
8.1.9 Audits .................................................................................................. 125 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
19 
 
8.1.10 Sample and data storage and usage ................................................ 126 
8.1.11 Dissemination of clinical study data .................................................. 126 
8.1.12 Data quality assurance ..................................................................... 126 
8.1.13 Source documents ............................................................................ 127 
8.1.14 Study discontinuation ........................................................................ 127 
8.1.15 Study management and governance ................................................ 127 
8.1.16 Publication policy .............................................................................. 128 
Appendix 2: Clinical Laboratory Tests ......................................................... 129 
Appendix 3: Toxicity Grading Scale for Lab AEs ......................................... 131 
Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting .......................................... 133 
8.4.1 Adverse event ..................................................................................... 133 
8.4.2 Serious adverse event ........................................................................ 133 
8.4.3 Potential adverse events related to SARS-CoV-2 infection ................ 135 
8.4.4 Recording, assessment and follow-up of AE and/or SAE................... 135 
8.4.5 Reporting of SAEs ............................................................................... 144 
8.4.6 Adverse reactions to non-IMPS .......................................................... 145 
8.4.7 Post-study AEs and SAEs .................................................................. 145 
8.4.8 Pregnancy ........................................................................................... 145 
Appendix 5: Normal Ranges ........................................................................ 147 
Appendix 6: Abbreviations ........................................................................... 148 
9. 
References ................................................................................. 151 
 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
20 
 
1. Protocol Synopsis 
1.1 Protocol Summary 
This is a dose optimisation study in healthy adults aged 18-30 who will be experimentally 
inoculated with SARS-CoV-2.  The aim is to cause PCR-confirmed upper respiratory infection 
in the majority of challenged individuals with minimal or no illness, providing data on the course 
of COVID-19 and the immune response to SARS-CoV-2 infection. This will establish an 
optimised dose and study design that will then be used to evaluate the efficacy of treatment 
and vaccine candidates plus level and duration of immune protection in follow-on trials. 
Title of the study 
A dose finding human experimental infection study in healthy 
subjects using a GMP-produced SARS-COV-2 wild type strain 
(SARS-CoV-2 Characterisation Study) 
Protocol number 
COVHIC001 
Estimated 
Timelines: 
January 2021 – June 2022 
Sites/Location: 
A single centre study carried out in a high containment unit at the 
Royal Free Hospital, London. Follow Up visits are being carried out at 
the Queen Mary BioEnterprises (QMB) Innovation Centre, London 
Challenge virus: 
SARS-CoV-2, intranasally 
Potential 
Intervention 
treatment 
Pre-emptive therapy - VEKLURY™ (Remdesivir) 
Rescue therapy – REGEN-COV™ (Regeneron Monoclonal Antibody 
cocktail) 
Study Outline 
This is a dose optimisation study in which escalating or de-escalating 
doses of wild-type SARS-CoV-2 (starting at 1x101 TCID50) will be 
given via nasal administration to different groups of volunteers in 
order to achieve a ≥50% attack rate (ideally between 50% and 70%), 
as determined by positive qPCR detection (viral load ≥LLOQ) in 
respiratory secretions (mid-turbinate swabs and/or throat swabs) at 
two consecutive 12 hourly time points.  
For initiation of each new dose level, up to 10 subjects will be included 
in the first cohort, with a sentinel group of 3 subjects initially assessed 
for safety and infectivity by the investigators, before proceeding with 
subsequent inoculations.  
A Data Safety Monitoring Board will review safety and quantitative 
virology after each cohort and will recommend continuation, dose 
escalation or de-escalation based on emergent data. A Trial Steering 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
21 
 
Committee (also known as the Medical Oversight Committee) will 
provide overall supervision of the project. 
Subjects may be given SARS-CoV-2 intervention treatment, 
depending on the stage of the study.  
Initially, subjects, upon evidence of infection, will be treated with a 
pre-emptive antiviral IV Remdesivir for five days.  
Subsequent cohorts, may include one of the following treatment 
plans: 
 
Pre-emptive therapy, upon evidence of infection 
(Remdesivir), 
 
Early “rescue” therapy, once disease progression criteria are 
met. 
 
No pre-emptive or “rescue” therapy 
Alternative treatments may be included that have shown compelling 
evidence of efficacy against SARS-CoV-2, if available, such as the 
IV REGEN-COV monoclonal antibody cocktail.  
Decisions on treatment plans for cohorts of subjects will be made by 
the CI/PI, and in discussion with the DSMB 
Subjects will remain in quarantine for a minimum of 14 days in a 
quarantine clinical trials unit (from inoculation), and until these criteria 
are met: 
 
For subjects with evidence of infection: 
o Two consecutive swabs with qPCR Ct >33.5 AND 
negative culture. 
o Lateral flow tests may be used in place of culture, if 
culture data is not available 
o A qualitative PCR may be used in place of quantitative 
PCR, if the latter is not available. 
o At the PI’s discretion if protracted quarantine is deemed 
to be causing harm to the participant’s mental or physical 
health and no viable virus is detected by culture or a 
lateral flow test is negative. 
 
For non-infected subjects: 
o 2 consecutive swabs with undetectable virus by PCR 
only prior to discharge. 
Population  
Sero-suitable healthy male and female volunteers 18-30 years of age 
(inclusive) with no known risk factors for severe COVID-19 
Number of Subjects up to 90  
Duration 
of 
Participation  
The total duration of study for participants is estimated approximately 
377 days from admission to the completion of last follow up visit. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
22 
 
Inclusion Criteria 
Healthy adults ages 18-30 years who are seronegative for SARS 
COV-2 antibodies and have no known risk factors for severe COVID-
19 
Exclusion 
Criteria 
(specific 
to 
the 
nasal challenge) 
Any significant abnormality altering the anatomy of the nose or 
nasopharynx, clinically significant history of epistaxis (nose bleeds) or 
any nasal or sinus surgery within six months of inoculation 
Estimated duration 
of the study  
The Sponsor estimates that the study will require approximately 52 
weeks from the time the first participant signs the informed consent 
until the last study related follow up.  
Primary 
Objective 
/Endpoint 
 
To identify a safe and infectious dose of wild type SARS-CoV-2 in 
healthy volunteers, suitable for future intervention studies, that: 
 
has an acceptable safety profile as measured by: 
o Occurrence of Adverse Events (AEs) within 30 days 
post-viral challenge (Day 0) up to Day 28 follow up. 
o Occurrence of Serious Adverse Events (SAEs) from 
the viral challenge (Day 0) up to Day 28 follow up.  
 
induces laboratory confirmed infection in ≥50% of participants 
(ideally between 50% and 70%). Laboratory confirmed 
infection is defined by:  
o Two 
quantifiable 
greater 
than 
lower 
limit 
of 
quantification 
(viral 
load 
≥LLOQ) 
RT-PCR 
measurements from mid turbinate and/or throat 
samples, reported on 2 or more consecutive 
timepoints, starting from 24 hours post-inoculation and 
up to discharge from quarantine. 
Secondary 
Objectives/endpoint 
 
To further assess SARS-CoV-2 viral infection rates in upper 
respiratory samples by qRT-PCR and cell culture  
 
To assess the incidence of symptomatic SARS-CoV-2 infection  
 
To assess the SARS-CoV-2 viral dynamics in upper respiratory 
samples (AUC, peak, duration, incubation period)  
 
To assess the SARS-CoV-2 induced symptoms (Sum, AUC, 
peak, peak daily, frequency) 
 
To assess the incidence of SARS-CoV-2 illness (Upper 
Respiratory Tract illness [URTI], Lower Respiratory Tract illness 
[LRTI], Systemic Illness (SI), Febrile Illness [FI], grade 1, 2 & 3 
symptoms) 
A full description of secondary endpoints is detailed in sections 2 and 
7. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
23 
 
Exploratory/Tertiary 
Objectives 
/ 
Endpoints 
 
To explore the safety of the wild type SARS-CoV-2 human 
challenge model (smell, cognition, pulmonary changes [CT, 
spirometry, FOT], safety laboratory tests, blood type, concomitant 
medications) 
 
To explore SARS-CoV-2 viral infection rates in saliva, by qRT-
PCR and cell culture 
 
To explore the SARS-CoV-2 viral dynamics in saliva, by qRT-PCR 
and cell culture (AUC, peak, duration, incubation period)  
 
To explore the host-pathogen relationship in the SARS-CoV-2 
human challenge model (including humoral and cellular immunity, 
proteomics, transcriptomics, host and viral genomics, microbiome 
and systems biology) 
 
To explore the Minimal Clinically Important Difference (MCID) in 
instrument change (e.g. Symptom diary cards) 
 
To explore environmental contamination in the SARS-CoV-2 
human challenge model (quantitation and detection of virus in air 
sampling, exhaled breath and surface swabbing) 
A full description of exploratory/tertiary endpoints is detailed in 
sections 2 and 7. 
Sample size 
The primary objective of the study is to identify a safe and infectious 
dose of wild type SARS-CoV-2 in healthy volunteers, suitable for 
future intervention studies. No formal sample size calculation has 
been performed for this early-stage dose finding study. However, a 
sample size of up to an expected 30 subjects for a dose level and 
treatment regimen (made up of 3 cohorts of up to an expected 10 
subjects, including the dose expansion cohort) with a total of up to 90 
subjects overall, is felt sufficient to meet the primary objective of 
escalating/expanding the dose in a safe manner whilst providing 
information on the attack rate.  
Statistics 
The following analysis sets are defined for this study: 
 
Full Analysis Set (FAS) is defined as all subjects that are 
inoculated with wild-type SARS-COV-2 challenge virus. The 
FAS will be considered as the primary analysis set for all 
primary, secondary and exploratory endpoints. 
 
Safety Analysis Set is defined as all subjects that are 
inoculated with wild-type SARS-COV-2 challenge virus. The 
Safety Analysis Set is identical to FAS and will be used for all 
safety endpoints. 
 
Per Protocol (PP) Analysis Set is defined as all FAS subjects 
that are sero-suitable, who have no major protocol deviations 
and who complete the quarantine period up to the final day of 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
24 
 
quarantine (study Day 14). The PP Analysis Set will be 
considered as the secondary analysis set for pre-specified 
primary, secondary and exploratory endpoints. 
Membership of subjects in each analysis set will be determined at a 
planned data review meeting (DRM), prior to any analysis and 
database lock. A ‘Laboratory confirmed infected’ subgroup will be 
identified and will be presented for certain pre-specified analyses. 
Primary, secondary and exploratory endpoints will be summarised 
using descriptive statistics. Continuous variables will be summarised 
using 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). A 95% confidence interval may be presented for certain 
pre-specified endpoints.  
Methods for dealing with missing data in the study analysis will be 
described within the Statistical Analysis Plan (SAP).  
Keywords 
SARS-CoV-2, COVID-19, immune, virus, viral challenge, viral lung 
disease, infection 
 
A list of abbreviations used in this document can be found in Appendix 6.


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
25 
 
1.2 Schedules of Activities (SoA) 
Table 1 Schedule of Activities 
  
Study Phase 
Screening  
Day -90 to Day -3 
Inpatient Quarantine  
Extended stay days 
Day 15. - 27 
Day 28 (+/- 3 days) 
Day 90 (+/- 7 days) 
Day 180 (+/- 14 days) 
Day 270 (+/- 14 days) 
Day 360 (+/- 14 days) 
Early withdrawal  
Study Day 
D-2 
D-1 
Day 0 Pre 
D0 Challenge 
Day 0 Post 
D1  
D2 
D3 
D4 
D5 
D6 
D7 
D8  
D9 
D10 
D11 
D12 
D13 
D14 
Written consent 
X* 
X
Eligibility criteria (+) 
X 
Xk* 
X 
Medical & medication 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Change in medical and 
medication history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X X
X
X X
Demographics 
X 
Height & weight, BMI (a)
X 
Xk 
 
 
 
 
 
Patient 
Health 
Questionnaire (PHQ-9)
(X) 
Xk 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
XW 
 
 
 
 
 
 
Generalised 
Anxiety
Disorder Questionnaire 
(GAD-7) 
(X) 
Xk 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
XW 
 
 
 
 
 
 
Alcohol breath test 
X 
Xk 
X 
X X
Urinalysis 
X 
Xk 
X 
X 
X 
X 
X 
X X
X
X X
Urine drugs of abuse & 
nicotine screen 
X 
Xk 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X X
Urine pregnancy test 
X 
X 
X 
X 
X X


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
26 
 
  
Study Phase 
Screening  
Day -90 to Day -3 
Inpatient Quarantine  
Extended stay days 
Day 15. - 27 
Day 28 (+/- 3 days) 
Day 90 (+/- 7 days) 
Day 180 (+/- 14 days) 
Day 270 (+/- 14 days) 
Day 360 (+/- 14 days) 
Early withdrawal  
Study Day 
D-2 
D-1 
Day 0 Pre 
D0 Challenge 
Day 0 Post 
D1  
D2 
D3 
D4 
D5 
D6 
D7 
D8  
D9 
D10 
D11 
D12 
D13 
D14 
Complete 
physical
examination 
X 
Xk 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
X 
(X)W 
 
X 
X X
X
X X
Directed 
physical
examination (inc nasal)
 
 
X 
 
X
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
Vital signs (HR, RR, 
SBP, DBP, SpO2 (b) (n)
X 
(X) QDS
QDS 
QDS QDS QDS QDS QDS QDS QDS QDS QDS QDS QDS QDS QDS QDSx QDSx
 
X 
X X
X
X X
Tympanic temperature 
(n) 
X 
(X) QDS
QDS 
QDS QDS QDS QDS QDS QDS QDS QDS QDS QDS QDS QDS QDS QDSx QDSx
 
X 
X X
X
X X
Symptom diary cards 
 
(X) TDS
TDS 
TDS TDS TDS TDS TDS TDS TDS TDS TDS TDS TDS TDS TDS TDSx TDSx
 
 
 
 
 
 
Smell Test (UPSIT) 
 
 
Xu 
 
 
 
Xu 
 
 
Xu 
 
 
Xu 
 
 
Xu 
 
 
Xu 
 
(X) 
 
Xu Xu Xu Xu Xu
Cognitive Tests 
 
 
Xv 
Xv
 
 
Xv 
Xv 
Xv 
Xv 
Xv 
Xv 
Xv 
Xv 
Xv 
Xv 
Xv 
Xv 
Xv 
Xv 
 
 
Xv Xv Xv Xv Xv
Chest X-ray (p) 
Xk 
Lung CT scan 
X0 
X0 
X0 
X0 
Echo (p) 
Xk 
12-lead ECG (n) 
X 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
X X
X
X X
Spirometry (c) 
X 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
X X
X
X X
FOT (c) 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
X X
X
X X
Telephone calls(r) 
X
Product Administration 
Challenge Virus 
inoculation 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
27 
 
  
Study Phase 
Screening  
Day -90 to Day -3 
Inpatient Quarantine  
Extended stay days 
Day 15. - 27 
Day 28 (+/- 3 days) 
Day 90 (+/- 7 days) 
Day 180 (+/- 14 days) 
Day 270 (+/- 14 days) 
Day 360 (+/- 14 days) 
Early withdrawal  
Study Day 
D-2 
D-1 
Day 0 Pre 
D0 Challenge 
Day 0 Post 
D1  
D2 
D3 
D4 
D5 
D6 
D7 
D8  
D9 
D10 
D11 
D12 
D13 
D14 
Administration of 
SARS-CoV-2 
intervention treatment 
 
 
 
 
 
 
 
 
(X) y 
 
 
 
 
 
 
 
Collection of blood samples 
Serum β-HCG 
pregnancy test (all 
females) (e) 
 
Xk* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, Hepatitis A, B, & C
X 
Xk 
Thyroid function test 
X 
Xk 
Coagulation 
(including d-dimer) 
X 
Xk 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
 
X 
X X
X
X X
Haematology (f) 
X 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
X X
X
X X
Biochemistry  
X 
Xk 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
X X
X
X X
Cardiac enzymes 
(including high 
sensitivity Troponin) 
X 
Xk 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
 
X 
X X
X
X X
Blood - Antibodies 
SARS-CoV-2 
X 
Xk 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X X
X
X X
Blood - plasma markers 
(h) (g) 
 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X X
X
X
Blood paxgene RNA 
Xk 
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X
X
X
Blood Lithium Heparin 
– PBMCs, other blood 
cells, +/- plasma  
 
Xk 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
X X
X
X


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
28 
 
  
Study Phase 
Screening  
Day -90 to Day -3 
Inpatient Quarantine  
Extended stay days 
Day 15. - 27 
Day 28 (+/- 3 days) 
Day 90 (+/- 7 days) 
Day 180 (+/- 14 days) 
Day 270 (+/- 14 days) 
Day 360 (+/- 14 days) 
Early withdrawal  
Study Day 
D-2 
D-1 
Day 0 Pre 
D0 Challenge 
Day 0 Post 
D1  
D2 
D3 
D4 
D5 
D6 
D7 
D8  
D9 
D10 
D11 
D12 
D13 
D14 
Collection of respiratory and environmental. Samples 
Nasopharyngeal swab- 
Respiratory pathogen 
screen - e.g. Biofire (i) 
(X) 
X (X)m  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nasopharyngeal swab- 
tolerance test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nasosorption – 
immunology & virology 
(q) 
 
 
BD
X 
 
X
BD
BD
BD
BD
BD
BD
BD
BD
BD
BD
BD
BD
BD 
BDx 
BDx 
 
X 
X X
X
X X
Saliva-virology (j) (g) 
X 
BD
BD
BD
BD
BD
BD
BD
BD
BD
BD
BD
BD
BD 
BDx 
BDx 
X 
X
Throat FLOQ swab - 
Virology (j) (g) 
 
 
X 
 
 
 
BD
BD
BD
BD
BD
BD
BD
BD
BD
BD
BD
BD
BD 
BDx 
BDx 
 
X (X)(X)  
 X
Mid turbinate FLOQ 
swab - Virology (j) (g) 
(m) 
 
 
X 
 
 
 
BD
BD
BD
BD
BD
BD
BD
BD
BD
BD
BD
BD
BD 
BDx 
BDx 
 
X (X)(X)  
 X
Mid turbinate and/or 
nasopharyngeal swab 
for cells for RNA (g) 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Mask wearing sampling 
(s) 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
 
 
 
 
 
 
Environmental viral 
sampling (t) 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
 
 
 
 
 
 
Safety Assessments 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
29 
 
  
Study Phase 
Screening  
Day -90 to Day -3 
Inpatient Quarantine  
Extended stay days 
Day 15. - 27 
Day 28 (+/- 3 days) 
Day 90 (+/- 7 days) 
Day 180 (+/- 14 days) 
Day 270 (+/- 14 days) 
Day 360 (+/- 14 days) 
Early withdrawal  
Study Day 
D-2 
D-1 
Day 0 Pre 
D0 Challenge 
Day 0 Post 
D1  
D2 
D3 
D4 
D5 
D6 
D7 
D8  
D9 
D10 
D11 
D12 
D13 
D14 
AE recording 
X 
X
SAE recording 
X 
X
Concomitant 
medications 
X 
 
X
 
Table 2 Key notes for SoA 
X 
Once 
BD 
Twice Daily. 
The timing of the baseline assessment will be the guide to establish the windows for subsequent measurements. For scheduling purposes, the baseline 
assessment will be defined as the first day when BD measurements are performed. Subsequent sampling/measures will be performed at the same time ± 1 
hour. 
TDS 
Three times daily.  
The timing of the baseline assessment will be the guide to establish the windows for subsequent measurements. For scheduling purposes, the baseline 
assessment will be defined as the first day when TDS measurements are performed. Subsequent sampling/measures will be performed at the same time ± 1 
hour. 
QDS 
Four times daily. 
The timing of the baseline assessment will be the guide to establish the windows for subsequent measurements. For scheduling purposes, the baseline 
assessment will be defined as the first day when QDS measurements are performed. Subsequent sampling/measures will be performed at the same time ± 1 
hour. 
T 
To determine tolerance of the procedure only (sample will not be tested). 
+ 
Only the applicable Inclusion/Exclusion criteria will be reviewed at each time point. 
a 
Height will be taken at Screening only. 
b 
Vital signs will be taken at the same time each day (± 1 hour). 
c 
Lung function measures will be performed at the same time each day during quarantine (± 1 hour). 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
30 
 
d 
A serum follicle stimulating hormone (FSH) test will be performed in all post-menopausal women 
e 
Blood serum pregnancy test (ß-HCG) will be performed in all female subjects 
f 
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). 
g 
Samples for related exploratory research 
h 
Virus serology will be performed to determine eligibility and seroconversion.  
i 
Nasopharyngeal swab for respiratory virus screen to assess for the presence of other respiratory viruses; if found positive the subject will not be eligible for the 
current quarantine.  
j 
Post inoculation Nasal virology samples will be collected and used for RT-qPCR and viral culture assay (as appropriate).  Samples may be used for related 
exploratory research 
k + k* 
Can be performed on Study Day -2 or Study Day -1. Special Note: k* Serum pregnancy test should be performed on either day -2 or -1, prior to Urine Pregnancy 
Test on Day 0 (pre-inoculation). 
l 
Study specific consent may occur on admission, providing all required eligibility information has been collected through the HRA approved study specific Screening 
process 
m 
If for the study, mid turbinate FLOQ swabs are not available (e.g. national shortage), nasopharyngeal FLOQ swabs may be taken as a viable alternative. The 
study should endeavor to be consistent in swab type across all the participants. 
n 
Assessments may additionally be continuously monitored (e.g. core temperature; vital signs (HR, RR, SBP, DBP, SpO2), activity, sleep, ECG) as per Section 5. 
o 
CT scan to be performed in all participants on day 5 or 6 and Day 10 or 11 dependent upon scanner availability; CT scan to be performed only in participants with 
PCR confirmed infection or symptoms consistent with COVID-19. 
p 
Chest X-Ray and ECHO will be obtained on Admission to quarantine on Day-2/Day-1.  Radiology assessments will not be repeated in the scenario where a 
subject is reinvited to attend a later Admission/Quarantine. 
q 
Two sets of nasosorption will be taken at each time point. Each set consists of 2 nasosorptions, 1 for each nostril (i.e. total of 4 nasosorption devices per time 
point). Timing between sampling of the sets should be at least 5 minutes apart. Samples may be used for: cytokines/chemokines, sIgA, and virology, as well as 
stored for future usage 
r 
Telephone calls with participants every 2 to 3 days 
s 
Participant will be asked to wear a single-use facemask for 60 – 90 minutes, 1 – 3 times a day to capture exhaled virus 
t 
Environmental viral sampling may be performed in rooms up to twice a day 
u 
The UPSIT is designed to be self-administered after explanation of the test by study staff and will be performed once before virus inoculation and then at least 
every third day starting from Day 1, though the test can be conducted more frequently at the discretion of the PI/study physician. If at Day 28 anosmia has 
subsided and smell has returned the UPSIT test can stop. If anosmia is still present UPSIT should continue until resolution or the end of the study. 
v 
Once daily, at the same time each day (+/- 1 hour) during quarantine and similar timing where possible during follow-up visits 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
31 
 
w 
Before discharge from quarantine each participant will undergo a complete physical examination (the date of this may vary dependent upon length of stay) and 
repeat GAD-7 and PHQ-9 questionnaires once. 
x 
Procedures should be performed at the appropriate scheduled timings, up until the point of discharge. 
y 
Subjects may be given SARS-CoV-2 intervention treatment, depending on the stage of the study. Treatment plans for subjects include one of the following: 
 
Pre-emptive therapy, upon evidence of infection (Remdesivir, once daily IV for 5 days) 
 
Rescue therapy, once disease progression criteria is met (e.g., REGEN-COV, once IV) 
 
No pre-emptive or rescue therapy 
Notes: 
Parenthesis indicates the assessment may be optional, or at the PI's discretion.  
Study specific consent may occur on the day of admission, providing all required eligibility information has been collected and the study fully explained to the 
participant through earlier screening visits and remote appointments process 
For all subjects QDS/TDS assessments on Day 0, the first assessment will be pre-virus challenge. 
The PI may perform additional safety assessments as required. 
Where any nasal sampling time points occur together, the order of sampling will typically be (1) Nasosorptions followed by (2) mid turbinate swab (3) 
Nasopharyngeal swab. 
 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
32 
2. Background to Research 
In the current COVID-19 emergency, controlled SARS-CoV-2 human infection has the potential 
to accelerate our understanding of pathogenesis, induction of immunity and immune mechanisms 
of resistance to disease, as well as a means to rapidly test novel diagnostics, treatments and 
vaccines, especially between waves of the pandemic, when occurrence of natural disease is 
relatively uncommon. Specifically, it will enable efficient early-stage testing of the many vaccine 
candidates in development so that the most promising can go forward quickly enough to large-
scale field efficacy trials to meaningfully tackle the ongoing pandemic. Early cost-benefit modeling 
suggested that a SARS-CoV-2 human infection challenge study used to test vaccine efficacy 
could accelerate approval, potentially averting an additional 1.1 million infections and 8,000 
deaths in the USA alone, compared to the next best clinical trial design (i.e. field trials with natural 
infection) (Berry et al., 2020). While this is not needed for the first generation of SARS-CoV-2 
vaccines that are now becoming available, these types of studies remain important.  Although first 
generation vaccines are disease-modifying, their transmission-blocking potential and longevity of 
protection are unknown and will need to be tested and improved upon. Greater efficacy in older 
adults and other high-risk groups, will almost definitely be required and it still remains unclear 
whether first generation vaccines will protect against severe disease as well as mild/moderate 
illness, the early trials having only enrolled small numbers in each of these subgroups. 
Furthermore, antivirals and monoclonal antibodies will still be needed for those who remain 
unvaccinated, become infected in spite of vaccination or cannot mount effective immune 
responses. In addition, the controlled nature of these studies can provide definitive answers to 
questions about protective immunity that cannot be achieved with episodic and sporadic natural 
infections, which will be critical for effective public health strategy. These studies have had expert 
(Eyal et al., 2020; Plotkin and Caplan, 2020) and public support (Gbesemete et al., 2020), but to 
reach these diverse goals, a safe and reproducible SARS-CoV-2 infection model must be first 
established. 
No alternative study design exists that can so rapidly provide clinical readouts using small 
numbers of volunteers in a controlled setting. With the roll-out of first-generation vaccines many 
middle-aged and older adults will be immune (at least for a period of time) and natural 
transmissions will fall. Field studies will therefore become increasingly unfeasible and only trials 
that can support extremely large sample sizes will be conducted. This includes household 
transmission studies, which also lack control (due to unmeasurable variations in viral strain, 
inoculum size, environmental and host factors) and make conclusive interpretation of resulting 
data highly challenging. In any case, these types of studies cannot be used to accelerate testing 
of vaccines or prophylaxis due to the sporadic and unpredictable nature of transmission.  
 
2.1 Why is the COVID-19 challenge model so important? 
There are many aspects of COVID-19 infection that scientists still don’t understand. The human 
challenge study may be the only way to get this information. We believe that the information 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
33 
obtained in the challenge study will have important public health benefits and play a significant 
role in the ongoing management of the pandemic. 
 
1. The “incubation period” of COVID-19 is the time from initial coronavirus exposure to the onset 
of symptoms and when people are most infectious. A human challenge study is the only way 
to accurately measure how long the incubation period is, and will assist and inform future track 
and trace efforts. 
2. A human challenge study will allow us to accurately measure how long people are infectious, 
from first exposure to the virus being cleared. This will determine exactly how long self-
isolation (quarantine) periods should be after exposure. 
3. Reinfection means a person was infected (got sick) once, recovered fully, and then later 
became infected for a second time. Based on what we know from similar viruses, some people 
could catch COVID-19 more than once. A human challenge study will help answer a number 
of important questions on re-infection, including how long natural immunity can protect people 
from re-infection; what makes people more at risk of re-infection; and whether re-infected 
people can spread the virus to others. A human challenge study will enable future testing of 
vaccines and antiviral treatments. A key question for new vaccines is whether they stop people 
carrying and spreading the virus as well as preventing symptoms.  
4. Many people infected with coronavirus have no symptoms (asymptomatic) and are a major 
cause of spreading the infection because they are unaware they are infected.   A human 
challenge study will allow researchers to learn much more about asymptomatic infection and 
importantly if vaccines can prevent it.  
 
 
Rationale: SARS-CoV-2 human infection challenge provides critical knowledge about the 
course of infection to guide public health measures, and accelerate vaccine and 
therapeutics development. This is achieved enabling small, rapid efficacy studies to 
compare and triage novel candidates in the face of increasing limitations to implementing 
field efficacy trials.  
 
Why conduct human challenge now vaccines are available? First generation SARS-
CoV-2 vaccines are now available. However, even with effective vaccines, SARS-CoV-2 
will almost definitely become endemic and repeated outbreaks will occur. The 
establishment of this model is therefore still critical to accelerate the development of next-
generation SARS-CoV-2 vaccines, test antivirals and monoclonal antibodies, understand 
immunity against coronaviruses, and prepare for viral mutation or future pandemics. 
 
Why are the first-generation vaccines not good enough? There is currently no antiviral 
treatment that works well to treat severe COVID-19. Improved vaccines are also still 
required that: 
 
1. definitively block transmission 
2. are deliverable to low resource settings (without cold chain or facilities/manpower 
to provide injections) 
3. can be administered with a single or smaller dose 
4. can provide cross-strain protection that will be needed as the virus mutates.  


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
34 
 
There is significant interest from vaccine producers with novel vaccine candidates not yet 
in field trials to use the challenge model to quickly determine proof of concept for their 
vaccine and/or provide supportive efficacy data to apply for emergency licensure of 
the vaccine.  
 
Why do we need to know about immune protection? Human challenge will answer 
critical questions about what type or level of immunity (after natural infection or 
vaccination) confers protection and how long the protection will last. Knowing this will have 
immediate public health impacts, including risk to individuals of infection/re-infection, 
choice of vaccines, and decisions on timing of vaccination and re-vaccination.  
 
Why not do field trials instead? Field trials of all kinds will become increasingly difficult 
and slow to conduct once widespread vaccination begins and natural infections decrease. 
Human challenge studies may therefore become the only way to test efficacy for most 
candidates (with young adults being last and least likely to be vaccinated) and to 
definitively understand the strength of immune protection quickly enough to make an 
impact on public health strategy. 
 
 
What will this first study immediately enable? This virus characterisation study is the 
key to enabling dependent studies. The following are already funded and will follow on 
immediately once we have preliminary results: 
1. The Vaccines Taskforce is funding studies to compare vaccine candidates head-
to-head against licensed vaccine(s). These will identify next-generation vaccines, 
formulations or dosing regimens that better address global needs and are planned 
to start in May 2021. 
2. The Department of Health and Social Care have funded a study led by the 
University of Oxford to show whether previously-infected people are immune to re-
infection and what level of antibodies equates to protection. 
3. The Wellcome Trust have pledged funding of the manufacture of further SARS-
CoV-2 challenge virus stocks that will be shared freely with investigators around 
the world to boost this research. 
 
How is this research relevant to patients? While young healthy adults may not fully 
recapitulate high risk groups, they provide a benchmark for optimal protective immunity 
and are highly suitable for antiviral and monoclonal antibody testing. People in this age 
group are also likely to be the main drivers of continuing pandemic transmission once 
older adults are vaccinated and will be the main target for vaccines that aim to prevent 
asymptomatic transmission by reduction of viral shedding in the upper respiratory tract. 
 
What are the risks to volunteers? Young healthy adults in the 18-30 year old age are at 
low risk of severe outcomes following COVID-19. As of 6th November 2020 in England and 
Wales, 95 individuals in this age range have died due to COVID-19, but most had risk 
factors. Risk of hospitalisation in this age group (without accounting for co-morbidities) 
has recently been estimated at 0.08-0.39%. Protracted symptoms (“long COVID”) can 
occur but are less common in young people with mild disease, almost always resolving 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
35 
within 4 months. This study is fully indemnified with no upper limit if a participant becomes 
unexpectedly unwell. 
 
What risk mitigations are in place? Since there may have been rare cases of severe 
disease in 18-30 year olds with no underlying risk factors, the following risk mitigations will 
be put in place to maximally limit the possibility of severe outcomes: 
1. The first-in-human virus characterisation study will be performed by an expert 
team with extensive respiratory virus human challenge experience. 
2. Inclusion/exclusion criteria will select the first participants with the lowest risk 
based on objective UK data with regular review as new data emerges. However, 
the DSMB will formally assess the criteria to maximise inclusion as soon as the 
challenge infection has been shown to be safe and well-tolerated. 
3. Dose finding will be performed in a cautious staged manner, starting with the 
lowest reliably quantifiable dose of 10 TCID50 using a GMP-manufactured virus. 
4. Intervention treatment (e.g. pre-emptive or rescue therapy) will be used as 
appropriate, when compelling evidence for efficacy of specific treatments exists 
and such treatments are available for use. Pre-emptive treatment occurs at a 
defined timepoint related to infection diagnosis; “rescue” therapy occurs at a 
timepoint related to disease progression. Participants will be quarantined at the 
Royal Free Hospital after inoculation and continuously monitored for 
unexpectedly severe symptoms. If necessary, they will have full access to world-
class NHS care by a highly experienced clinical team. 
5. Participants will be followed up for 12 months to monitor for protracted symptoms 
and managed appropriately (with specialist referral if necessary). 
2.2 Research Strategy 
The two endpoints in a human challenge model which could provide hard evidence in evaluation 
of vaccines and other interventions are (i) virological (i.e. quantified evidence of infection of the 
participant) and (ii) disease-based (i.e. a measure of symptom intensity in the participant). A 
significant proportion of natural SARS-CoV-2 infections are asymptomatic, and at the present time 
the force of infection, probability of disease given infection, and the host and microbial factors 
which determine progression from infection to disease are not defined. In view of this, and so that 
the risk of associated morbidity is minimized, the Key Protocol & Research Contributors agreed 
that measurement of viral concentrations within the upper respiratory tract (URT) would provide 
the safest and most reliably-defined endpoint, rather than a measured symptom/disease-based 
read-out.    
The current study design is therefore a dose titration to identify the virus dose that is safe and 
well tolerated while resulting in reproducible levels of SARS-CoV-2 viral infection in the URT and 
immune responses in inoculated subjects, without necessarily inducing symptoms. 
In order to develop SARS-CoV-2 human challenge studies, a comprehensive review of potential 
safety concerns and risk mitigation is necessary. To ensure the safety of the challenge model 
participants, it is also paramount that the challenge virus be produced compliant with Good 
Manufacturing Practice (GMP) and the manufacturing and testing processes subject to detailed 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
36 
regulatory review and approval.  Inclusion criteria must take account of the population risk for the 
selected group (including age, demographics and co-morbidities). The challenge study must be 
conducted in a fully equipped clinical study unit with appropriate containment conditions and 
under the care of experienced medical and nursing staff. Additionally, research subjects must be 
closely monitored using state of the art medical monitoring including CT imaging to sensitively 
identify changes in the lung.  
2.3 Virology of SARS-CoV-2 
SARS-CoV-2 is an enveloped positive sense single-stranded RNA virus with a genome of 
approximately 29,000 nucleotides in length. SARS-CoV-2, along with SARS1 (the cause of SARS 
in 2002-3), are members of the genus Betacoronavirus, subgenus Sarbecovirus. SARS-CoV-2 
shows 79% nucleotide similarity with SARS1 virus but is suggested to be most closely related to 
the horseshoe bat Sarbecovirus, RaTG13, having diverged from this around 40-70 years ago. It 
is likely that SARS-CoV-2 has been circulating in bats and intermediate species (possibly the 
pangolin) before crossing into humans in Hubei province of China in late 2019.  
SARS-CoV-2 enters a human host cell by binding to the human angiotensin-converting enzyme 
2 (ACE2) receptor with the viral spike (S) protein via the spike receptor binding domain (RBD). 
Since January 2020, SARS-CoV-2 has spread globally. It has a relatively low mutation rate of 
around 2.5 mutations/genome/month (similar to other coronaviruses), but the rapid global 
expansion has resulted in the accumulation of over 2,000 known mutations within the viral 
genome. The significance of these mutations to pathogenesis and transmission is not yet clear 
and require further study. However, recent mutations in strains transmitted from mink have shown 
changes in recognition by S protein-specific antibodies, highlighting the risk that viral mutation 
may lead to immune evasion and therefore reduction in protective efficacy of first generation 
vaccines based on the sequences of early viral isolates.  Furthermore, emerging data from the 
UK suggests a new variant that potentially can transmit more readily but it is unclear at this point 
if this is associated with any change in virulence or significant antigenicity changes.  Typically, as 
viruses evolve to more readily transmit between their hosts this is more often associated with a 
decrease in virulence.  
2.4 Virological Correlates of Infection 
Figure 1 shows SARS-CoV-2 viral load in the upper respiratory tracts of naturally infected 
symptomatic patients by qPCR and culture. The highest viral loads, are observed in the first 14 
days after onset of symptoms. With respect to recovery from infection, many people have viral 
RNA (detected by swab PCR test on a nasal sample) but do not shed live virus that can be grown 
in a lab or infect others. The loss of viral infectivity happens at around day 8-9 (van Kampen et 
al., 2020), when the viral load (detected by PCR) is in decline and antibody is starting to appear. 
A qPCR Ct value >35 has been presented to the New and Emerging Respiratory Virus Threats 
(NERVTAG) committee as associated with lack of infectivity (Wendy Barclay and Peter 
Openshaw, Imperial College London, personal communication). 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
37 
 
Figure 1 SARS-CoV-2 viral load in naturally infected patients by qPCR and culture. 
The Scientific Advisory Group for Emergencies (SAGE) has been advised by NERVTAG that it is 
unlikely that people who are recovering from SARS-CoV-2 infection and have developed antibody 
in nasal secretions, blood or serum are still infectious.  
2.5 Immunology of COVID-19 
Following SARS-CoV-2 infection, an immunological response is demonstrated, but despite 
extensive studies, there is still limited evidence about the type and level of immune response that 
protects people from re-infection. However, with the efficacy of first-generation vaccines and the 
number of documented re-infections remaining low despite high incidence rates in some 
countries, it is clear that immunity after vaccination or natural infection can provide resistance to 
re-infection, although the duration of protection remains unknown.  
Antibody responses 
The frequency with which people infected with SARS-CoV-2 make an antibody response to the 
major antigens (including the spike protein S and the nucleoprotein N) is dependent on the test 
used. Previous reports that a high proportion of those with mild disease fail to show a response 
were based on earlier versions of the antibody test, that have now been superseded. 
Recent evidence from animal models showed that antibodies against spike protein administered 
passively protect against subsequent challenge with SARS CoV2 virus (Rogers et al., 2020).  This 
is especially true when the antibodies are neutralizing in vitro. Such antibody protects cells from 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
38 
infection by blocking the interaction between the spike receptor binding domain and the ACE2 
receptor.  However, other antibodies that bind to spike protein but did not neutralize in vitro may 
fail to protect against infection. The success of the passively transferred antibodies in animal 
models suggests that antibody prophylaxis (and possibly, therapy) either with convalescent 
plasma or with cloned antibodies could be protective in humans. The optimal therapy might be 
with polyclonal antibody, since single antibodies might drive virus escape.  
Most people make a polyclonal response after virus infection that targets many different proteins 
and epitopes within them (Brouwer et al., 2020). Thus, it might be expected that most people will 
make neutralizing antibodies that are protective against reinfection. However, the specific 
protective (neutralizing) antibodies are not measured in all the different antibody tests that have 
been developed so far. For example, some tests measure antibodies against N protein. Some of 
the latest serological tests do measure antibodies that target the receptor binding domain 
specifically, or even measure the antibody’s ability to disrupt the interaction between spike and 
ACE2 receptor. A positive, high titre result in these tests would give some reassurance that an 
individual was ‘immune’ and unlikely to be susceptible to reinfection. This is supported by efficacy 
data from first-generation SARS-CoV-2 vaccines, which primarily have sought to stimulate high 
antibody levels. 
However, it remains uncertain what titre of neutralizing antibody is required for immunity; it is also 
uncertain how long antibody persists and how effectively it is boosted by re-exposure or 
vaccination. In addition, antibody in the blood may not be reflected by protection against lung 
disease (although this seems probable) or against infection of the nose and pharynx (less likely). 
Early results from non-human primate vaccine and challenge studies performed on the ChAdOx 
Oxford vaccine showed modest levels of antibody and some protection against disease but not 
against infection in the upper airway (van Doremalen et al., 2020). However, the studies were 
performed very early after vaccination and with a high dose of challenge virus delivered both to 
the upper and lower airway. The design of the study was inherently likely to give a less than 
protective signal.  
 
T cell responses 
T helper (CD4+) cells are essential to durable B cell (antibody-mediated) immunity. The T cells 
respond to antigen presenting cells that present fragments of virus (T cell epitopes) in conjunction 
with MHC class II. T cell epitopes have recently been described for SARS-CoV-2 (Grifoni et al., 
2020) and are located in spike, nucleoprotein and M proteins as well as in other non-structural 
viral proteins. A substantial number (>40%) of people unexposed to SARS-CoV-2 were found to 
have CD4+ T cell responses that were likely elicited by infection with previous seasonal 
coronavirus infections. The presence of CD4+ T cell epitopes in spike protein suggests that 
vaccines that consist only of spike will elicit an immune response, but it will differ from that after 
natural infection. Infection will normally generate durable CD4 T cell responses, but purified 
antigens may not, although these cells have been detected after ChAdOx1 nCoV-19 vaccination.  
CD8+ T cells responses have been detected in people recovering from SARS-CoV-2 infections. 
Some reacted to spike proteins, but several other proteins were more dominant. In another study 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
39 
CD8+ T cells were present in lungs of people with mild but not with severe disease suggesting 
they may modify disease outcome (Bost et al., 2020). Purified spike protein vaccines are unlikely 
to elicit CD8+ responses unless formulated with an adjuvant that promotes such responses, and 
the value of CD8 responses is undetermined. 
Harmful Immune responses 
There has been some concern around antibody dependent enhancement (ADE) of disease and 
other mechanisms by which re-infection with SARS-CoV-2 in the presence of suboptimal pre-
existing immunity may lead to more severe disease, for example due to immunopathology 
(Iwasaki and Yang, 2020). While there have only been a few cases of documented re-infection 
reported, one recent case report described a young healthy adult whose first episode of COVID-
19 was mild but who was re-infected with a variant strain with more severe disease requiring 
hospitalisation (Tillett et al., 2020). There is therefore a theoretical risk that previous immune 
responses (by infection or vaccination) may contribute to more severe disease on re-infection. 
However, there is still no robust evidence of this for SARS-CoV-2. In one paper using passive 
transfer of antibody to hamsters, there was a small signal of increased weight loss over control 
for the groups receiving low dose antibody (Rogers et al., 2020). Numbers were too small to 
conclude this was ADE and no mechanistic studies were performed. In respiratory syncytial virus 
(RSV) disease (which shows many similarities to COVID-19 in terms of mechanisms of disease 
and immunity), T cells may contribute to enhanced disease in the absence of neutralising 
antibody.  
The key immunological questions that might be resolved by human challenge therefore include: 
 
The protection afforded by new vaccines 
 
The role of antibody vs. cellular immunity in immune protection and disease 
 
The immune biomarkers that predict variations in symptoms  
 
The durability of immunity in those previously infected with SARS-CoV-2 
 
The effects of passive antibody therapy on viral infection and recovery 
2.6 Clinical outcomes of SARS-CoV-2 infection 
This protocol has been designed to minimise, as much as possible, risk to participants and their 
contacts, whilst providing a robust platform for vaccine efficacy evaluation. For the purpose of 
protocol design and informed consent, the degree of risk can be semi-quantified using data from 
observational studies of natural infection, which have also identified factors associated with risk 
of severe disease such as age, co-morbidities, gender and ethnicity. Animal models provide 
information correlating severity of pathology with route and dose of inoculation. In addition, there 
is emerging information concerning the efficacy of antiviral and immunomodulating therapy, which 
has the potential to attenuate risk to participants. 
Much of the information that informs the general public of COVID-19, and indeed the scientific 
community, is derived from hospital-treated cases, that are, by definition, at the severe end of the 
spectrum. In conducting a dose ranging study commencing with an inoculum at the lowest 
measurable dose, investigators aim to achieve a model in which volunteers experience an 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
40 
infection that results in no symptoms, or symptoms no more severe than the common mild 
response of healthy people of the same age within the general population.   
Age as a risk factor for severe COVID-19 
Age has been a major factor in severe outcome of COVID-19 in all series published so far 
(Spiegelhalter, 2020). In one large meta-analysis by the Imperial group of data from China, an 
estimated 20% of hospital-treated infections were severe with an overall infection-mortality rate 
of approximately 2% (Salje et al., 2020). Using this huge dataset, it was estimated that the 
infection-mortality rate (95% confidence interval) in 20–29-year-olds was 0·0309% (0·0138–
0·0923), and in 30-39 year olds was 0·0844% (0·0408–0·185). In contrast, the estimated 
infection-mortality rate in the over-60s was 3·28% (1·82–6·18).  
Modelling from France estimated that 0.5% of 20-29 year olds who were infected during the first 
pandemic wave (including those with co-morbidities) were admitted to hospital, using denominator 
data from passive surveillance and proportions of asymptomatically infected individuals from the 
Diamond Princess cruise ship to estimate the total number of infections over the same period  
(Sakurai et al., 2020). These are likely to have been over-estimates, as more recent analysis of 
severe outcomes from several European countries using denominators estimated by 
seroprevalence data showed the following in young adults <30 years old  (Kuiper et al., 2020). 
 
Risk of death following infection: 1.2-6.1 per 100,000 (0.0012-0.0061%) 
 
Risk of ICU following infection: 0.9-4.5 in 10,000 (0.009-0.045%) 
 
Risk of hospitalization following infection: 0.8-3.9 per 1,000 (0.08-0.39%) 
Even these are likely to be over-estimates for a healthy young adult group, as the figures do not 
take risk factors or co-morbidities into account. No published data exist specifically describing the 
risk of hospitalization in the UK of individuals in the 18-30 year old age group once they are 
already infected. As of 6th November 2020, 95 adults aged 18-30 have died due to COVID-19, the 
majority of whom had co-morbidities or other risk factors (Ben Humberstone, Office of National 
Statistics [ONS], personal communication, 
https://www.england.nhs.uk/statistics/statistical-work-areas/covid-19-daily-deaths/).  
 
Data from the ONS from the 16 weeks between 7th March and 26th June 2020 (Williamson et al., 
2020) covering the peak of the first pandemic wave show an estimated absolute risk of death in 
those aged 15-24 years of 0.5 in 100,000 (0.0005%) and those aged 25-34 of 1.6 in 100,000 
(0.0016%). Additionally, the QCOVID living risk prediction algorithm (Harrison, 2020) provides an 
absolute risk of COVID-associated hospitalization in a White British 30 year old woman with no 
risk factors as 1 in 5076 (0.0197%).   
Extrapolating study findings from young adults to high risk groups such as older people with co-
morbidities is not always possible. However, young adults with mature intact immune systems are 
the benchmark for optimal immune responses. They are therefore the best group in which to 
identify correlates of protection against which vaccine-induced responses can be compared. So 
far, phase III studies have shown no major differences between young and older vaccinees, which 
also reassures about extrapolating in this context. Furthermore, a vaccine candidate tested by 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
41 
infection challenge of young adults that showed no effect on infection rate or viral shedding can 
reasonably be understood to have little protective efficacy in those with young healthy immune 
systems, and therefore would be even less likely to show efficacy in more high-risk populations 
with impaired immune responses. Host factors such as age are also less likely to impact the 
efficacy of antiviral drugs and monoclonal antibodies, so extrapolation is more feasible for these 
types of studies. Finally, with widespread vaccination in the near future, the majority of high-risk 
individuals will have been vaccinated and almost all efficacy studies, including head-to-head 
comparisons of drugs and vaccines, will need to take place in younger volunteers. While young 
adults with no known underlying conditions may still develop unexpectedly severe outcomes 
following virus or drug administration, these are likely to be rare and can be further mitigated in 
an early phase clinical trial setting. 
Detailed analyses of the existing phase III vaccine trials are not yet available, so although 
preliminary announcements have suggested no difference in efficacy in older adults and other 
high-risk groups this has yet to be fully evaluated. In the published Pfizer data, analysis was based 
on only 170 infections, with only 20 cases in those aged >65 and 5 cases in those aged >75, who 
are likely to respond least well to vaccination (Polack et al., 2020). Similar issues with statistical 
power apply to subgroups with co-morbidities or immunosuppression, so we would argue that the 
efficacy of these first-generation vaccines remains uncertain and there remains a strong rationale 
to continue developing vaccines to improve protection in those who have difficulty mounting good 
immune responses. 
Ethnicity as a risk factor for severe COVID-19 
Initial 
analysis 
by 
the 
Office 
for 
National 
Statistics 
(ONS) 
(https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/articl
es/updatingethniccontrastsindeathsinvolvingthecoronaviruscovid19englandandwales/deathsocc
urring2marchto28july2020) showed that the rate of death involving the coronavirus (COVID-19) 
among almost all ethnic groups has been significantly higher than that of those of White British 
ethnicity. Based on an initial statistical model adjusting for age, males of Black African ethnic 
background were 3.8 times more likely to die from a COVID-19-related death and females of 
Black African ethnic background were 2.9 times more likely than males and females who self-
identified as White British People.  Bangladeshi, Pakistani, Indian and Mixed ethnicities also had 
statistically significantly raised risk of death involving COVID-19 compared with those of White 
ethnicity. However, much of this increased risk disappeared after taking into account geography, 
socio-economic characteristics and health measures such as pre-existing conditions, with Black 
African males having a 2.5 times higher corrected risk, Black African females having a 2.1 times 
greater corrected.  For other ethnic minority groups the increased rate of COVID-19 mortality was 
also reduced following correction and the ONS concluded that the majority of the difference 
between ethnic groups in COVID-19 mortality was a result of socio-economic disadvantage and 
other circumstances such as high rates of employment in essential services including front line 
health care.   
These data have been partially supported by findings from other studies. The OpenSAFELY study 
showed that after adjustment for other factors, Black and South Asian people were at higher risk 
with hazard ratios of 1.48 and 1.45 respectively (He et al., 2020). However, the ISARIC-4C study 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
42 
showed an increased risk only in South Asian people after correction for other factors (Tenforde, 
2020). Some of this remaining increased risk may be due to unmeasured social and environment 
factors, although it is not possible to exclude biological risk factors at this stage. Thus, while there 
is an increased risk of poor outcomes following COVID-19 in people of some ethnic backgrounds, 
most is due to exposures, socioeconomic and health inequality factors, the data for which are 
incomplete. Furthermore, while the relative risk of death may be higher even when certain factors 
have been taken into account, in young adults this still represents a very low absolute risk of 
severe outcomes. This is reflected in the QCOVID risk model, where risk of severe outcomes in 
young adults remains extremely low irrespective of ethnicity (Harrison, 2020).  
Consequences of natural infection 
Natural infection by SARS-CoV-2 mostly results in no or minor symptoms. In the careful 
observation of passengers and crew in quarantine on board the cruise ship Diamond Princess, 
712 of a total of 3711 persons were found to be infected with SARS-CoV-2, and 410 (58%) of 
those infected were asymptomatic at the time of testing. Amongst the latter asymptomatic cases, 
a small fraction - 12% - subsequently developed symptoms (Berlin et al., 2020). Where infection 
results in symptoms, international published epidemiological surveys indicate a median 
incubation period of 5 days. People infected with SARS-CoV-2 are most infectious (i.e. exhibit 
significant viral shedding) from 2 days before, until 7 days after symptom onset (Docherty et al., 
2020).  
Evidence from observational studies of infected individuals and non-human primates have shown 
that changes occur in the lungs even sometimes during asymptomatic (Long et al., 2020). These 
are generally seen as ground-glass shadows on imaging that may be temporary or persistent. 
They can be early (around 5 days post-infection) or late (around 10 days) and can progress to 
more severe lung inflammation characterised by widespread changes in both lungs.  
A wide range of symptoms can occur from disease onset. In a detailed, multi-site CDC  study of 
274 people in the United States with symptoms, who were tested as outpatients and found to be 
positive by RT-PCR and then interviewed in the period 14-21 days after the initial swab, the 
complaints experienced in descending order of frequency were fatigue, cough, headache, body 
ache, fever, chills, loss of taste, loss of smell, diarrhoea, congestion, dyspnoea, nausea, sore 
throat, chest pain, abdominal pain, confusion and vomiting. Among respondents aged 18–34 
years with no chronic medical condition, 19% (9 of 48) reported not having returned to their usual 
state of health. Age ≥50 versus 18–34 years (adjusted odds ratio [aOR] = 2.29 ) and reporting 3 
or more versus no chronic medical conditions (aOR = 2.29) were associated with failure to regain 
usual health. Obesity (body mass index ≥30 kg per m2) (aOR 2.31) and a psychiatric condition 
(aOR 2.32) also were associated with failure to recover completely after adjusting for age, sex, 
and race/ethnicity. 
Consequences of development of disease 
In a minority of higher-risk individuals, initial symptoms of natural infection are followed by a 
dramatic decline in clinical state, characterized by worsening dry cough, severe dyspnoea and 
profound malaise. This is caused primarily by uncontrolled viral replication and dissemination to 
the lower respiratory tract followed by onset of a diffuse maladaptive lung inflammation causing 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
43 
failure of gas exchange resulting in low arterial oxygen saturation. This, together with generalised 
sepsis (including coagulation disorders and cardiac complications) can lead to multi-organ failure. 
Severe COVID-19 may also lead to acute cardiac, kidney, and liver injury, in addition to cardiac 
arrhythmias, rhabdomyolysis, coagulopathy, and septic shock. In a small number of children and 
teenagers, a condition (Paediatric Inflammatory Multisystem Syndrome temporally associated 
with COVID-19 or PIMS-TS) has also been reported that leads to more severe disease (Jiang et 
al., 2020; Whittaker et al., 2020). It is unclear whether this syndrome occurs in adults. 
The UK ISARIC study investigated 20,133 people with COVID-19 admitted to hospitals whose 
median age was 73 years (interquartile range 58-82), the median duration of symptoms before 
admission was 4 days and the median duration of hospital stay was 7 days (Docherty et al., 2020). 
Amongst this cohort, 23% had no documented reported comorbidity. The commonest 
comorbidities of the remainder were chronic cardiac disease (31%), diabetes (21%), chronic 
pulmonary disease (18%), asthma (14%) and Chronic Kidney disease (16%).  Increased age and 
comorbidities including obesity were associated with a higher probability of mortality. The 
investigators reported 3 major and distinct clusters of symptoms: (i) respiratory (cough, sputum, 
sore throat, runny nose, ear pain, wheeze, and chest pain) – the commonest cluster; (ii) systemic 
(myalgia, joint pain and fatigue); and (iii) enteric (abdominal pain, vomiting and diarrhoea). Across 
the entire cohort, 41% of patients were discharged alive, 32% died and 41% continued to receive 
care at date of reporting. 17% required admission to High Dependency or Intensive Care Units; 
of these, 17% were discharged alive, 37% died and 46% continued to receive care at the reporting 
date. Of those receiving mechanical ventilation, 20% were discharged alive, 53% died and 27% 
remained in hospital. Overall, younger age, female sex, and lack of co-morbidities or obesity were 
associated with lower mortality in hospital. However, individuals aged 18-30 made up only a small 
proportion of cases (with no male preponderance) (Docherty et al., 2020). 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
44 
 
Figure 2 Outcomes of 20,133 hospitalised COVID-19 patients by age 
Together, these data suggest that SARS-CoV-2 infection in healthy young adults with no co-
morbidities rarely causes more than mild self-limiting symptoms. 
Treatment of Severe COVID-19 
Patients with severe COVID-19 often require oxygen and ventilatory support, together with 
correction of physiological dysfunction usually in intensive care units. The most severely ill usually 
require mechanical ventilation, plus one or more of haemodynamic support, correction of 
coagulopathy, treatment of heart failure and correction of acute renal failure. Standard of care of 
severely ill people now includes dexamethasone, Remdesivir and Tocilizumab. In patients 
hospitalized with COVID-19, the use of dexamethasone resulted in lower 28-day mortality among 
those who were receiving either invasive mechanical ventilation or oxygen alone at randomization 
but not among those receiving no respiratory support (Horby et al., 2020). While the efficacy 
differs between studies, treatment with the anti-viral drug Remdesivir 200mg IV daily has been 
shown to be superior to placebo in shortening the time to recovery in adults hospitalized with 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
45 
COVID-19 and evidence of lower respiratory tract infection (Beigel et al., 2020) In contrast, the 
recent SOLIDARITY trial (WHO_Solidarity_Trial_Consortium, 2020) suggested no overall 
improvement in mortality or clinical outcome in hospitalized patients, but this non-placebo 
controlled international multi-centre study enrolled a wide range of patients at various stages 
including late disease, which cannot be extrapolated to early treatment of mild infection (see 0 
Pre-clinical and clinical experience with Remdesivir for COVID-19). 
Potential long-term complications of COVID-19 
Currently, it is still too early to assess the long-term complications of COVID-19. However, it is 
possible that severe ARDS may be associated with long-term pulmonary pathology including 
fibrosis. In the case of the SARS outbreak of 2003, a 2‐year study of a selected population of 
SARS survivors, showed significant impairment of DLCO, exercise capacity and health status had 
persisted (Ngai et al., 2010). In the wake of the SARS epidemic, some survivors experienced 
chronic fatigue syndrome for several years after illness (Lam et al., 2009). Currently, large cohort 
studies (such as the UK sponsored PHOSP-Covid) have been set up to collect this information. 
However, to date, there has been no evidence that long-term sequelae are significantly 
associated with asymptomatic or mild SARS-CoV-2 infection. “Long COVID” is currently being 
widely discussed (Maxwell, 2020) and refers to a post-infective state that has been experienced 
by COVID-19 patients including health care workers, characterised by fatigue and lassitude, 
extending for weeks and even months. The incidence and nature of this illness is currently being 
investigated by several groups internationally (Nabavi, 2020). 
Data from the COVID Symptom Study (led by Tim Spector and Claire Steves at King’s College 
London) is using self-reported symptom data from a mobile phone app to analyse the frequency 
and duration of symptoms related to COVID-19. In that dataset, preliminary data were obtained 
of 629 individuals in the 18-30 year old age group with PCR-confirmed SARS-CoV-2 infection and 
who were non-smokers, had a BMI<25, had no co-morbidities and consistently logged into the 
app (data extracted September 2020, personal communication, Claire Steves, King’s College 
London). In this cohort, 78% were women but the frequencies and duration of symptoms were 
similar between men and women (Table 3 & Table 4). The most frequent symptoms were fatigue 
(78%), headache (74%), loss of smell (61%), sore throat (59%) and cough (48%) as shown in 
Table 3. On average, these symptoms lasted no more than 5 days although some rare individuals 
experienced loss of smell and fatigue for up to 4 months before resolution (Table 4, Figure 3). 
Nevertheless, fatigue had resolved in 75% of individuals after 11 days or fewer and 90% of 
individuals after 19 days or fewer, and loss of smell in 75% after 9 days or fewer and 90% after 
14 days or fewer (Figure 2). Further analysis of the overall dataset has allowed the development 
of a risk prediction system for “long COVID”, which has shown relatively lower risk in younger 
individuals with <5 symptoms (Sudre et al., 2020). 
 
 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
46 
 
Table 3 Frequency of COVID-19 related symptoms in healthy 18-30 year olds with PCR-
confirmed infection 
 
 
 
Frequency 
Overall 
Male 
Female 
Fatigue 
0.783784 
0.791045 
0.780933 
Headache 
0.739269 
0.671642 
0.756592 
Loss of smell 
0.605723 
0.544776 
0.62069 
Sore Throat 
0.586645 
0.514925 
0.604462 
Persistent cough 
0.481717 
0.492537 
0.476673 
Shortness of breath 
0.36725 
0.343284 
0.371197 
Fever 
0.36407 
0.425373 
0.344828 
Chest pain 
0.357711 
0.291045 
0.375254 
Skipping meals 
0.349762 
0.298507 
0.363083 
Unusual muscle pains 
0.343402 
0.358209 
0.338742 
Hoarse voice 
0.298887 
0.246269 
0.312373 
Diarrhoea 
0.233704 
0.186567 
0.245436 
Dizziness 
0.197138 
0.156716 
0.208925 
Abdominal pain 
0.18124 
0.156716 
0.184584 
Eye soreness 
0.151033 
0.141791 
0.15213 
Confusion, disorientation 
or drowsiness 
0.138315 
0.164179 
0.127789 
Rashes 
0.028617 
0.014925 
0.032454 
Blisters 
0.009539 
0.007463 
0.010142 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
47 
Table 4 Duration of COVID-19 related symptoms in healthy 18-30 year olds with PCR-
confirmed infection. 
Duration (days) 
Symptom 
Median 
Min 
Max 
75th 
centile 
90th 
centile 
Loss of smell 
5 
1 
119 
9 
14 
Fatigue 
5 
1 
102.5 
11 
19 
Persistent cough 
4 
1 
46 
9 
14.8 
Headache 
3.5 
1 
72 
8 
15 
Shortness of breath 
3 
1 
92 
9 
17 
Chest pain 
3 
1 
92 
7 
17 
Skipping meals 
3 
1 
66 
6 
10 
Sore Throat 
3 
1 
52.5 
7 
12.2 
Hoarse voice 
2.5 
1 
46 
6 
11 
Confusion, disorientation or 
drowsiness 
2.5 
1 
34 
6 
11.4 
Dizziness 
2.5 
1 
32.5 
7 
18 
Rashes 
2.25 
1 
9.5 
4.75 
6.9 
Unusual muscle pains 
2 
1 
92 
5 
9.5 
Abdominal pain 
2 
1 
66 
5.75 
12 
Fever 
2 
1 
46 
4 
8 
Diarrhoea 
2 
1 
32.5 
4 
9 
Eye soreness 
2 
1 
29 
4 
9.2 
Blisters 
1.25 
1 
9 
1.75 
5.5 
 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
48 
 
Figure 3 Frequency of individuals with the most common COVID-19 associated symptoms 
by duration. 
From these data and considering the intranasal inoculation of SARS-CoV-2 in this study, loss and 
alteration of smell is a potential specific risk, even in healthy young adults and may persist in rare 
cases for weeks to months. Objective testing has shown that anosmia may be even more common 
than when assessed by self-report and may be the only symptom, particularly in young adults. In 
addition, parosmia (alteration in the sense of smell that can severely impair appetite due to familiar 
foods triggering a foul smell) has previously been reported in a large proportion of those with post-
viral loss of smell. It is now also being reported during the COVID-19 pandemic and may persist 
for longer than anosmia. While anosmia is most common in those aged 40-45, parosmia may 
occur with similar frequency across the age ranges. Some data exist that suggests the usefulness 
of treatments including steroid rinses, topical vitamin A and omega-3 supplements that may 
reduce these symptoms or speed recovery. A placebo-controlled randomized controlled trial 
accepted for publication has shown that oral and intranasal steroids given at 4 week in those with 
persistent anosmia achieves better recovery rates (Claire Hopkins, ENT consultant, Guy’s and St 
Thomas’ Hospital, personal communication).  
2.7 Mitigating Risk in Experimental Human SARS-CoV-2 Infection 
Taken together, these data suggest that to minimise the likelihood of injury to participants, the 
inclusion criteria should specify young age (18-30 years) and exclusion criteria should consider 
currently known risk factors such as obesity and any comorbidity detected on screening. 
Additionally, a risk prediction tool such as QCOVID should be used for personalised risk 
assessment of volunteers using a pre-specified absolute risk threshold until the challenge 
infection has been shown to be safe and very well tolerated. Other ways to reduce risk as much 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
49 
as possible include (i) use of a low infecting dose, (ii) intranasal deposition of inoculum (avoiding 
direct instillation to the lung), (iii) early recognition of features associated with progression to 
severe disease, including viral hyper-replication and lower airway inflammation and (iv) 
intervention treatment of infected participants in the form of pre-emptive or rescue therapy, when 
indicated. 
Role of inoculum density in severity of infection 
It is intuitive that the concentration of virus to which a participant is exposed is likely to determine 
the chances of successful infection, but also of severity of the inflammatory response and, 
potentially, the disease. We are not aware of relevant infecting dose experiments with animal 
models of COVID-19, but animal models of other viral infections show that variation in the infecting 
dose determines the severity of the disease. A dose-response has been shown in mouse models 
with several strains of SARS-CoV-1. The infectivity varies between different strains of the virus, 
which modifies the shape of the dose-response curve, but nevertheless consistent dose-response 
relations are observed with the severity of the infection (Roberts et al., 2008). Human influenza 
infection challenge studies have also demonstrated higher infection rates related to dose (Watson 
et al., 2015). In this study, we will therefore adopt a strategy of infecting participants with the 
lowest dose of SARS-CoV-2 that can be consistently administered, and then conduct a series of 
dose increment cycles until we identify the lowest dose which achieves the objective of viral 
replication in the upper respiratory tract of >50-70% of participants. 
Significance of high viral loads within the upper airway 
Longitudinal studies have not established any correlation between SARS-COV-2 viral load in the 
respiratory tract and disease severity in younger patients due to the high frequency of 
asymptomatic disease. In symptomatic hospitalised patients, the highest levels of pharyngeal 
virus shedding occur during the first week of symptoms, with a peak on day 4 (Wölfel et al., 2020). 
Transient peak viral loads of 7x108 RNA copies/swab have been reported in upper and lower 
respiratory tract samples but decline rapidly after day 5. In hospitalised patients with mild-severe 
disease, the median duration of infectious virus shedding is 8 days (van Kampen et al., 2020). 
Shedding of viral RNA from respiratory tract samples generally outlast the end of symptoms. Viral 
loads above 107 RNA copies/mL samples have been independently associated with detection of 
infectious SARS-CoV-2. Patients with <106 viral RNA copies/mL are highly unlikely to be 
infectious (van Kampen et al., 2020; Wölfel et al., 2020).  
Personalised risk assessment using the QCOVID tool 
The safety of volunteers enrolled in these studies is of utmost concern and ethnicity has been 
discussed widely as a potential risk factor for hospitalisation and death with COVID-19. The role 
of ethnicity as an exclusion factor was therefore discussed extensively in the protocol 
development group, specifically that of Black, Asian and minority ethnicities (BAME). Analysis by 
the Office of National Statistics and the OpenSAFELY and ISARIC 4C studies of hospitalized 
patients have all concluded that the majority of the increased risk seen (particularly in Black and 
South Asian groups) was related to socioeconomic factors including greater exposure due to 
disproportionately being in front-line jobs. However, there remained some element of increased 
risk in BAME individuals that was still unexplained, with up to ~2.5 times increased risk of severe 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
50 
outcomes in Black African men, for example. Our public and participant inclusion and engagement 
as well as reviews by experts in BAME health (including Kevin Fenton, PHE, and Kamlesh Khunti, 
Centre for BME Health) highlighted two opposing views: (1) that inclusion and diversity should be 
maximized, and (2) that BAME people should not be subjected to any increased risk before those 
with no documented risk had been through the study procedures. To take these views into account 
and since this increase in risk was not identical across ethnicities, it was felt that a personalised 
risk assessment would be a better way to balance inclusivity with safety. Furthermore, a 
recruitment approach should be responsive to the most up-to-date data. The QCOVID risk scoring 
tool (qcovid.org) published by a consortium led by Julia Hippisley-Cox (University of Oxford) is an 
independent, validated risk assessment algorithm that integrates age, sex, ethnicity, geography, 
body mass index and co-morbidities to provide an individualised estimate of absolute mortality 
and hospitalisation risk. This provides an objective absolute risk of death and hospitalization 
based on the best available UK epidemiologic data. The tool is CE marked and will be recalibrated 
with up-to-date data every 3-6 months. 
Table 5 Representative risk assessments using QCOVID 
Absolute risk of death 
Absolute risk of 
hospitalisation 
Age 
Sex 
Ethnicity 
BMI 
1 in 250,000 (0.0004%) 
1 in 4902 (0.020%) 
30 
F 
White British 
23.5 
1 in 250,000 (0.0004%) 
1 in 7143 (0.014%) 
30 
M 
White British 
23.5 
1 in 250,000 (0.0004%) 
1 in 8475 (0.012%) 
22 
M 
Black African 
23.5 
1 in 250,000 (0.0004%) 
1 in 5319 (0.019%) 
26 
M 
Indian 
23.5 
1 in 250,000 (0.0004%) 
1 in 9901 (0.010%) 
24 
M 
Chinese 
23.5 
1 in 250,000 (0.0004%) 
1 in 4587 (0.022%) 
27 
F 
Chinese 
23.5 
1 in 250,000 (0.0004%) 
1 in 4329 (0.023%) 
30 
F 
White British 
27.7 
1 in 250,000 (0.0004%) 
1 in 6211 (0.016%) 
30 
M 
White British 
27.7 
1 in 250,000 (0.0004%) 
1 in 7143 (0.014%) 
22 
M 
Black African 
27.7 
1 in 250,000 (0.0004%) 
1 in 3984 (0.025%) 
27 
M 
Indian 
27.7 
1 in 250,000 (0.0004%) 
1 in 8621 (0.012%) 
24 
M 
Chinese 
27.7 
1 in 250,000 (0.0004%) 
1 in 4000 (0.025%) 
27 
F 
Chinese 
27.7 
1 in 200,000 (0.0003%) 
1 in 2475 (0.04%) 
22 
F 
Black African 
23.5 
1 in 200,000 (0.0003%) 
1 in 2959 (0.034%) 
23 
F 
Indian 
23.5 
1 in 200,000 (0.0003%) 
1 in 4329 (0.023%) 
30 
F 
Chinese 
23.5 
1 in 166,667 (0.0006%) 
1 in 3333 (0.03%) 
30 
M 
Indian 
23.5 
1 in 125,000 (0.0008%) 
1 in 2632 (0.038%) 
30 
F 
Indian 
23.5 
1 in 111,111 (0.0009%) 
1 in 2169 (0.046%) 
30 
F 
Black African 
23.5 
1 in 100,000 (0.001%) 
1 in 4739 (0.021%) 
30 
M 
Chinese 
23.5 
1 in 83,333 (0.0012%) 
1 in 2755 (0.036%) 
30 
M 
Black African 
23.5 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
51 
2.8 Pre-clinical and clinical experience with Remdesivir for COVID-19 
In a macaque model of COVID-19, treatment with Remdesivir 12 hours after respiratory tract 
inoculation of SARS-CoV-2 reduced subsequent signs of respiratory disease, radiologically 
defined pulmonary infiltrates and virus titres in bronchoalveolar lavages 2 hours after the first 
treatment administration. However, virus shedding from the upper respiratory tract was not 
reduced by Remdesivir treatment (Williamson et al., 2020). In a clinical study of 1063 patients 
with COVID-19, the data and safety monitoring board recommended early unblinding because of 
shortened time to recovery in the Remdesivir group (Beigel et al., 2020). Results from 1062 
patients (541 assigned to Remdesivir and 521 to placebo) with data available after randomization 
indicated that those who received Remdesivir had a significantly reduced median recovery time 
of 10 days compared with 15 days in those who received placebo (Beigel et al., 2020). Estimates 
of mortality by 15 days were 6.7% with Remdesivir and 11.9% with placebo. Serious adverse 
events were no more frequent in the Remdesivir group compared with placebo.  In a further study, 
treatment with Remdesivir 200mg IV daily for 5 days achieved similar clinical outcomes to 10 days 
(Goldman et al., 2020).  
However, in a smaller Chinese study of Remdesivir 237 patients with proven COVID and 
hypoxaemia were enrolled and randomly assigned to a treatment group (158 to Remdesivir and 
79 to placebo), Remdesivir was not associated with a difference in time to clinical improvement. 
Nevertheless, although not statistically significant, patients receiving Remdesivir had a 
numerically faster time to clinical improvement than those receiving placebo among patients with 
symptom duration of 10 days or less (hazard ratio 1·52 [0·95-2·43]). Adverse events were 
reported in 102 (66%) of 155 Remdesivir recipients versus 50 (64%) of 78 placebo recipients. 
Remdesivir was stopped early because of adverse events in 18 (12%) patients versus four (5%) 
patients who stopped placebo early (Wang et al., 2020). Recently, data from the non-placebo 
controlled multi-centre WHO Solidarity trial also showed no difference in mortality or length of 
hospitalization in patients treated with Remdesivir compared to placebo (Pan et al., 2020). 
However, subgroup and meta-analysis conducted by the investigators did show statistically 
significant reductions in hospital stay in younger patients with less severe disease and oxygen 
requirement (Shrestha et al., 2020). This supported the randomized placebo-controlled ACTT-1 
trial data that showed significant reduction in hospital duration in those individuals treated with 
earlier and less severe disease. Furthermore, data from immunosuppressed individuals have 
shown viral suppression and improvement in clinical indices correlating directly with Remdesivir 
treatment (Buckland et al., 2020; Helleberg et al., 2020). These data clearly indicate physiological 
and antiviral effects of Remdesivir in vivo, despite the clinical benefit for most hospitalized patients 
remaining in question (due to unavoidably delayed treatment in the clinical setting). 
In the hospitalized patients described in clinical trials to date, it is not possible to administer 
Remdesivir at the early pre-symptomatic timepoints proposed here. Antivirals against influenza 
have invariably shown greater efficacy when given early in the disease course and a number of 
antivirals against influenza and RSV have shown greater efficacy (and in some cases only shown 
efficacy) in the controlled human challenge model and not in clinical practice (DeVincenzo et al., 
2015; Hayden et al., 1999). This along with the non-human primate data imply that the same may 
be true for Remdesivir, where early pre-emptive treatment while viral load is low is likely to have 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
52 
greater efficacy than later treatment in the context of uncontrolled viral replication and 
inflammatory responses that can no longer be ameliorated by reduction in viral load. 
The UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) granted early access 
to Remdesivir in its medicines scheme for conditions with a high unmet medical need. The fact 
sheet for healthcare providers (https://www.gilead.com/-/media/files/pdfs/remdesivir/eua-fact-
sheet-for-hcps.pdf) lists adverse events including raised liver transaminases, headache and 
nausea as common or very common. However, in clinical practice, these are generally mild and 
easily managed. In young adults (Humeniuk et al., 2020), the excellent safety profile of 
Remdesivir has been established in two phase I trials (single and repeat dose cohort studies), 
which included a diverse range of participants (male, female, and diverse ethnicities). Repeat 
dosing was given up to 14 days with 150mg once daily IV, which is a 50% higher dose and longer 
duration than current the current standard. In all cases, adverse effects were mild (with only grade 
1 adverse events and no grade 3 or 4 adverse drug reactions). A number developed mild 
transaminitis (grade 1-2) but ALT and AST values universally returned to normal during the study. 
Additionally, in the final report of the randomized controlled trial of 1062 hospitalised COVID-19 
patients, there was no difference in severe adverse events between Remdesivir (24.6%) and 
placebo (31.6%), nor grade 3 or 4 nor any other adverse events (Beigel et al., 2020). Thus, while 
its efficacy as pre-emptive treatment in the setting of the human challenge model has yet to be 
shown, it is unlikely that Remdesivir in the young adult age group treated with a short course leads 
to harm. These considerations should be explained to potential study participants. 
2.9 Pre-clinical and clinical experience with REGEN-COV (Regeneron Monoclonal Antibody 
cocktail) for COVID-19 
Monoclonal antibodies that recognise SARS-CoV-2 are believed to be able to block viral 
replication and either prevent or reduce the severity of disease. The leading example is from 
RegeneronTM, which has developed 2 non-competing, high-affinity human IgG1 anti-SARS-CoV-
2 monoclonal antibodies (mAbs), REGN10933 (casirivimab) and REGN10987 (imdevimab) [52,  
53]. These mAbs bind specifically to the RBD of the SARS-CoV-2 spike glycoprotein and act as 
potent neutralising antibodies by blocking interaction with the host ACE2 receptor, which is  
responsible for viral uptake into host cells. REGN10933 and REGN10987 are intended to be  used 
as a combination therapy (REGEN-COV) as they bind to distinct and non-overlapping regions of 
the RBD with the view to broaden cover against circulating viral variants (40). Additionally, in vitro 
studies have demonstrated that using this non-competing combination minimises the risk of 
escape mutation development due to selection pressure, with no escape mutants developing with 
the dual non-competing REGEN-COV mAB regime compared with development of escape 
mutations occurred when single mAb or dual competing mAb therapies were tested in vitro [53]. 
Clinical studies in both hospitalised and outpatient SARS-CoV-2 infected individuals are ongoing. 
However, interim results released from the phase 1 and 2 portions of a phase 1-3 double blind 
outpatient SARS-CoV-2 study (COV-2067) prompted the FDA to issue an emergency use 
authorisation (EUA) on 21st November 2020 for treatment of non-hospitalised patients with mild 
to moderate COVID-19 who are at high risk for progressing to severe disease and/or 
hospitalisation [55].  In this study, non-hospitalised participants received a single intravenous 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
53 
infusion of REGEN-COV within 3 days of having a positive SARS-CoV-2 PCR test.  According to 
the EUA, 799 participants were randomized to receive one of two doses of REGEN-COV 
combination, either the 2,400 mg dose (n = 266) or the 8,000mg dose ((n = 267), or placebo (n = 
266). Results from this study demonstrated a tolerable safety profile, with serious adverse events 
being numerically more frequent with placebo than REGEN-COV treatment (0.8% high dose 
REGEN-COV, 1.6% low dose REGEN-COV; 2.3% placebo). None of the SAEs were considered 
to be related to the study drug. Numerically more infusion reactions occurred with the REGEN-
COV high dose compared to placebo but not with the low dose REGEN-COV regime (1.5% high 
dose; 0% low dose; 0.4% placebo). This study demonstrated that overall, the average daily 
change in viral load through day 7 (mean time-weighted average change from baseline) was a 
0.36 log10 copies/mL greater reduction with REGEN-COV compared to placebo (combined dose 
groups; p=0.0003). The greatest benefit in viral load reduction was seen in individuals who had 
higher starting viral loads and those who were seronegative at baseline (i.e. slow immune 
responders) [54, 55].  
Efficacy in the outpatient cohort was recorded as the number of medically attended events. 
Treatment with REGEN-COV reduced COVID-19 related medical visits by 57% through day 29 
(2.8% combined dose groups; 6.5% placebo; p=0.024). This benefit was greater in those who had 
one or more risk factors for progression to severe COVID/hospitalisation with a reduction in 
medically attended events of 72% (combined dose groups; nominal p = 0.0065)[55].  Results 
showed no significant difference in virologic or clinical efficacy between the REGEN-COV high 
dose (8 grams) and low dose (2.4 grams). More recently, Regeneron have made public (not yet 
peer reviewed) data showing that the efficacy and safety of a 1.2g dose is comparable to that of 
the 2.4g dose. [56] This demonstrated that median time for symptom duration was reduced by 4 
days in both 2.4g and 1.2g doses (10 v 14 days in placebo). Viral load reductions, hypersensitivity 
reactions and SAEs were comparable across both of these dose groups as well. Furthermore, 
the positive effect is strongest in those with high viral loads, which have been evident in the 
challenge model to date.  
The applicability of this data to our cohort is limited. We are excluding any individuals with risk 
factors for severe COVID-19.  However, it is clear that this is a safe and well-tolerated treatment 
with evidence of a significant reduction in medically attended events related to COVID-19. It would 
also be expected that a targeted treatment against SARS-CoV-2 infection would have greatest 
impact when given early in the course of infection. Given the deliberate inoculation of individuals 
with SARS-CoV-2, using a targeted pre-emptive or rescue therapy is an important ethical 
consideration recognised by the World Health Organisation in their regulatory framework for 
challenge models [57].  
2.10 Human respiratory virus challenge studies in the UK 
The UK is world-class in having extensive recent experience using models of respiratory viral 
challenge, and several of the study team have developed and/or used such models. At Imperial 
College London, Chris Chiu and Peter Openshaw began conducting experimental human 
infections with RSV in 2010, with the goal of establishing challenge studies in an academic setting. 
In 2015, the influenza challenge model was established at Imperial and together these models 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
54 
have been shown to be safe and well-tolerated as well as providing unique platforms for the study 
of immunity and immunopathogenesis during acute infection (Guvenel et al., 2020; Habibi et al., 
2020; Jozwik et al., 2015). Imperial have now safely challenged >150 participants with these 
respiratory viruses and are currently the only academic group in Europe conducting these studies. 
The clinical research organisation hVIVO also has extensive experience in conducting respiratory 
virus challenge studies, mainly in the commercial sector. With a dedicated unit in East London 
and a large and experienced team that has conducted 56 studies with approximately 3000 
volunteers inoculating with influenza and RSV to test a number of vaccine and therapeutic 
candidates, hVIVO has unparalleled expertise in running high-throughput human respiratory viral 
challenge studies (Bagga et al., 2013; DeVincenzo et al., 2014; DeVincenzo et al., 2010; Jones 
et al., 2009; Lambkin-Williams et al., 2016; McClain et al., 2016; Nguyen-Van-Tam et al., 2020; 
Wilkinson et al., 2012). Additionally, in developing this protocol, we have drawn on the expertise 
of a large group of UK experts with expertise in the ethics, regulation, virology, clinical 
implementation and interpretation of human infection challenges studies (see Key Protocol & 
Research Contributors). These include Robert Read (Southampton), whose extensive experience 
of initiating and developing new respiratory tract human infection challenge models, including 
genetically modified Neisseria lactamica and wild type Bordetella pertussis (de Graaf et al., 2020), 
and mitigation of risks against potentially hazardous challenge pathogens has been invaluable in 
study development. 
2.11 Study Rationale 
During 2021 it is likely that there will be widespread deployment of early generation Coronavirus 
vaccines in the UK. The need to refine and improve these vaccines will remain yet it will become 
increasingly difficult to test new vaccines in the field because (a) target groups will be already 
vaccinated, and (b) the natural incidence of disease will diminish. 
A large number of SARS-CoV-2 vaccine candidates are at various stages of development 
internationally including some which have recently entered mid-to-late stage clinical testing in field 
studies. Under ordinary circumstances, vaccine development is a long process because of the 
time and risks involved in providing clinical data from field studies necessary to meet regulatory 
approvals. In order to attain a profound and timely impact on public health, there is an urgent 
need to select the most promising vaccines in the shortest possible timeframe.  
Human challenge studies can provide a high precision model for the testing of vaccines and 
therapeutics as well as for studying host–pathogen interactions in small numbers of participants 
(generally about 25–100 people). Such studies have previously been conducted with many 
pathogens, including seasonal coronaviruses, Respiratory Syncytial Virus (RSV), rhinovirus and 
both seasonal and pandemic influenza virus strains. A controlled human infection model for 
COVID-19 has been widely discussed in the scientific literature (Berry et al., 2020). No 
alternatives to this approach exist that can provide the same level of predictive value within a 
short timeframe using small numbers of participants. Data from animal models, while informative, 
have no guarantee of carrying over into humans and frequently do not. Primate models often vary 
between the species tested. Alternative study designs in humans, such as phase III field efficacy 
trials, would take many years to provide the same answers (Berry et al., 2020). During this time, 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
55 
deaths in the population would accumulate while waiting for months or years to gather such 
evidence.   
The recent announcement of preliminary efficacy results of a SARS-CoV-2 vaccine by 
Pfizer/BioNTech does not negate the need for these studies.  First, the capacity of this and other 
first-generation SARS-CoV-2 vaccines to reduce transmission as well as modify disease is 
unknown.  Second, it is unclear whether this vaccine can protect against severe disease as well 
as it does against mild illness.  It is also likely that these vaccines will perform less effectively in 
older adults and other high-risk groups, limitations which other vaccine candidates may overcome.  
There will therefore remain a critical need for improved vaccines to be developed and for vaccines 
to be compared in a controlled system so that these improvements can be accelerated. 
Using these carefully selected endpoints, it should be possible using human infection challenge 
studies to identify vaccines which do or do not elicit any protective activity with potential to provide 
a health benefit, before investment of time, effort and resources in large scale field trials. This 
decreases the risk of late-stage failure. Well optimised human infection challenge studies also 
enable efficacy studies to be conducted during periods of low transmission (such as between 
pandemic waves) due to their guaranteed high infection rate. These studies will enable promising 
and innovative candidates to be prioritised even when they come from smaller academic or 
biotechnology groups that are unable to access costly field efficacy trials. While data from human 
infection challenge studies in young healthy adults may not always be directly translatable to 
populations at higher risk (such as elderly people with co-morbidities), a vaccine candidate tested 
by infection challenge of young adults that showed no effect on infection rate or viral shedding 
could reasonably be understood to have little protective efficacy in those with young healthy 
immune systems, and therefore would be even less likely to show efficacy in more high-risk 
populations with impaired immunity. The controlled nature of human infection challenge will also 
permit direct comparison between different vaccine candidates to prioritise the most promising. 
In addition, human infection challenge can contribute to the identification of correlates and 
mechanisms of protection against infection and shedding of virus in vaccinated volunteers, as 
well as the durability of protection in seropositive individuals with documented prior wild type 
infection. 
Thus, we will establish a SARS-CoV-2 human infection challenge system that will let us test 
vaccines and treatments reliably in a controlled setting with a participant group that is very unlikely 
to suffer a severe disease. In turn, these interventions may save the lives of a much larger section 
of the population, for whom COVID-19 is potentially serious. The quicker development of vaccines 
that can protect everyone using this strategy balances the managed risk to a small number of 
study participants with potential benefit to millions, who might otherwise suffer while more 
effective interventions are being developed. 
This first virus characterisation study will: 
 
Enable the immediate start of a study of protective immunity at University of Oxford funded 
by the Department of Health and Social Care. We are collaborating closely with Helen 
McShane, who will lead that study using the same challenge virus and closely aligned 
clinical and laboratory methods. Around 2 weeks after our dose escalation study of 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
56 
seronegative individuals begins if no safety signals are seen in the sentinel groups, she 
will start parallel dose escalations in previously-infected seropositive volunteers to show 
safety in this participant group. Once the optimal dose is established, she will proceed to 
inoculate groups of participants with a history of previous COVID-19 and different levels 
of antibody and T cells to test infection rates and viral shedding. Data will be shared with 
our seronegative study to establish the protection afforded by previous infection. Thus, by 
July/August 2021, we will have determined whether immune responses to previous 
infection are protective and started to define the levels of pre-existing immunity required 
for protection. These will have immediate impacts, such as determining whether to allow 
return to unfettered travel and normal daily activities, as well as critical information to 
determine the need and timing of vaccination and re-vaccination in the context of previous 
infection. 
 
Enable studies of existing and novel antiviral drugs. We are in discussions with Regeneron 
and Gilead to implement studies to test the efficacy of different dosing regimes, including 
prophylaxis and early pre-emptive treatment. These will have particular impacts on 
outbreaks in hospitals and care homes to prevent clusters of severe disease. 
 
Lead directly to comparative studies of next-generation SARS-CoV-2 vaccine candidates 
(funded by the Vaccines Taskforce) by establishing the model ready for vaccine 
testing, i.e. determining the dose of virus to use and providing data to accurately conduct 
sample size powering calculations for the vaccine challenge studies. These vaccine 
challenge studies will compare vaccines based on differing technologies against licensed 
vaccines, with formulations and regimens (such as low or single-dose) that will improve 
efficacy (such as seen with the improved results following low-dose priming of the 
AstraZeneca/Oxford vaccine) and global accessibility (by making the same amount of 
vaccine go further and delivered more simply). If these relied on field study approaches, 
direct comparisons could not be made (due to heterogeneity of natural infection events), 
and efficacy data could potentially take years to be obtained and therefore less relevant 
to the current pandemic. Furthermore, these challenge studies will be able to accurately 
ascertain if the vaccines are effective at preventing asymptomatic infection, which is not 
possible to do with field trials.  This is crucial as asymptomatically infected individuals are 
considered to be driving the continuation of the pandemic, being unable to self-isolate as 
they are unaware of their infectious status.  Human challenge is a key component of the 
Vaccines Taskforce strategy in order to deliver safe and effective vaccines and 
therapeutics to the UK population as well as for future pandemics. The UK government is 
in active discussion with vaccine companies to initiate these studies by May 2021. 
 
2.12 Research Hypotheses 
1. SARS-CoV-2 infection in experimentally infected healthy young adult volunteers is safe 
and well tolerated. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
57 
2. Experimental COVID-19 allows early viral replication to be measured and enables 
monitoring of innate and adaptive immune responses and radiological changes which act 
as surrogates of protection and disease. 
2.13 Benefit/Risk Assessment 
Risk determination 
All study procedures involve no more than minimal risk to participants. Similar procedures have 
been used for many years without severe adverse effects. These include blood and nasal 
sampling; participants will be counselled as follows: 
Blood draws: risks include discomfort as the needle goes through the skin and/or bruising. 
Infection, excess bleeding, clotting, or fainting are also possible, although unlikely. 
Nasosorption strips (a soft strip placed up the nose for one minute) and nasopharyngeal swabs: 
may tickle, make their eyes water or be slightly uncomfortable.  They should not be painful.  The 
oral swabs are not painful.  
The risks of SARS-CoV-2 infection in the study population are explained in Background to 
Research. 
Potential adverse effects of chest x-ray and CT 
Each volunteer enrolled in the study will have a single chest X-ray at day -2/-1 prior to inoculation, 
which is to act as a baseline for further imaging that may be necessary and to ensure that no 
significant pulmonary infection or other pathology is present at the start of the study. The 
estimated dose will be 0.02 mSv which is approximately equivalent to 3 days of average natural 
background radiation and carries a risk of inducing a cancer of approximately 1:1,000,000 based 
on risk factors for a healthy adult. This is classified as minimal risk (HPA-CRCE-028). 
The CT chest scans will be associated with a higher radiation dose. The delivered dose varies 
but is likely to be about 1.5 mSv per scan, which is approximately equivalent to 18 months of 
average natural background radiation and carries a risk of inducing a cancer of around 1:1,000-
10,000. This is classified as low risk (HPA-CRCE-028). 
Pregnant or breastfeeding women will be excluded from the study. The known risks to participants 
are detailed in Table 6. 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.


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
58 
Table 6: Risk Assessment  
Potential Risk of Clinical 
Significance 
Rationale for Risk 
Mitigation Strategy 
Study Intervention  
Intravenous dosing with 
SARS-CoV-2 intervention 
treatments 
Local signs and symptoms associated with the cannula 
insertion (peripheral access) and drug administration may 
include erythema, swelling/induration, phlebitis, haematoma 
and pain/tenderness at the insertion site. 
Local reactions will be monitored but are generally short-term and do 
not require treatment. Aseptic technique used for cannula insertion 
and hypoallergenic dressings. 
Other side effects include rash 
Side effects will be monitored but are generally short-term and do not 
require treatment.  
Other less common but serious side effects reported include 
anaphylaxis and anaphylactic shock and other severe acute 
hypersensitivity reactions 
Medications (e.g. epinephrine) will be available in the clinic to treat 
serious allergic reactions promptly. Participants with a known severe 
allergy, or history of anaphylaxis or other serious adverse reactions 
will be excluded from the study. The study site should have medical 
treatment available in case of severe allergic reactions. 
Systemic exposure to SARS-CoV-2 intervention treatments 
To minimise any risks associated with systemic exposure to SARS-
CoV-2 intervention treatments, male and female participants must be 
on highly effective contraception methods during the study and up to 
90 days post dosing with SARS-CoV-2 intervention treatments. 
Intravenous Dosing with 
Remdesivir 
Lack of pre-clinical reproductive toxicity evaluation as well as 
clinical toxicity evaluations in pregnancy due to target 
population indication (high-risk children <24 months) of 
Remdesivir and requirements for licensing for indication. 
Although reproductive toxicity studies are not considered 
appropriate for the study intervention. 
Participants will be advised to use appropriate methods of 
contraception during the study and for 90 days after administration of 
Remdesivir for male participants (equivalent to the sperm life cycle) 
and 30 days for female participants (equivalent to the length of a 
menstrual cycle). 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
59 
Potential Risk of Clinical 
Significance 
Rationale for Risk 
Mitigation Strategy 
Remdesivir may interfere with immunological-based SAR-
CoV-2 diagnostic tests such as some antigen detection-
based assays. In addition, Remdesivir inhibits virus 
replication in cell culture, and therefore may also interfere 
with viral culture assays. Remdesivir does not interfere with 
reverse transcriptase-polymerase chain reaction-based 
assays. Assay interference could lead to false-negative 
SAR-COV-2 diagnostic test results. Therefore, diagnostic 
test results, when obtained, should be used in conjunction 
with clinical findings to guide medical decisions 
Discharge from quarantine will utilise a PCR based test instead of an 
antigen test. 
PCR based tests will be used to confirm the incidence of infection 
and to quantify virus shed by infected participants. 
Implications for culture-based quantification of SAR-CoV-2 will be 
assessed. 
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 study doctor will provide the participant’s general practitioner 
(GP), or doctor with a referral letter if the participant agrees. 
Nasal sampling 
Collection of 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. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
60 
Potential Risk of Clinical 
Significance 
Rationale for Risk 
Mitigation Strategy 
SAR-COV-2 infection from inoculation 
SAR-COV-2 infection & 
severe complications 
Chance of becoming infected with SAR-CoV-2. Typical SAR-
CoV-2 illness: abrupt onset of fever, malaise, myalgia 
(muscle aches), alteration or loss of smell, cough and sore 
throat. 
Severe SAR-CoV-2 infections are known to occur rarely in 
both infants and adults. In adult populations, multiple factors 
including older age, are independently associated with 
severe 
SAR-CoV-2 
complications 
including 
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.  
The safety profile of the SAR-COV-2 in young healthy adults has 
been described in the Background to Research. SAR-CoV-2 infection 
in healthy young adults usually resolves without treatment within 11 
to 14 days. Fatigue and loss of smell may be protracted but in almost 
all cases resolve completely. 
Strict inclusion and exclusion criteria, combined with stringent health 
screening, will apply to ensure only healthy young adults with no 
known risk factors for severe COVID-19 are enrolled in this study. 
There will be a daily medical monitoring in a quarantine unit for at 
least 14 days post-challenge.  
Qualified medical and nursing staff in the quarantine unit will regularly 
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. 
Cardiac enzymes are tested daily at screening, during quarantine 
and during follow up. 
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. 
 
SAR-CoV-2 virus in nasal secretions can cause infection in 
close contacts. 
Discharge criteria have been established, as detailed in Section 
5.18.5 to reduce risk of transmission outside of the quarantine unit. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
61 
Potential Risk of Clinical 
Significance 
Rationale for Risk 
Mitigation Strategy 
Transmission 
of 
SAR-
COV-2 
to 
participants’ 
close contacts 
Passing the SAR-CoV-2 Challenge Virus to others, including 
vulnerable people (see below for definition of vulnerable 
populations). 
To reduce the risk, participants will be asked to avoid, where possible,
contact with vulnerable people for 14 days after they leave quarantine
(Section 2.13.1). 
Passing the SAR-COV-2 Challenge Virus to study staff. 
Clinic staff in contact with participants in the quarantine unit will require
to wear Personal Protective Equipment (PPE) as per local SOPs, to
avoid the transmission of the SAR-CoV-2 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. 
Robust infection control measures will be implemented to prevent
transmission, including disinfection of equipment, sample dispatch,
infection control instructions to volunteer concerning their belongings. 
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 reference – Reference Safety Information for Remdesivir and REGEN-COV for further details. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
62 
2.13.1 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: 
 
Persons ≥65 years of age 
 
Children ≤2 years of age 
 
Residents of nursing homes 
 
Women who are pregnant or who are trying to become pregnant. 
 
Persons of any age with significant chronic medical conditions such as:  
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)  
2.13.2 Benefit assessment 
Healthy participants in clinical studies will not receive direct benefit from treatment during their 
participation. Participants may 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 therapies in an area of 
unmet medical need. 
2.13.3 Overall benefit: risk conclusion 
Taking into account the measures taken to minimise risk to participants in this study, the potential 
risks are justified by the anticipated benefits linked to the evaluation of a viral challenge model 
which is being developed to then be able to use the model as an efficient method of testing 
vaccine efficacy.  Furthermore, the viral challenge model will also subsequently contribute to the 
identification of mechanisms of protection against viral infection and shedding of virus in 
vaccinated volunteers. The challenge model may be valuable in establishing of the durability of 
protection in seropositive individuals with wild type infection.


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
63 
2.14 Objectives and Endpoints 
To develop the first human challenge model for wild-type SARS-CoV-2 virus infection in healthy 
human subjects. 
A prospective open label dose escalation study in healthy participants to establish the safety and 
identify the infectious dose of SARS CoV-2 challenge virus needed to induce infection and active 
viral replication in ≥50 of participants (ideally between 50% to 70%) with minimal or no disease in 
healthy young adults after intranasal inoculation. 
The study will comprehensively describe the attack rate, host immune responses, viral kinetics 
and clinical disease induced by pre-emptively treated infection in this model. 
OBJECTIVES
ENDPOINTS 
PRIMARY  
To identify a 
safe 
and 
infectious 
dose of wild 
type 
SARS-
CoV-2 
in 
healthy 
volunteers, 
suitable 
for 
future 
intervention 
studies 
To evaluate the safety of wild type SARS-CoV-2 challenge in healthy participants 
by assessing: 
 
Occurrence of unsolicited AEs within 30 days post-viral challenge (Day 0) up 
to Day 28 follow up. 
 
Occurrence of SAEs related to the viral challenge from the viral challenge (Day 
0) up to Day 28 follow up. 
To identify a SARS-Cov-2 inoculum dose that safely induces laboratory confirmed 
infection in ≥50% of participants (ideally between 50% and 70%). Laboratory 
confirmed infection is defined as: 
 
Two quantifiable greater than lower limit of quantification (≥LLOQ) RT-PCR 
measurements from mid turbinate and/or throat samples, reported on 2 or more 
consecutive timepoints, starting from 24 hours post-inoculation and up to 
discharge from quarantine. 
SECONDARY 
To 
further 
assess 
SARS-CoV-2 
viral infection 
rates in upper 
respiratory 
samples 
in 
healthy 
volunteers, by 
 
To assess the incidence of laboratory confirmed infection rates using a) mid 
turbinate samples, b) throat swabs, and c) both mid turbinate and throat swabs, 
as defined by: 
 
Variant 2:  Occurrence of at least two quantifiable (≥LLOQ) RT-PCR 
measurements, reported on 2 or more consecutive timepoints, starting from 24 
hours post-inoculation and up to discharge from quarantine. 
 
Variant 3: Occurrence of at least two detectable (≥LLOD) RT-PCR 
measurements, reported on 2 or more consecutive timepoints, starting from 24 
hours post-inoculation and up to discharge from quarantine. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
64 
inoculum 
dose 
 
Variant 4: Occurrence of at least one quantifiable (≥LLOQ) SARS-CoV-2 viral 
cell culture measurement, starting from 24 hours post-inoculation and up to 
discharge from quarantine. 
To assess the 
incidence 
of 
symptomatic 
SARS-CoV-2 
infection, 
in 
healthy 
volunteers, by 
inoculum 
dose 
 
To assess the incidence of lab-confirmed symptomatic SARS-CoV-2 infection 
using a) mid turbinate samples, b) throat swabs, and c) both mid turbinate and 
throat swabs, defined as: 
 
Variant 1: 
o Occurrence 
of 
at 
least 
two 
quantifiable 
(≥LLOQ) 
RT-PCR 
measurements, reported on 2 or more consecutive timepoints, starting 
from 24 hours post-inoculation and 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  
 
Variant 2: 
o Occurrence 
of 
at 
least 
two 
detectable 
(≥LLOD) 
RT-PCR 
measurements, reported on 2 or more consecutive timepoints, starting 
from 24 hours post-inoculation and 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  
 
Variant 3:  
o Occurrence of at least one quantifiable (≥LLOQ) SARS-CoV-2 viral cell 
culture measurement, starting from 24 hours post-inoculation and 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  
To assess the 
SARS-CoV-2 
viral dynamics 
in 
upper 
respiratory 
samples 
(AUC, 
peak, 
duration, 
incubation 
period) 
in 
To assess the viral dynamics using a) mid turbinate samples, and b) throat swabs, 
as measured by: 
 
Area under the viral load-time curve (VL-AUC) of SARS-CoV-2 as determined 
by qRT-PCR, starting from 24 hours post-inoculation and up to discharge from 
quarantine. 
 
Peak viral load of SARS-CoV-2 as defined by the maximum viral load 
determined by quantifiable (≥LLOQ) qRT-PCR measurements, starting from 24 
hours post-inoculation and up to discharge from quarantine 
 
Duration of SARS-CoV-2 quantifiable (≥LLOQ) qRT-PCR measurements, 
starting from 24 hours post-inoculation and up to discharge from quarantine. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
65 
healthy 
volunteers, by 
inoculum 
dose 
Duration is defined as the time (hours) from the first quantifiable of the two viral 
quantifiable positives used to assess infection until first confirmed undetectable 
assessment after their peak measure (after which no further virus is detected).
 
Incubation period of SARS-CoV-2 qRT-PCR measurements. Incubation period 
is defined as the time (hours) from inoculation to the first quantifiable of the two 
viral quantifiable positives used to assess infection, starting from 24 hours post-
inoculation and up to discharge from quarantine. 
The above endpoints will also be evaluated using quantitative cell culture. 
To assess the 
SARS-CoV-2 
induced 
symptoms, in 
healthy 
volunteers, by 
inoculum 
dose 
 
Sum total symptoms diary card score: sum total clinical symptoms (TSS) as 
measured by graded symptom scoring system, starting one day post-viral 
challenge (Day 1) up to discharge from quarantine 
 
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), starting one day post-viral challenge (Day 1) up to discharge from 
quarantine. 
 
Peak symptoms diary card score: peak total clinical symptoms (TSS) as 
measured by graded symptom scoring system (categorical and visual analogue 
scales, starting one day post-viral challenge (Day 1) up to discharge from 
quarantine 
 
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. 
 
Number (%) of participants with Grade 2 or higher symptoms 
To assess the 
incidence 
of 
SARS-CoV-2 
illness, 
in 
healthy 
volunteers, by 
inoculum 
dose 
The incidence of: 
 
Upper Respiratory Tract illness (URT) 
 
Lower Respiratory Tract illness (LRT) 
 
Systemic illness (SI) 
 
Febrile illness (FI) 
 
Proportion of Subjects with Grade 3 symptoms on any occasion at any time 
from the last assessment on Day 0 to quarantine discharge 
 
Proportion of Subjects with Grade 2 or higher symptoms on any occasion at 
any time from the last assessment on Day 0 to quarantine discharge 
 
Proportion of Subjects with Grade 2 or higher Symptoms on two separate 
occasions at any time from the last assessment on Day 0 to quarantine 
discharge 
 
Proportion of Subjects with any symptom (grade >=1) on any occasion at any 
time from the last assessment on Day 0 to quarantine discharge 
 
Proportion of Subjects with any symptom (grade >=1) on two separate 
occasions at any time from the last assessment on Day 0 to quarantine 
discharge 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
66 
TERTIARY 
Tertiary/exploratory endpoints include, but are not limited to; 
To explore the 
safety of wild 
type 
SARS-
CoV-2 human 
challenge 
model 
in 
healthy adults 
To explore safety related measures of wild type SARS-CoV-2 challenge in healthy 
participants by assessing:  
 
Changes in smell (anosmia/parosmia) and cognition through infection 
 
Pulmonary changes due to experimental infection, as measured by: 
o High-resolution CT 
o Spirometry (FEV1, FVC) 
o Forced Oscillatory Technique (FOT) 
 
Association of ABO blood group and susceptibility to infection 
 
Occurrence of haematological and biochemical laboratory abnormalities during 
the quarantine period. 
 
Use of concomitant medications within 30 days post-viral challenge (Day 0 up 
to Day 28 follow up). 
To explore the 
SARS-CoV-2 
viral infection 
rates in saliva 
in 
healthy 
volunteers, by 
inoculum 
dose 
To measure the laboratory confirmed infection rates, as defined by: 
 
Occurrence of at least two quantifiable (≥LLOQ) RT-PCR measurements, 
reported on 2 or more consecutive timepoints, starting from 24 hours post-
inoculation and up to discharge from quarantine. 
 
Occurrence of at least two detectable (≥LLOD) RT-PCR measurements, 
reported on 2 or more consecutive timepoints, starting from 24 hours post-
inoculation and up to discharge from quarantine. 
 
Occurrence of at least one quantifiable (≥LLOQ) SARS-CoV-2 viral cell culture 
measurement, starting from 24 hours post-inoculation and up to discharge from 
quarantine. 
To explore the 
SARS-CoV-2 
viral dynamics 
in 
saliva 
in 
healthy 
volunteers, by 
inoculum 
dose 
To assess viral dynamics, as defined by: 
 
Area under the viral load-time curve (VL-AUC) of SARS-CoV-2 as determined 
by qRT-PCR measurements in saliva, starting from 24 hours post-inoculation 
and up to discharge from quarantine. 
 
Peak viral load of SARS-CoV-2 as defined by the maximum viral load 
determined by quantifiable qRT-PCR measurements in saliva, starting from 24 
hours post-inoculation and up to discharge from quarantine. 
 
Duration of SARS-CoV-2 quantifiable qRT-PCR measurements in saliva, 
starting from 24 hours post-inoculation and up to discharge from quarantine. 
Duration is defined as the time (hours) from first the quantifiable of the two viral 
quantifiable positives used to assess infection until first confirmed undetectable 
assessment after their peak measure (after which no further virus is detected).


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
67 
 
Incubation period of SARS-CoV-2 qRT-PCR measurements in saliva. 
Incubation period is defined as the time (hours) from inoculation to the first 
quantifiable of the two viral quantifiable positives used to assess infection, 
starting from 24 hours post-inoculation and up to discharge from quarantine. 
 
The above endpoints may also be evaluated using quantitative cell culture. 
To explore the 
host-
pathogen 
relationship in 
the 
SARS-
CoV-2 human 
challenge 
model 
in 
healthy adults 
The primary, secondary, and tertiary endpoints may be explored in relation to 
immunological levels at baseline and after SARS-CoV-2 challenge. Assays 
performed on serum and mucosal samples may include, but are not limited to:  
 
Humoral immunity / systems serology SARS-CoV-2 (for example: SARS-CoV-
2 neutralizing titres, ELISAs to IgG, IgM, IgA, sIgA, ADCC) 
 
Proteomic levels and changes (for example, cytokine and chemokines) 
 
Cellular cell quantification and quality of immunity (for example T and B cell 
frequencies, 
phenotypes 
and 
functionality 
assays, 
ELISPOTs, 
ICS, 
cytokine/chemokine responses) 
 
Transcriptome levels and changes (for example, RNAseq, single cell RNAseq, 
microarray, PCR) 
 
Human genomics in relation to SARS-CoV-2 susceptibility, infection (e.g. HLA 
typing, SNPs, GWAS) 
 
Viral genomics to assess the possible emergence of mutations in SARS COV-
2 over the duration of the study 
 
Viral genomics in relation to SARS-CoV-2 population changes through infection
 
Microbiome analysis in relation to viral infection, disease and susceptibility (e.g. 
PCR, NGS, 16s rRNA) 
To explore the 
Minimal 
Clinically 
Important 
Difference 
(MCID) 
in 
instrument 
change 
To explore the average amount of instrument-assessed change for all participants 
who rate themselves as "a little better" or "somewhat better". Instruments include 
but are not limited to: 
 
Symptom diary card (Categorical Scale) 
 
Symptom diary card (Visual Analogue Scale) 
To 
explore 
environmental 
contamination 
in the SARS-
CoV-2 human 
challenge 
model 
in 
healthy adults 
To explore the environmental contamination of SARS-CoV-2 as a result of infection 
in participants, as measured by: 
 
Air sampling for virus detection and quantification 
 
Exhaled breath sampling with the use of a face mask for virus detection and 
quantification 
 
Surface swabbing for virus detection and quantification 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
68 
3. Study Design 
A schematic overview of the study design is presented in Figure 1. 
3.1 Overall Design 
This is a dose finding human experimental infection study in healthy adults 18 to 30 years of age 
inclusive with no known risk factors for severe COVID-19, using a GMP-produced SARS-CoV-2 
wild type strain. 
The study is divided into two phases, outpatient phase and quarantine phase (confinement 
phase).   
Specific procedures to be performed during the study, as well as their prescribed time points and 
associated visit windows, are outlined in the SoA in Table 1. Details of each procedure are 
provided in Section 5.  
Where multiple assessments are scheduled for collection at the same time point, assessments 
can be performed before or after the specified time point, within their permitted time windows, as 
required. If blood sampling or vital signs measurement is scheduled for the same time point as 
ECG recording, the procedures will be performed in the following order: ECG(s), vital signs, blood 
draw. Actual dates and times of all assessments will be recorded in the CRF. 
3.2 Screening Phase  
Screening of potential participants will take place in two stages with an initial screening visit, 
followed by a study specific remote consultation to go through the full study participant information 
(if not already done at the screening visit), thus allowing the informed consent form (ICF) to be 
signed at admission to the quarantine unit, following adequate time for ICF and participation in 
the study to be considered. Screening visits will take place at hVIVO QMB Innovation Centre. 
Between Day -90 to Day -2 potential participants will be screened under a separate study-specific 
screening protocol using a screening ICF and advertising material that has been approved by the 
Research Ethics Committee (REC) and Health Research Authority (HRA). Screening activities 
under the separate screening protocol may continue up until subjects sign the study specific 
consent. Recruitment will be done through a number of channels: 
 
Approved advertising, including social media 
 
hVIVO volunteer database (Volunteers already registered with any other hVIVO database 
may be contacted to determine their interest in participating in SARS-CoV-2 research.) 
 
Referral 
 
Organic search (e.g. via Google or other search engines) 
Where volunteers who have previously registered or been screened by hVIVO have given written 
consent, their data may be used as part of the screening process. Volunteers that do not enroll in 
this study for any reason will be recorded as screen failures and may be eligible to participate in 
other studies. If they consent, the results of their screening questionnaires and some or all 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
69 
screening tests may be used to assess their suitability for other ethically-approved studies, if they 
fall within the screening window. 
The screening process will consist of several stages: registration (if not already registered); 
webform questionnaire; telephone questionnaire; screening visit. 
Volunteers already registered with any other hVIVO database may be contacted to determine 
their interest in participating in SARS-CoV-2 research. Others interested in participating will be 
asked to register their details on a SARS-CoV-2 specific web page UKcovidchallenge.com. All 
advertising and media will direct volunteers to this web page to register their interest. If they fit 
the age criteria, they will be contacted and guided to a webform questionnaire. They will then be 
contacted by telephone to complete a telephone questionnaire to collect further demographic and 
health information. 
If inclusion/exclusion criteria are provisionally met based on answers to these questions, an 
appointment for screening will be scheduled and a confirmation email plus both screening and full 
study Participant Information Sheets (PIS)/Informed Consent Forms (ICF) will be sent. Screening 
appointments will be conducted at hVIVO. At the screening visit, the PIS/ICF will also be 
discussed with them by the study doctor or nurse.  Volunteers will have their QCOVID risk scores 
calculated and explained to them. When the subject has had enough time to consider their 
participation in this study, ask any questions they may have, and only when they have agreed to 
take part will they be asked to read, sign and date the relevant consent form in the presence of 
the study doctor or nurse who will also sign the consent form.  Written consent will be obtained 
prior to any history-taking, examination or tests are carried out. A copy will be kept in the research 
file, a copy given to the patient and a copy put into their medical notes. 
Following informed consent, medical history, examination and screening assessments will be 
undertaken (see SoA, Table 1). The volunteer’s medical history will be requested from their GP 
and reviewed to assess suitability. Subjects may be invited for repeat assessment where / if 
required at the PI’s discretion. GP medical histories that have been previously received by hVIVO 
and assessment results from earlier quarantine admissions (if the subject did not go on to be 
inoculated) may be used for screening purposes if obtained within the screening window. 
3.3 Study Specific Consent 
Following the screening phase, suitable participants willing to take part in the study will be 
provided with a study specific Participant Information Sheet (PIS) and Informed Consent Form 
(ICF), if this was not available at the screening visit. In all cases, the PIS/ICF will be provided prior 
to admission to the quarantine unit to allow adequate time for participants to read and consider 
the PIS/ICF, discuss the study with family members and/or friends and ask questions about the 
research. A follow-up appointment (conducted remotely due to the COVID-19 pandemic) will be 
made for the participant to go through the details of the study and PIS/ICF with a trained study 
team member to ensure understanding of the risks and unknowns of the study and given an 
opportunity to ask further questions. A multiple-choice quiz will then be conducted to check the 
volunteer’s understanding of the study rationale, procedures and risks. If they do not pass the 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
70 
quiz, the study team member will check the incorrect quiz answers and re-review with the 
volunteer the relevant ICF sections to ensure understanding.  
On Day -2/-1, the participant will be admitted to the quarantine unit. Prior to any study specific 
procedures taking place, participants will have a further opportunity to discuss the research 
protocol with a trained study team member before signing the full study specific ICF. The full 
consent process will be audio recorded. 
To minimise the risk of admitting someone incubating SARS-CoV-2, a risk-based approach based 
on the Royal Free London NHS Trust Standard Operating Procedures for elective admissions will 
be used prior to enrolment: 
 
1. Participants will be advised to stay at home for the requisite number of days before 
admission, not leaving the house for any reason other than an emergency or to have a 
COVID test. 
2. A swab test will be sent to the participant. This must be taken within 72 hours before 
admission and shown to be negative for SARS-CoV-2. 
3. On admission, they will be met by staff wearing PPE and will go directly into their own en-
suite room.  
4. During their stay, they will only have contact with staff wearing PPE, thus mitigating 
onward transmission if they have undiagnosed infection.  
5. Participants will then be re-tested for SARS-CoV-2 (along with a panel of other respiratory 
viruses and bacteria) with a negative result required before inoculation.  
It is recognized that the Royal Free London NHS Trust Standard Operating Procedures for 
elective admissions may change over time, and as such the risk mitigating steps listed above may 
be adjusted to align with the procedures, as appropriate. 
3.4 Quarantine Phase  
Subjects will stay overnight for a period of at least 16 days, from 1 to 2 days before the viral 
challenge, to at least the 14th day after viral challenge (see discharge criteria, Section 5.18.5). 
This period of quarantine has been chosen to eliminate the possibility of subjects in the study 
transmitting the virus to anyone not involved in the study (i.e. family, household contacts, and the 
wider community).  During the quarantine period, all study procedures will take place in the Royal 
Free Hospital Quarantine Unit designated for this study. 
Around one week before each challenge cohort, a panel of leaders of the North Central London 
(NCL) Adult Critical Care Network will meet with the CI, PI and clinical team to assess clinical 
capacity as follows: 
 
Using their direct access to daily capacity data across the network, plus local and national 
projections, the panel will provide an evidence-based opinion on clinical capacity at the 
start of each challenge group as well as the weeks to come, and advise whether it is safe 
to commence.  
 
This will also include review of non-ITU bed state and radiology capacity.  


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
71 
 
This decision will be recorded in the Trial Master File and no dosing will take place 
without a favourable opinion from this panel. 
3.5 Follow Up Phase  
There will be telephone calls every 2-3 days between discharge from Quarantine and Day 28 (+/- 
3 days). During follow up phase all participants will be required to attend 5 clinic visits at the 
hVIVO site (QMB) on Day 28 (+/- 3 days), Day 90 (+/- 7 days), Day 180 (+/- 14 days), Day 270  
(+/- 14 days) and Day 360 (+/- 14 days), as specified in the SoA, Table 1. 
3.6 End of Study Definition 
A participant is considered to have completed the study if he/she has completed all phases 
including the last scheduled visit shown in the SoA Day 360 (± 14 days) 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. See 
Section 4 for procedures in the event of Discontinuation of study intervention or volunteer 
withdrawal. 
Subjects will return to the care of their own GP following discharge from the quarantine unit.  
Should any abnormal assessment or finding  be reported that is deemed clinically significant the 
subjects GP will be informed. 
3.7 Study Population 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions are not permitted in this study. 
3.8 Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply:  
NO 
INCLUSION CRITERIA  
1 
An informed consent document signed and dated by the participant and the 
Investigator. 
2 
Male or female, age between 18 and 30 years inclusive (at the time of consent) 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
72 
3 
Seronegative to the challenge virus SARS-CoV-2, no history of SARS-CoV-2 
infection and no previous participation in a SARS-CoV-2 vaccine trial. 
4 
Female participants with a documented menstrual period within 28 days before 
the inoculation (unless using a contraceptive method that suppressed 
menstruation as indicated in the study protocol) and willing and able to use 
contraception as described in the study protocol from 2 weeks before the 
scheduled date of viral challenge until 6 months after receipt of the final dose of 
study virus or intervention treatment (whichever occurs last).  Negative urine 
pregnancy tests will be required at screening and on day 0 prior to inoculation. 
On admission to the quarantine unit a Negative serum beta human chorionic 
gonadotropin (β-hCG) is required.  
Contraceptive requirements: 
Established use of hormonal methods of contraception described below (for 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:  
1)  combined (oestrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation:  
i. oral  
ii. intravaginal  
iii. transdermal  
2). progestogen-only hormonal contraception associated with inhibition of 
ovulation:  
i. oral  
ii. injectable  
iii. implantable 
3) Intrauterine device (IUD)  
4). Intrauterine hormone-releasing system (IUS)  
5). Bilateral tubal ligation  
6). 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.  
7). 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 subject.  
5 
Men who are willing to use one of the contraception methods described in the 
study protocol, from the time of the date of viral challenge, until 6 months after 
receipt of the final dose of study medication (if applicable). 
Contraceptive requirements: 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
73 
3.9 Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
NO 
STANDARD EXCLUSION CRITERIA   
Any potential subject who meet any of the criteria below will be excluded from participating 
in this study. 
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 study virus or 
intervention treatment.  
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 subjects.  
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 subject.  
 
In addition to the contraceptive requirements above, male subjects must agree 
not to donate sperm following discharge from quarantine until 6 months after the 
date of study virus receipt or intervention treatment (whichever occurs last).  
 
6 
In good health with no history of clinically significant medical conditions (as 
described in Exclusion criteria) that would interfere with subject safety, as defined 
by medical history, physical examination and routine laboratory tests, ECG, and 
Chest X-Ray and determined by the Investigator at an admission evaluation. 
7 
Subjects will have a documented medical history either prior to entering the study 
and/or following medical history review with the study physician at screening 
8 
Willing and able to commit to participation in the study 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
74 
NO 
STANDARD EXCLUSION CRITERIA   
Clinical history 
1.  
History or evidence of any clinically significant or currently active cardiovascular, 
(including thromboembolic events), respiratory, dermatological, gastrointestinal, 
endocrine, haematological, hepatic, immunological, rheumatological, metabolic, 
urological, renal, neurological, psychiatric illness. Specifically: 
a) Subjects with any history of physician diagnosed and/or objective test 
confirmed asthma, chronic obstructive pulmonary disease, pulmonary 
hypertension, reactive airway disease, or chronic lung condition of any 
aetiology or who have experienced: 
o Significant/severe wheeze in the past 
o Respiratory symptoms including wheeze which has ever resulted 
in hospitalisation 
o Known bronchial hyperreactivity to viruses 
b) History of thromboembolic, cardiovascular or cerebrovascular disease 
c) History or evidence of diabetes mellitus 
d) Any concurrent serious illness including history of malignancy that could 
interfere with the aims of the study or a subject completing the study. 
Basal cell carcinoma within 5 years of treatment or with evidence of 
recurrence is also an exclusion 
e) Migraine with associated neurological symptoms such as hemiplegia or 
vision loss.  Cluster headache/migraine or prophylactic treatment for 
migraine 
f) History or evidence of autoimmune disease or known immunodeficiency 
of any cause. 
g) Other major disease that, in the opinion of the Investigator, could interfere 
with a subject completing the study and necessary investigations. 
h) Immunosuppression of any type 
2.  
Any significant abnormality altering the anatomy or function of the nose or 
nasopharynx in a substantial way (including loss of or alterations in smell or 
taste), a clinically significant history of epistaxis (large nosebleeds) within the last 
3 months, nasal or sinus surgery within 6 months of inoculation. 
3.  
Clinically active rhinitis (including hay fever) 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. 
4.  
History of anaphylaxis and/or a history of severe allergic reaction or significant 
intolerance to any food or drug, as assessed by the PI. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
75 
NO 
STANDARD EXCLUSION CRITERIA   
5.  
History or presence of alcohol addiction, or excessive use of alcohol (average 
weekly intake in excess of 28 units alcohol; one unit being a half glass of beer, a 
small glass of wine or a measure of spirits), or use of drugs of abuse 
6.  
Psychiatric illness including subjects with a history of depression and/or anxiety 
with associated severe psychiatric comorbidities, for example psychosis. 
Specifically,  
a) Subjects with history of anxiety-related symptoms of any severity within 
the last 2 years if the Generalized Anxiety Disorder-7 score is ≥4 
b) Subjects with a history of depression of any severity within the last 2 years 
if the Patient Health Questionnaire-9 score is ≥4 
 
7.  
Subjects who have smoked ≥5 pack years at any time [5 pack years is equivalent 
to one pack of 20 cigarettes a day for 5 years]). 
 
Subjects who have smoked <5 pack years - at any time in the 3 months prior 
to admission to the quarantine unit they have used tobacco in any form (e.g., 
smoking or chewing) or other nicotine-containing products in any form (e.g., 
gum, patch) or electronic cigarettes. 
8.  
Family history of 1st degree relative aged 50 years or less with sudden cardiac 
or unexplained death  
9.  
Family History of Severe COVID or response to any other viral disease 
e.g. Guillain–Barré 
Measurements and investigations 
10.  
A total body weight of ≤ 50kg and a Body Mass Index (BMI) ≤18 kg/m2 and ≥28 
kg/m2. The upper limit of BMI may be increased to ≤ 30kg/m2 at the PI’s 
discretion, in the case of physically fit muscular individual 
11.  
Venous access deemed inadequate for the phlebotomy and cannulation 
demands of the study. 
12.  
Any clinically significant abnormal finding on screening biochemistry, 
haematology and microbiology blood tests or urinalysis i.e. grade 1 lab 
abnormalities or above (see Appendix 3 Toxicity Grading Scale for Laboratory 
AEs) apart from minor deviations which are clinically acceptable and approved 
by the Principal Investigator 
a) Elevated random glucose and HbA1C 
b) Positive HIV, active/chronic hepatitis A, B or C test. 
c) Confirmed positive test for drugs of abuse on admission and urinary 
cotinine at quarantine. 
13.  
A forced expiratory volume in 1 second (FEV1) and a forced vital capacity (FVC) 
<80% of predicted value calculated using ATS/ERS guidance (refer to section 5, 
respiratory samples)  


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
76 
NO 
STANDARD EXCLUSION CRITERIA   
14.  
Twelve-lead ECG recording with clinically relevant abnormalities as judged by 
the study physician/PI. 
15.  
Echocardiogram outside normal parameters at baseline 
Recent respiratory infection 
16.  
History of, or currently active symptoms suggestive of upper or lower respiratory 
tract infection (including reduced sense of taste and smell, raised body 
temperature and/or persistent cough) within 6 weeks prior to viral challenge. 
17.  
Presence of cold-like symptoms and/or fever (defined as subject presenting with 
a temperature reading of >37.9ºC) on Day -2, Day -1 and/or pre-challenge on 
Day 0. 
18.  
Evidence of any respiratory viruses (on nasopharyngeal swab analysis) prior to 
challenge virus inoculation on admission to the quarantine unit. These include: 
VIRUSES: 
● Adenovirus 
● Coronavirus HKU1 
● Coronavirus NL63 
● Coronavirus 229E 
● Coronavirus OC43 
● Human Metapneumovirus 
● Human Rhinovirus/Enterovirus 
● Influenza A 
● Influenza A/H1 
● Influenza A/H3 
● Influenza A/H1-2009 
● Influenza B 
● Parainfluenza Virus 1 
● Parainfluenza Virus 2 
● Parainfluenza Virus 3 
● Parainfluenza Virus 4 
● Respiratory Syncytial Virus 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
77 
NO 
STANDARD EXCLUSION CRITERIA   
 
BACTERIA: 
● Bordetella parapertussis 
● Bordetella pertussis 
● Chlamydia pneumoniae 
● Mycoplasma pneumoniae 
Receipt of medications and interventions 
19.  
Evidence of a live vaccine within 60 days prior to the planned date of viral 
challenge, a non-live vaccine within 30 days prior to the planned date of viral 
challenge, or intention to receive any vaccination(s) before the day 28 follow-up 
visit. (NB. No travel restrictions applied after the Day 28 Follow-up visit). 
20.  
Receipt of blood or blood products, or loss (including blood donations) of 550 mL 
or more of blood during the 3 months prior to the planned date of viral challenge 
or planned during the 3 months after the final visit. 
21.  
Medications 
a) Use of any medication or product (prescription or over-the-counter), for 
symptoms of hayfever, nasal congestion or respiratory tract infections or 
dermatitis/eczema including the use of regular nasal or medium-high 
potency dermal corticosteroids, antibiotics and First Defence™ (or 
generic equivalents) within 7 days prior to the planned date of viral 
challenge apart from those described in Table 7, Permitted Medication or 
agreed by the Principle Investigator 
b) Receipt of any investigational drug within 3 months prior to the planned 
date of viral challenge. 
c) Receipt of three or more investigational drugs within the previous 12 
months prior to the planned date of viral challenge. 
d) Prior inoculation with a virus from the same virus-family as the challenge 
virus. 
e) Receipt of systemic (intravenous and/or oral) glucocorticoids or systemic 
antiviral drugs within 6 months prior to the planned date of viral challenge.
f) Over the counter medications (e.g., paracetamol or ibuprofen) where the 
dose taken over the preceding 7 days prior to the planned date of viral 
challenge had exceeded the maximum permissible 24-hour dose (e.g., 
>4g per day of paracetamol over the preceding week). 
g) Use or anticipated use within 7 days prior to the planned date of viral 
challenge and during the conduct of the study of concomitant medications 
(prescription and/or non-prescription), including vitamins or herbal and 
dietary supplements within the specified windows. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
78 
NO 
STANDARD EXCLUSION CRITERIA   
h) Chronically used medications, vitamins or dietary supplements, including 
any medication known to be a moderate/potent inducer or inhibitor of 
cytochrome P450 enzymes, within 21 days prior to the planned date of 
viral challenge. 
i) 
Subjects who have received any systemic chemotherapy agent, 
immunoglobulins, or other cytotoxic or immunosuppressive drugs at any 
time. 
22.  
Prior participation in another human viral challenge study in the preceding 12 
months taken from the date of viral challenge in the previous study to the date of 
expected viral challenge in this study. 
23.  
Any nasal sampling procedure in the 6 months before date of expected viral 
challenge in this study (excluding study tolerance test or routine tests for COVID-
19) 
General 
24.  
Subject was mentally or legally incapacitated in the opinion of the Investigator. 
 
25.  
Females who: 
a) Are breastfeeding within 6 months of study commencement, or 
b) Had been pregnant within 6 months prior to the study, or 
c) Had a positive pregnancy test at any point during screening or prior to 
inoculation with challenge virus 
26.  
Those in close domestic contact (i.e. sharing a household with, caring for, or daily 
face to face contact) with children under 2 years, the elderly (>65 years), 
immunosuppressed persons, or those with chronic respiratory disease 
Other 
27.  
Was employed or was a first-degree relative of anyone employed by the 
Sponsor, a participating clinical trial site, or any Contract Research Organisation 
involved in the study. 
28.  
Any other reason that the Investigator considered made the subject unsuitable 
to participate. 
29.  
Participants with no knowledge of their family history 
Prior to enrolment, each potential participant deemed to be suitable for entry into the study (based 
on inclusion/exclusion criteria and their screening assessments) will undergo a personalised risk 
assessment using the QCOVID tool in combination with emergent results from individuals 
experimentally infected with SARS-CoV-2 in this study. The risk assessment will be reviewed by 
a member of the study medical team, documented and discussed with the participants before 
enrolment.  
Personalised risk assessment using the QCOVID tool - 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
79 
https://qcovid.org/PatientInformation/PatientInformation 
3.10 Lifestyle Considerations 
3.10.1 Meals and dietary restrictions 
No dietary restrictions are required before or after dose administration.  
3.10.2 Caffeine, alcohol and tobacco 
During quarantine, participants must abstain from ingesting more than three cups of coffee, tea 
or other caffeine-containing products per day. Decaffeinated drinks will be made available. 
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, use tobacco or any nicotine containing products for 3months prior 
to and during quarantine.   
3.10.3 Activity 
Participants will abstain from strenuous exercise that is unusual for them, for 48 hours prior and 
during quarantine and for 48 hours prior to each clinic visit (this is at the discretion of the 
Investigator). 
3.11 Screen Failure 
Screen failures are defined as participants who sign the screening study Informed Consent Form 
(ICF) but who are not subsequently enrolled in the study.  
For individuals who do not meet the criteria for participation in this study (screen failure), the 
Investigator will decide whether the participant should be permanently excluded from the study or 
invited back for repeat assessments (i.e. repeat clinical laboratory test) if the initial screening 
assessments are still within the allowed screening windows, or rescreening for a later quarantine, 
as appropriate. 
 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
80 
4. Study Intervention(s) 
Study interventions administered to participants are described in Table 7. 
4.1 Summary of Study Intervention(s) Administered 
Table 7 - Study Interventions 
Intervention 
Name 
 
SAR-COV-2 
 
Veklury® (Remdesivir) 
 
REGEN-COV 
 
(casirivimab with imdevimab) 
Type  
 
Virus 
 
Drug (Pre-emptive treatment) 
 
Drug (Rescue treatment) 
Dose 
Formulation 
 
Ampoule, Liquid 
VEKLURY™ (Remdesivir) for injection, 
100 
mg, 
available 
as 
a 
sterile, 
preservative-free, white to off-white to 
yellow lyophilized powder 
The solution for each vial should be clear to 
slightly opalescent, colourless to pale yellow 
Unit 
Dose 
Strength(s) 
 
The 
titre 
of 
the 
undiluted 
Challenge Virus stock (Master 
Virus Bank) is determined in an 
infectivity assay and is reported 
in Tissue Culture Infective Dose 
units per mL (TCID50/mL). The 
inoculum 
virus 
vials 
are 
produced by dilution of the 
master virus bank to achieve 
targeted challenge doses, as 
follows: 
 
Dose level 1 ~ 10 TCID50 (~101 
TCID50 dose) 
Each 100 mg single-dose vial contains 
a sterile, preservative-free lyophilized 
powder that is to be reconstituted with 
19 mL of Sterile Water for Injection and 
diluted into 0.9% sodium chloride prior 
to 
administration 
by 
intravenous 
infusion. Following reconstitution, each 
vial contains 100 mg/20 mL (5 mg/mL) 
of 
VEKLURY 
(Remdesivir) 
concentrated solution. 
Casirivimab and imdevimab solutions must be 
diluted prior to administration. 
Casirivimab with Imdevimab 1,200 mg Dose.  
Further details are described in the pharmacy 
manual. recovery-regn-cov2-pharmacy-manual-
v4-0-2020-11-04.pdf (recoverytrial.net) 
 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
81 
 
Dose level 2 ~ 100 TCID50 (~102 
TCID50 dose) 
 
Dose level 3 ~ 1,000 TCID50 
(~103 TCID50 dose) 
 
Optional additional Dose levels 
(e.g. 
~1 
TCID50, 
~10,000 
TCID50, ~ 100,000 TCID50, 
Dosage 
Level(s) 
 
Different doses of virus will be 
evaluated. 
Dose 
volume 
delivery method is provided in 
the Section 4.2.5. 
 
The recommended dosage for 
adults weighing at least 40 kg is a 
single loading dose of VEKLURY 
(Remdesivir) 200 mg on Day 1 
followed 
by 
once-daily 
maintenance doses of VEKLURY 
(Remdesivir) 100 mg from Day 2. 
The treatment duration is 5 days. 
 
The dosage in adults is 600 mg of casirivimab 
and 600 mg of imdevimab administered 
together as a single intravenous infusion via 
pump or gravity. The duration of treatment is 
1 day 
Route 
of 
Administration 
 
Intranasal 
 
IV infusion 
 
IV infusion 
Use 
 
Infectious challenge agent 
 
Pre-emptive antiviral treatment 
 
Rescue treatment 
IMP and NIMP 
 
N/A 
 
NIMP  
 
NIMP 
Sourcing 
 
Provided centrally by hVIVO 
 
Provided centrally by the Sponsor. 
 
Provided centrally by the Sponsor. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
82 
Packaging and 
Labelling 
 
Challenge Inoculum will be 
provided in single-dose vials. 
The 
details 
of 
the 
virus 
challenge agent will be provided 
in the Analytical Plan 
 
Packaging and Labelling of the 
study Intervention is described   in 
the 
Investigational 
Medicinal 
Product 
Dossier 
2.1.P.3 
Manufacture 
[Remdesivir 
(GS-
5734™) for Injection]. 
 
Packaging and Labelling of the study 
Intervention 
is 
described 
in 
the 
Investigational Medicinal Product Dossier.  
Current/Former 
Name(s) 
or 
Alias(es) 
 
N/A 
 
Remdesivir ™, Veklury 
 
REGEN-COV (casirivimab with imdevimab) 
Refer to Section 4 and the pharmacy manual for details regarding administration of the study intervention, and Section 4 of the analytical 
plan for further details of the virus inoculum. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
83 
4.2 SARS-CoV-2 Challenge Virus 
4.2.1 Provenance of the wild type SARS-CoV-2 challenge virus 
The SARS-COV-2 challenge virus strain was originally obtained from a nose/throat swab taken 
from a patient in the UK who developed respiratory symptoms consistent with COVID-19. The 
virus was isolated by inoculation with the clinical sample of a qualified cGMP Vero Cell line.  A 
Seed Virus Stock was then generated by a further passage on the same cGMP Vero Cell line.   
The Zayed Centre for Research (ZCR) GMP manufacturing facility of Great Ormond Street 
Hospital (GOSH) subsequently used the Seed Virus Stock to manufacture the Challenge Virus in 
accordance with cGMP and produce a Challenge Virus Master Virus Bank.      
Individual person inoculum vials were then produced in accordance with cGMP by GOSH by 
dilution of the cGMP MVB with cGMP sucrose diluent.   Inoculum vials have been produced at a 
range of viral concentrations.  The challenge virus has undergone extensive quality testing 
performed as part of the GMP manufacturing release processes according to pre-determined 
specifications (including identity, infectivity and contaminant / adventitious agent tests). The 
challenge virus will be stored in a secure –80°C freezer (normal temperature range –60°C to –
90°C). This virus has not been used in previous human virus challenge studies. 
4.2.2 Justification for treatment dose and route of administration 
The starting SARS-CoV-2 dose (101 TCID50) was selected as a dose that is below the lowest 
reliably quantifiable amount of infectious virus. Refer to section 4 for more details on dose 
escalation.  
4.2.3 Supply and accountability of challenge virus 
The study site will establish a system for control of challenge virus in accordance with site SOPs 
and as detailed in the analytical plan. The PI will maintain accurate records of receipt and 
condition of all challenge virus inoculum stock used for challenge in accordance with the site 
SOPs, including details and dates of the batch and vial numbers, quantities dispensed and used 
in the study. Any departures from the protocol-dispensing regimen will be fully documented. 
Accountability records will be maintained as per the hVIVO site and hVIVO laboratory SOPs.  
4.2.4 Storage of challenge virus 
Stocks of challenge virus will be maintained as per the site analytical plan and SOPs and will be 
stored in a secure –80°C freezer (normal temperature range –60°C to –90°C). Vials will be thawed 
just before inoculum preparation. Once thawed, vials of stock virus will not to be re-used for 
human challenge studies. The residual of the inoculum in the vials used for challenging the 
subjects with the challenge virus will be frozen and stored in accordance with the analytical plan. 
All storage records were maintained as per the analytical plan. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
84 
4.2.5 Preparation and administration of challenge virus 
All participants will be administered GMP-compliant SARS-CoV-2 at one of dose levels by 
intranasal drops on Day 0, starting at 101 TCID50 dose (see Section 6). In this exploratory dose 
optimisation study, increasing doses of wild-type SARS-COV-2 will be given via nasal 
administration to healthy volunteers. Up to three viral dose levels are anticipated to be needed, 
however higher or lower doses may be required, as appropriate: 
 
Dose level 1 ~ 10 TCID50 (~101 TCID50 dose) 
 
Dose level 2 ~ 100 TCID50 (~102 TCID50 dose) 
 
Dose level 3 ~ 1,000 TCID50 (~103 TCID50 dose) 
 
Optional additional Dose levels that may be evaluated  
o > 1,000 TCID50 (i.e. ~10,000 TCID50, ~ 100,000 TCID50,) 
o < 10 TCID50 (e.g. ~1 TCID50) 
SARS-CoV-2 virus will be used for experimental infection of volunteers. On the day of inoculation 
(Day 0), aliquots of challenge virus will be removed from storage in the -80 ᵒC freezer and 
transferred to the quarantine unit on dry ice.  
A clinically trained staff member will inoculate each volunteer in the high containment room in 
which the volunteer will subsequently remain quarantined, with another staff member acting as 
scribe-/timekeeper/assistant. A sign will be placed on the door of the room to indicate that 
inoculation is taking place and to prevent accidental entry of others. Staff will wear full PPE (FFP3 
mask or respirator; full waterproof gown; visor; gloves; and shoe covers) when in the participant’s 
room during and at all times after inoculation.  
The inoculum dose will be rapidly defrosted by warming in the hand and then placed on ice (if 
necessary).  Subjects will then be inoculated with intra-nasal drops (100 µl/naris) with inoculum 
at a given dose divided equally between the two nostrils. Inoculations using intranasal drops will 
be done using a pipette with subjects’ supine (face and torso facing up and remaining so for at 
least 20 minutes post inoculation). This will be done slowly with at least 30s intervals between 
each nostril (inoculation) to ensure maximum contact time between with the nasal and pharyngeal 
mucosa. Subjects will be asked not to swallow during the procedure to ensure maximal 
pharyngeal contact and not to shower or blow their nose for at least two hours. Following 
inoculation, advice regarding infection control, emergency call and hand hygiene will be given. 
To quantify the amount of SARS-COV-2 inoculated into each volunteer within a cohort, a 
quantitative culture (infectivity assay) may be performed on an aliquot of the challenge inoculum 
removed before participant administration, stored on ice and transported immediately to the 
virology laboratory. Volunteer inoculations may also be back titrated using qRT-PCR. Where 
doses given that may not be quantifiable by cell culture given (e.g. 101 TCID50) due to the 
limitations of the assay sensitivity, the genome copies may be used to confirm that the intended 
dose was given.  


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
85 
4.3 Antiviral Treatment (Remdesivir as Pre-emptive Medication) 
Participants administered SARS-COV-2 may receive Remdesivir as an IV infusion for five days 
in a total volume of up to 250 mL 0.9% sodium chloride over 30 to 120 minutes. If pre-emptive 
treatment planned to be given, Remdesivir treatment will commence after either:  
 
confirmation of SARS-CoV-2 infection at two consecutive time points*, or  
 
immediately after symptoms, signs or investigations suggestive of COVID-19 
*dosing will commence the following day of the second confirmed swab or confirmed 
symptoms, if this falls during the night 
Details of Remdesivir dose preparation and administration will be described in the Pharmacy 
Manual. Please refer to the study pharmacy manual for instructions.  
The timing and benefit of Remdesivir will be kept under constant review by the DSMB. 
4.4 Dose Preparation 
Remdesivir doses for each individual participant will be prepared by a pharmacist or designee 
(e.g. nurse) in the quarantine unit at the Royal Free Hospital. Dose preparation process will be 
described in the pharmacy manual and in accordance with the Veklury® (Remdesivir) 
Investigator’s Brochure. 
4.5 Early “Rescue” Therapy 
Early “rescue” therapy, when backed by compelling evidence of efficacy and when available, is 
indicated for challenge model infections that demonstrate warning features beyond mild signs and 
symptoms that are confined to the upper respiratory tract. Indications to consider rescue therapy 
in those subjects confirmed to be infected include:  
 
Persistent tachypnoea – Respiratory Rate ≥ 21 for ≥ 8 hours  
 
Persistent Fever – Fever (≥ 37.9) from a time point 5 days post symptom onset and 
present for at least once each day for ≥ 72 hours  
 
Severe and persistent cough – Grade 3 (defined as “quite bothersome most or all of the 
time, and it stops me from participating in activities”) reports of coughing via symptom 
diary cards that is largely persistent over 48 hours  
 
For CT changes related to SARS CoV-2 infection, anything more than mild changes 
(based on the British Society of Thoracic Imaging COVID reporting scale) represents a 
standalone trigger and mild changes in combination with other concerning clinical features 
could also be considered. 
 
Any event of confirmed hypoxia (≤ 94%, usually confirmed over a 1-hour period) should 
this occur without the above ‘warnings’   
Importantly CI/PI discretion will be used at all times in the decision to start Rescue Therapy. 
Biochemical markers (e.g. elevated CRP/D-dimer) will not be used in isolation, though a 
combination of factors outside of the triggers above could still lead to a decision to start therapy.  


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
86 
Once a decision to commence rescue therapy has been made by the CI/PI, the NHS Infectious 
Diseases team at the Royal Free Hospital will be made aware. The subject will remain within the 
quarantine unit to receive rescue therapy unless protocol stated criteria for transfer to NHS care 
are met. 
“Rescue” treatment using Regeneron COV2 
Participants administered SARS-COV-2 may receive REGEN-COV as a rescue therapy (when 
indicated) as a single IV infusion in a total volume of up to 250 mL 0.9% sodium chloride over 30 
to 120 minutes. 
Details of REGEN-COV dose preparation and administration will be described in the Pharmacy 
Manual. Please refer to the study pharmacy manual for instructions.  
The benefit of REGEN-COV will be kept under review by the CI/PI, to decide whether or not it is 
appropriate to continue to use REGEN-COV, with discussion with the DSMB. 
 
4.6 Dose Preparation 
REGEN-COV doses for each individual participant will be prepared by a pharmacist or designee 
(e.g. nurse) in the quarantine unit at the Royal Free Hospital. Dose preparation process will be 
described in the pharmacy manual and in accordance with the Investigator’s Brochure. 
 
4.7 Handling, Storage, and Accountability 
All study interventions: 
1. The Principal 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 Principal Investigator, is responsible for study intervention accountability, 
reconciliation, and record maintenance (i.e., receipt, reconciliation, and final disposition 
records) 
4. Disposal of used and unused Virus inoculum vials will be done in accordance with hVIVO’s 
SOPs 
5. Procedure for partly used or unused supplies of intervention treatment will be described 
in the pharmacy manual. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
87 
4.8 Randomisation and Blinding 
Not applicable. 
4.9 Study Intervention Compliance 
Interruptions from the protocol-specified intervention plan require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.  
Any non-compliance or problems with the administration of the study intervention will be recorded 
in the participant’s source notes and documented as a protocol deviation if appropriate. 
4.10 Concomitant and Prior Therapy 
Permitted Medication 
 
Subjects who were taking, wanted to take, or were required to take regular medication 
(whether prescribed or not) during their participation are excluded from this study with the 
exception of those therapies listed below or unless agreed with the PI. Use of all permitted 
therapies has to be documented and agreed at the screening visit. 
 
The use of concomitant medications other than those listed in Table 8 is prohibited unless 
approved by the PI, including over-the-counter or prescribed medications. Where there is 
uncertainty, the PI is encouraged to discuss the use of any concomitant medications with 
the CI/Chief Investigator before initiating therapy. 
 
The Investigator is to be informed as soon as possible about any medication taken by a 
subject from the time of screening until the completion of the follow-up visit on Day 28. 
Agreed concomitant medications taken during the quarantine phase will be stored, 
prescribed and administered in line with their label-specific requirements and full 
accountability will be maintained. Use of all concomitant medications will be recorded in 
the case report form (CRF). Concomitant medications include all prescription drugs, herbal 
preparations, over-the-counter medications, vitamins and minerals. 
 
Table 8: Permitted medications and restrictions 
Permitted medication 
Restrictions 
Oral, injected or implanted contraceptives 
or hormone replacement therapies 
Recommended dosing 
Paracetamol 
Maximum daily dose of 4 g from 7 days 
before Day -1 and throughout the duration 
of the study 
Mild potency topical steroids 
Recommended dosing 
Over-the-counter 
creams 
and 
topical 
treatments 
Recommended dosing 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
88 
Prescription and non-prescription medications, including vitamins or herbal and dietary 
supplements, not listed in prohibited medications are subject to approval by the PI. 
 
Prohibited Medication 
All medications, other than those noted above are to be stopped before the planned date of viral 
challenge unless in the opinion of the Investigator and/or Sponsor’s Medical Monitor, the 
medication will not interfere with the study procedures or compromise subject safety. Certain 
medications requiring a specific washout period before a subject is eligible to enter the study; 
details are provided in Table 9. These medications are prohibited until day 28. 
Table 9 Prohibited Medications 
Prohibited medication 
Washout required 
Systemic corticosteroid (oral and parenteral) 
therapy 
6 months before the planned date 
of viral challenge 
Systemic (oral and parenteral) antiviral drugs 
6 months before the planned date 
of viral challenge 
Vaccinations 
30 days (non-live vaccine) or 60 
days (live vaccine) before the 
planned 
date 
of 
the 
study 
depending on the vaccine 
Short and long-acting anti-histamines 
7 
days 
before 
study-specific 
screening 
Any medication or product (prescription or over-
the-counter), for symptoms of nasal congestion or 
respiratory tract infections including nasal steroids
7 days before the planned date of 
viral challenge 
Herbal supplements 
7 days before the planned date of 
viral challenge 
Chronically used medications, vitamins or dietary 
supplements, including any medication known to 
be an inducer or inhibitor of cytochrome P450 
.enzymes 
21 days before the planned date of 
viral challenge 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
89 
4.11 Dose Escalation, De-escalation and Confirmation 
The study will involve dose escalation of SARS-CoV-2 to demonstrate safety and identify an optimum dose in participants with no 
evidence of previous SARS-CoV-2 infection including no detectable antibodies. Groups of up to 20 individuals will be challenged at a 
time as shown in Figure 4: 
 
Figure 4 Group and Dose Escalation Scheme 
Starting dose 10^1 TCID50
Sentinel group (n=3) 
If no pausing rules at 14 days then 
continue to
total n of up to 10
(Includes Remdesivir)
Low dose 10^1 TCID50
Planned n=10 (up to 20)
(with or without treatment)
Low dose 10^1 TCID50
Planned n=10 (up to 20)
Adaptive (see Criteria for 3rd
expansion group)
(with or without treatment)
Low/Medium dose 10^2 TCID50
Sentinel group (n=3) 
If no pausing rules at 7 days then 
continue to
total n of up to 10
(with or without treatment)
Low/Medium dose 10^2 TCID50
Planned n=10 (up to 20) 
(with or without treatment)
Low/Medium dose 10^2 TCID50
Planned n=10 (up to 20)
Adaptive (see Criteria for 3rd
expansion group)
(with or without treatment)
Medium dose 10^3 TCID50
Sentinel group (n=3) 
If no pausing rules at 7 days then 
continue to
total n of up to 10 
(with or without treatment)
Medium dose 10^3 TCID50
Planned n=10 (up to 20) 
(with or without treatment)
Medium dose 10^3 TCID50
Planned n=10 (up to 20)
Adaptive (see Criteria for 3rd
expansion group)
(with or without treatment)
If cohort ≥40% infected*
If cohort <40% infected*, 
or if sentinel 0% infected**
If cohort ≥40% infected*
If cumulative ≥70% 
infected*
If cohort ≥40% infected*
If cumulative < 70% infected***
If cumulative < 70% infected***
If cumulative < 70% infected***
If cumulative < 70% infected***
If cumulative ≥70% 
infected*
If cumulative ≥70% 
infected*
If cohort <40% infected*, 
or if sentinel 0% infected**
Low dose 10^0 TCID50
Planned n=10 (up to 20)
(with or without treatment)
Low dose 10^0 TCID50
Planned n=10 (up to 20)
(with or without treatment)
Low dose 10^0 TCID50
Planned n=10 (up to 20)
Adaptive (see Criteria for 3rd
expansion group)
(with or without treatment)
If cohort ≥40% infected*
If cumulative ≥70% 
infected*
If cumulative < 70% infected***
If cumulative < 70% infected***


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
90 
*Next inoculation ~1 week from last participant discharge (minimum 2 weeks of data), if agreed by DSMB, unless symptoms or investigations of 
concern by CI/PI.  
**If no infections in sentinel participants, progress to next dose level (Low dose requires a minimum of 14 days data, higher doses require a minimum 
of 7 days data). 
***If cumulative infection rate of all participants challenged at that dose level is <70%, the CI/PI may choose to progress to the next dose level ~1 
week from last participant discharge (minimum 2 weeks of data), if agreed by DSMB, unless symptoms or investigations of concern by CI/PI.  
 
Confirmation (blue arrow) of the same dose will occur if the following criteria are met (and in agreement with the DSMB): 
 
Safety criteria:  
 
No safety concerns identified at dose level 
 
Removal/addition of Remdesivir treatment in expanded cohorts will be decided upon after data review, and in agreement with the 
DSMB 
 
Additional expansion cohorts may be performed. 
 
Infectivity/disease criteria: If the infection criteria is met (i.e. ≥40% or ≥70%, as appropriate), and 
 
<2 infected participants present with any grade 3 symptom of wheeze, shortness of breath, or chest tightness* and 
 
<2 infected participants have grade 3 physician findings (DPE signs) of abnormal breath sounds (new wheezing, râles, rhonchi, 
other) 
 
Escalation (green arrow) may be performed if both of the following criteria are met (and in agreement with the DSMB): 
 
Safety criteria: No safety concerns identified at dose level 
 
Infectivity/disease criteria: If the infection criteria is not met (i.e. <40% or <70% as appropriate), and 
 
<2 infected participants present with any grade 3 symptom of wheeze, shortness of breath, or chest tightness* and 
 
<2 infected participants have grade 3 physician findings (DPE signs) of abnormal breath sounds (new wheezing, râles, rhonchi, 
other) 
 
De-escalation (orange arrow) may be performed if either of the following criteria are met (and in agreement with the DSMB): 
 
Safety criteria:  
 
Safety concerns are identified at the dose level, but that do not fulfil study stopping criteria 
 
Removal/addition of Remdesivir treatment in expanded cohorts will be decided upon after data review, and in agreement with the 
DSMB 
 
Infectivity/disease criteria: no infectivity requirement, and 
 
≥2 infected participants present with grade 3 symptoms of wheeze, shortness of breath, or chest tightness * or 
 
≥ 2 infected participants have grade 3 physician findings (DPE signs) of abnormal breath sounds (new wheezing, râles, rhonchi, 
other) 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
91 
Dose escalation will proceed as follows: 
 
The starting dose (101 TCID50) was selected as a dose below the lowest reliably 
quantifiable infectious amount of virus. At this lowest dose, three sentinel individuals will 
be challenged. If none of the first three sentinel individuals develop infection after 14 days 
and no pausing rules are met (based on severity and frequency of adverse events, see 
Group Safety Holding Rules), the dose will be escalated to 102 TCID50. If any of the first 3 
participants develop infection after 14 days and no pausing rules are met, the remaining 
7 participants in the group will be challenged.  
 
If any of the first 10 participants become infected, the next group of participants will be 
challenged at the earliest 7 days after the last participant was discharged (i.e. minimum of 
3 weeks between viral inoculation).  
 
If the number of infected participants in the first group do not meet the pre-defined attack 
rate threshold*, the next group of participants will be inoculated with a higher dose.  
 
With each subsequent higher dose level, three sentinel individuals will be challenged. After 
14 days, if no pausing rules are met (based on severity and frequency of adverse events, 
see Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting) the next 7 participants in the group can be challenged.  
 
If none of the first 10 participants at a dose level become infected by qPCR criteria, the 
next group will be challenged with the higher dose once all participants in the first group 
are discharged from quarantine (i.e. minimum of 2 weeks between viral inoculation).  
 
If any of the first 10 participants at a dosing level become infected, the next group will be 
challenged at the earliest 7 days after the last participant planned discharge (i.e. minimum 
of 3 weeks between viral inoculation).  
 
If the number of infected participants in the first group does not meet the pre-defined attack 
rate threshold*, the next group may be inoculated with a higher dose.  
 
If the highest dose of 103 TCID50 is reached and the number of infected participants in the 
first group does not meet the pre-defined attack rate threshold* and no pausing rules are 
met, further dose escalations to 104 and 105 TCID50 may take place. 
 
If the number of infected participants in the first group do meet the pre-defined attack rate 
threshold*, a second group of 10 participants will be challenged with the same dose level 
(i.e. resulting in 20 participants challenged at that dose level) to increase confidence for 
the attack rate at that dose level.  A third group of 10 participants may be challenged if 
review of clinical and virological outcome data suggest that a larger sample size is needed 
to establish confidence in the attack rate using the same experimental conditions (see 
Statistics and Data Analysis).  
 
If following dose escalation, review of clinical and virological outcome data suggest a risk of 
participants being exposed to excess risk (due to extremely high attack rates or high viral loads), 
the next group will be challenged with a lower dose and confidence in the attack rate of that lower 
dose will be increased (see Figure 4) Note: Dose escalations, de-escalations and confirmation 
group decisions will be made at the discretion of the Investigators with the advice of the DSMB. 
Decisions will be based not only on meeting the attack rate threshold but also take into account 
the quantity of viral load, symptomatology and other clinical factors to identify the dose that is not 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
92 
only safe but also most appropriate for future use of the model for vaccine and therapeutics 
testing. Therefore, the attack rate thresholds defined above will not be absolute criteria for group 
progression but will be considered together with these other data. For example, if at a given dose 
the attack rate does not reach the pre-determined threshold but is associated with high viral loads 
in most group participants (such as a peak viral load of ≥107 copies/mL), may be decided that a 
further group at the same dose is challenged rather than escalating to a higher dose level. 
Conversely, if an attack rate threshold is reached but the peak viral load by qPCR is low in all 
group participants (e.g. <106  copies/mL) and therefore unlikely to be culturable), dose escalation 
may still take place if deemed to be safe. Dose escalation decisions will be documented on site 
and entered into the s-cubed database who will provide oversight under their remit as database 
vendors.  
Participant Withdrawal (Early Discontinuation of Quarantine only) 
A participant may elect to leave quarantine before discharge criteria are met without withdrawing 
their consent to continue participating in the study. Wherever possible, the tests and evaluations 
listed for the Early Withdrawal Visit (EWV) should be carried out prior to the participant leaving 
the quarantine unit, and the participant should attend planned follow-up visits. It is likely that some 
of the assessments required as part of the EWV will already have been performed for the study 
day as per the SoA, in this case the completed assessments will not be repeated on the same 
day unless clinically indicated and the participant agrees.  
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 quarantine period, the participant 
will be encouraged to stay in the quarantine unit and would be advised of the potential risks of 
carrying SARS-COV-2 infection into the community, and to vulnerable groups in particular. 
However, if withdrawal occurs after virus inoculation, every effort will be made to manage their 
withdrawal and do the following: 
 
The participant will be counselled about the risk of onward transmission of SARS-CoV-2 and 
the legal requirement to self-isolate according to PHE and government rules at the time 
 
The participant will be counselled about any risks due to the withdrawal and specifically any 
risks due to missed safety monitoring that cannot be performed at home 
 
The participant will be reminded about infection control procedures and receive re-training if 
necessary, in handwashing and isolation rules 
 
The participant will be informed they will not receive rescue therapy and the potential 
consequences 
 
The participant will be transported home in private transport with appropriate PPE, and in 
accordance with national guidance 
 
Daily follow-up calls will be made to check on participant’s health until the medical discharge, 
in line with their wishes.  


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
93 
 
Once the quarantine discharge criteria are met, the participant will be informed they can de-
isolate. Where it is not possible to obtain further virology swabs following departure from the 
quarantine unit, de-isolation will be advised according to government guidelines. 
Participant Withdrawal  
A participant may withdraw their consent to participate in the study at any time and for any reason, 
without prejudice to his/her future medical care. Participants may decline to give a reason for their 
withdrawal. If a participant withdraws from the study during the quarantine phase, an EWV will be 
completed, where possible, prior to the participant leaving the quarantine unit. It is likely that some 
of the assessments required as part of the EWV will already have been performed for the study 
day as per the SoA, in this case the completed assessments will not be repeated on the same 
day unless clinically indicated and the participant agrees.  
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 quarantine period, the participant 
will be encouraged to stay in the quarantine unit and would be advised of the potential risks of 
carrying SARS-COV-2 infection into the community, and to vulnerable groups in particular. 
However, if withdrawal occurs after virus inoculation, every effort will be made to manage their 
withdrawal and do the following: 
 
The participant will be counselled about the risk of onward transmission of SARS-CoV-2 and 
the legal requirement to self-isolate according to PHE and government rules at the time 
 
The participant will be counselled about any risks due to the withdrawal and specifically any 
risks due to missed safety monitoring that cannot be performed at home 
 
The participant will be reminded about infection control procedures and receive re-training if 
necessary, in handwashing and isolation rules 
 
The participant will be informed they will not receive rescue therapy and the potential 
consequences.   
 
The participant will be transported home in private transport with appropriate PPE, and in 
accordance with national guidance 
 
The participant will be reminded of how to seek medical help from their GP or hospital if they 
feel more unwell 
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. Additionally, Participants can be 
withdrawn from the study for the reasons listed below if the Investigator feels this is necessary.  
 
Non-compliance with the study requirements and restrictions. 
 
Clinically significant abnormal laboratory findings, which in the opinion of the 
Investigator(s) and/or Sponsor, precludes further participation in the study. 
 
Development of inter-current illness which, in the opinion of the Investigator would 
compromise the health of the participant or the study objectives. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
94 
 
The Investigator’s decision that withdrawal from further participation would be in the 
participant’s best interest. 
 
Termination of the study at the discretion of the Investigator(s) or Sponsor for safety, 
behavioural, or administrative reasons. 
 
Any intervention (Virus) related SAEs.  
 
The participant becomes pregnant. 
 
The wish of the participant. 
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.  
If the participant withdraws consent for future disclosure of 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. 
In the event that the participant loses capacity during the course of the study, they will be 
withdrawn from the study. 
Criteria for Clinical Escalation of Participants 
Participants will be closely monitored throughout by the study medical team.   
Any illness recorded from the following list will lead to provision of immediate medical treatment, 
if necessary, followed by discussion with the CI/PI and possible referral for assessment by the 
RFH Patient Assessment and Response Team (PARRT) as agreed with the RFH and 
documented in the study specific Standard Operating Procedure (SOP). 
 
Cardiovascular compromise, such as - 
 
Sustained elevated heart rate >120bpm AND sustained low blood pressure SBP<100 for 
greater will than 30 minutes 
 
Respiratory compromise, such as  
 
Sustained elevated respiratory rate >30/min AND sustained low blood oxygen SaO2<94% 
for greater than 30 minutes 
 
Decrease in lung function of ≥15% in FEV1 (highest value) below the baseline value (Day 
0, pre-inoculation) on consecutive readings over 30 minutes 
 
Fever (grade 2 or higher) for >48 hours 
 
Evidence of pneumonia on clinical examination 
 
New ECG abnormalities (compared to baseline), such as 
 
Confirmed Fridericia-corrected QT (QTcF) >500 msec; confirmed increase of QTcF >60 
msec above baseline value 
 
Deranged and progressively worsening laboratory safety tests 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
95 
 
Any symptoms, signs or investigation results that are deemed to be of clinical concern by 
the CI / PI 
A complete medical history will be provided to the receiving physician including the possibility of 
SARS-CoV-2 infection. If following assessment by the receiving clinician the participant is 
transferred for further care in the emergency department or in-patient ward, infection control 
measures, transfer procedures and further medical or surgical management will be according to 
local Royal Free Hospital SOPs. Hospitalisation of any participant for the above reasons will lead 
to immediate suspension of further inoculations.  
In the event of a cardiac arrest, the hospital crash team will be summoned to respond. 
The DSMB will be convened to assess the clinical evidence in order to determine whether the 
study may proceed (see Data Safety Monitoring Board). 
Wherever possible, safety assessments and Follow Up Visits for participants who enter the NHS 
pathway, will continue, after their discharge from the NHS until completion of the study. 
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, in accordance with hVIVO SOP. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit schedule 
and ascertain whether or not the participant wishes to and/or should continue in the study. 
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. 
Should the participant continue to be unreachable, he/she will be considered to have withdrawn 
from the study.  
Participant Discontinuation of Study Intervention Therapy (Pre-emptive therapy / Rescue 
therapy)  
Participants will be discontinued from study intervention therapy for the reasons listed below and 
at the discretion of the Principal Investigator. Although Participants will not receive any further 
intervention therapy, they will continue to be followed for safety and monitoring as per the SoA, 
including any additional unscheduled assessments as required for safety reasons. 
 
Any intervention therapy related SAEs.  
 
Clinically significant abnormal laboratory findings, which in the opinion of the 
Investigator(s) and/or Sponsor, precludes further receipt of study intervention therapy. 
 
The Investigator’s decision that withdrawal from further intervention receipt would be in 
the participant’s best interest. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
96 
 
Anaphylactic reaction following intervention therapy receipt. The wish of the participant. 
Participants who are discontinued from the study intervention therapy will complete their 
Quarantine stay and be required to attend their Follow Up Visits, with assessments as detailed in 
the SoA. 
4.12 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), the inoculation will be postponed until transient circumstances 
have been resolved and the participant will be re-invited to a later quarantine group within the 
allowed time window. 
4.12 Participant Replacement Strategy 
Participants who withdraw or are discontinued from the study may be replaced in order to achieve 
the planned evaluable number of participants as follows, if deemed appropriate by the PI and with 
the approval of the CI/Sponsor: 
Withdrawals or early discontinuation prior to virus inoculation may be replaced.  
4.13 Stopping Rules 
The CI, PI and the DSMB will perform safety reviews on available clinical and virology data during 
the quarantine period, as appropriate.  
The Clinical scenario relating to the incidence of SAEs/AEs during the study and the procedures 
that should be performed in this instance are presented in Table 10. 
Table 10 Study Stopping Rules 
Status 
Criterion 
Procedure 
 
1 
Virus-related SAE or Virus-related 
AEs of clinical concern have been 
reported 
following 
Human 
Viral 
Challenge. 
 
 
If such a status occurs at any point during 
the study, then the CI, PI and the DSMB 
will review the data and make a decision.  
Further administration of the virus will be 
paused. The CI, PI and the DSMB will 
review the data and make a decision on 
whether it is appropriate to recommence 
inoculation (via a substantial amendment, 
if indicated) or terminate the study.  
In any event, participant follow-up should continue until resolution or stabilisation of AEs and final 
follow-up on Day 360 (± 14 days). 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
97 
Page Intentionally Blank. 
 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
98 
5. Study Assessments and Procedures  
Study procedures and their timing, including follow-up period at the Queen Mary BioEnterprise 
Centre (QMB) (Day 28-day – Day 360) 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.  
All screening evaluations must be completed and reviewed at D-2/-1 to confirm potential 
participants meet all eligibility criteria. A screening log will be maintained 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 inoculation will be used as the baseline 
measure for assessments. 
Procedures conducted as part of the Screening Protocol 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 filed in the Trial Master File 
(TMF).  
5.1 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]. Medical history from the participant’s GP will be 
obtained at screening and reviewed for eligibility. 
5.2 Demographics 
Demographic data will be recorded at screening and repeated at D -2/-1 in accordance with the 
SoA. 
5.3 Height, Weight and Body Mass Index (BMI) 
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 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
99 
5.4 Alcohol Breath Testing 
Breath alcohol testing will be conducted to determine compliance with the study alcohol 
restrictions in accordance with hVIVO SOP. Additional tests may be conducted for assessing 
eligibility at the discretion of the investigator. Results will be recorded in the source documents. 
5.5 Physical Examinations 
A complete physical examination will include a full systemic assessment and will be conducted 
by an investigator or medically qualified designee.  
Directed physical examinations will be conducted as deemed appropriate by the CI/PI 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. 
5.6 Vital Signs 
Subjects will be rested in a supine position for a minimum of 5 minutes before vital signs 
assessments. During vital signs assessments, subjects will be rested in a quiet setting without 
distractions (e.g., television, mobile phones, computers). 
Vital signs assessments will be recorded as follows: 
 
Heart rate (HR) will be recorded in beats per minute. 
 
Respiratory rate (RR): respirations will be counted and recorded as breaths per minute. 
 
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. 
 
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 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
100 
original reading. The assessment may then be repeated at the PI’s discretion and in accordance 
with SOPs. 
Study specific normal ranges are provided in Section 8 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 Division of Microbiology 
and Infectious Diseases (DMID) Adult Toxicity Table November 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. 
5.7 Temperature 
The study specific normal range for tympanic temperature is detailed in Appendix 5.The severity 
of out of normal range values will be assigned using the DMID toxicity scale as a guide. 
Temperature may be more frequently monitored in quarantine if deemed necessary by the 
Investigator. 
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 ≥ 37.9 oC. 
5.8 Radiology  
Chest X-rays and CT scans will be carried out in the hospital radiology department associated 
with the quarantine unit, according to local NHS SOPs. A chest x-ray will be performed upon 
admission to quarantine. Where possible, this should be acquired with the patient erect, taking a 
full inspiration and using a Posterior-Anterior (PA) projection. Where an admitted volunteer was 
unable to be inoculated in a quarantine and asked to return for a subsequent quarantine, a repeat 
X-ray may not be required for subsequent admissions, unless requested by the CI/PI. 
 
A CT of the chest will be acquired in all participants at either Day 5 or 6.  The CT scan will be 
repeated on Day 10 or 11 in those participants with PCR-confirmed infection or symptoms 
consistent with COVID-19. An unenhanced volumetric CT scan will be performed. The patient will 
be positioned supine with their arms above their head and the scan performed with the patient at 
held full inspiration. The scan will be acquired from the lung apices to the costophrenic sulci to 
obtain full coverage of the lung parenchyma using a 0.625mm section thickness and 
reconstructed using a lung algorithm. The radiation dose from the CT scan makes it difficult to 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
101 
justify performing an additional routine CT chest in the screening phase of the study, particularly 
given that the likelihood of finding abnormalities prior to inoculation is very low. 
5.9 Echocardiogram 
Transthoracic echocardiograms will be performed by a trained echocardiographer on admission 
to the quarantine unit before virus inoculation according to local NHS SOPs. 
5.10 Electrocardiogram 
Study specific normal ranges are provided in Appendix 5. 
Twelve-lead ECGs will be obtained to evaluate the electrical activity of the heart, In accordance 
with hVIVO SOP. 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. 
5.11 Lung Function 
5.11.1 Spirometry 
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 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).  
FEF25-75 can be collected by hVIVO on a study-by-study basis as an exploratory endpoint 
governed by PI/sub-investigator discretion. This would not be used for eligibility assessment. 
FEF25-75 will be assessed from admission to quarantine discharge. As the variability of FEF-25-
75, measured as coefficient of variation (CV), has been shown to be 20-30% for within test 
measurements on the same individual compared to 10-15% for FEV1, FVC etc as well as the fact 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
102 
that FEF25-75 has been reported not to influence clinical decision making hVIVO will collect FEF-
25-75 as an exploratory endpoint only (Quanjer et al., 2014; Stanojevic et al., 2008)  
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. 
5.11.2 Forced oscillation technique (FOT) 
Forced oscillation technique (FOT) is a versatile, non-invasive assessment of respiratory 
mechanics based on tidal breathing analysis. Airwaves of multiple frequencies (typically 5 to 30 
Hz) are applied to the respiratory tract during relaxed breathing. The test involves participants 
breathing through a breathing handle in a seated position, wearing a nose-clip, with cheeks 
supported. Breathing is recorded for approximately 1 minute. During this time the instantaneous 
pressure-flow relationship, measured at the mouth at varying frequencies, are analysed in order 
to measure Respiratory Impedance (Zrs). Zrs is made up of an in-phase, termed resistance (Rrs) 
and out-phase, referred to as reactance (Xrs). Resistance at 5Hz penetrates the periphery of the 
lung, providing information of the entire respiratory tract. Resistance > 20Hz represents 
respiratory resistance of the proximal airways. Distal lung resistance can be calculated by 
subtracting total airway resistance from proximal airway resistance (R5-R20). Xrs comprises of 2 
elements that are dependent upon frequency. At higher frequencies (>20 Hz) Xrs is positive in 
sign and represents the inertive force needed to move air in the conducting airways. At low 
frequencies of 5 Hz (X5) is negative in sign and indicates the capacitance of the lung periphery. 
A minimum of 3 tests will be performed and the mean values reported. Testing will take 
approximately 5 minutes. 
5.12 Patient Health Questionnaire (PHQ-9) and Generalised Anxiety Disorder (GAD-7) 
Questionnaire 
PHQ-9 and GAD-7 questionnaire will be used at the discretion of the investigator at screening 
and/or quarantine admission to assess participants’ eligibility in terms of ability to tolerate isolation 
in the quarantine unit. 
5.13 Participant Symptom Diary Card – Clinical scores 
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 (± 1 hour), using the Symptom 
Diary Card.  
The following symptoms in the 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  
 
grade 4: Symptoms at rest. (Shortness of Breath and Wheeze only)  


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
103 
Table 11 List of symptoms recorded by subjects 
Runny Nose 
Cough 
Chilliness/Feverishness 
Stuffy Nose 
Chest tightness 
Dizziness 
Sneezing 
Shortness of Breath 
Rashes 
Sore Throat 
Wheeze 
Blisters 
Hoarse voice 
Malaise/Tiredness 
Diarrhoea 
Eye Soreness 
Headache 
 
Earache 
Muscle and/or Joint ache 
 
Additional to the categorical symptom diary card, a Visual Analogue Scale diary card using a 
100mm scale, with the same symptoms, will be completed by the participants. 
Once a day, (in the evening, approx. every 24 hours) participants will also be asked to confirm 
(Yes/No) if they have experienced any ‘Confusion, disorientation or drowsiness’ or any ‘Loss of 
appetite’ in the last day (24 hours). 
Participant cold perception questions 
Two additional cold-related questions will also 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. 
i. 
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. 
ii. 
Compared to yesterday, I feel that my cold is: 
 
Very much better 
 
Somewhat better 
 
A little better 
 
The same 
 
A little worse 
 
Somewhat worse 
 
Very much worse 
5.14 University of Pennsylvania Smell Identification Test (UPSIT) 
UPSIT is a well-validated and reliable test (test-retest r = 0.94) that employs microencapsulated 
“scratch and sniff” odorants. It is provided as booklets containing a series of cards that the 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
104 
participants scratch and smell then asked to identify the odours, which have been previously 
validated in an English population. The test provides an index of absolute dysfunction (ie, 
anosmia, severe microsmia, moderate microsmia, mild microsmia, normosmia, factitious), as well 
as relative dysfunction based upon age and gender-adjusted normative percentile ranks. The total 
number of odorant stimuli out of 40 that is correctly identified serves as the test measure. Scores 
on this test correlate well with other types of olfactory tests, including threshold tests. The UPSIT 
is designed to be self-administered after explanation of the test by study staff and will be 
performed once before virus inoculation and then at least every third day starting from Day 1, 
though the test can be conducted more frequently at the discretion of the PI/study physician. 
5.14 Cognitive Testing 
To assess changes in cognition associated with infection, a computerised system for repeated 
assessment of cognitive function will be used. This has been developed by Dr Adam Hampshire 
(Imperial College London) and has been successfully used in healthy individuals and clinical 
populations inclusive of traumatic brain injury. Participants will be provided with a study tablet 
computer assigned to them for from the time of their admission to the quarantine unit until 
discharge that will contain a pre-loaded app (CogAsses) and factory-provided software only. This 
app will provide a brief battery of computerised tasks and questionnaires to track speed of 
information processing, memory, attention, executive function and sleep. The battery of tests will 
last for ~20-30 minutes. Participants will be asked to complete the cognitive assessment every 
day around the same time of day during their admission within the quarantine unit. In addition, a 
standardised questionnaire about the quality of sleep from the preceding night will be included in 
the app. The cognitive tasks included within this battery of tests are: 
1. 
Motor Control  
2. 
Object memory-Immediate recall 
3. 
Simple Reaction Time 
4. 
Choice reaction time 
5. 
2D Manipulations 
6. 
Allocentric towers 
7. 
Spatial span 
8. 
Target detection 
9. 
Tower of London  
10. 
Verbal analogies 
11. 
Object memory-Delayed recall 
Participants will also be invited to complete this assessment battery at each follow-up visit. All 
data from the cognitive assessments will be collected on a remote web server. The servers are 
behind a firewall in a secure cloud computing facility. These measures represent a high-level of 
data security that are the standard for any website. Remote storage of performance data will be 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
105 
in a pseudo-anonymised format and will be linked across tasks using anonymised user identifier 
codes. Identifiable information will be stored in an encrypted database ‘key’ that is separate from 
the test scores.  
5.15 Urinalysis 
Clinical urine safety analysis will be undertaken using commercially available urine test strips that 
provide an instant result and will be documented in the source data. 
Urinalysis will be performed to evaluate the parameters described in Appendix 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. 
5.15 Urine Drugs of Abuse and Nicotine Test 
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. 
5.16 Pregnancy Test 
Female participants are to have a urine pregnancy test at screening and at quarantine prior to 
inoculation (Day 0) and a serum pregnancy test on either day -2/-1. Participants will only be 
enrolled if the pregnancy tests are negative. 
Note: Pregnancy test must be performed even if the participant is menstruating at the time of the 
study visit. 
5.17 Blood Samples 
A maximum volume of 550 mL of blood may be taken from each participant in any 8-week period 
(e.g. from screening through to the Day 28 follow up visit). 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. 
Blood will be taken for multiple purposes including: 
 
Eligibility, safety and pathogenicity assessments (haematology, biochemistry, and other 
eligibility safety monitoring tests) Safety blood samples and Appendix 2  
 
Immunology assays  


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
106 
 
Exploratory research  
Further instructions for the collection, handling, storage, shipment and analysis of samples are 
provided in the Analytical Plan. 
5.17.1 Safety blood samples 
Appendix 2 describes the safety blood tests that will be performed including, but not limited to, 
haematology, biochemistry and cardiac enzymes. Additional safety assessments (e.g. 
coagulation) will be conducted at the discretion of the PI/Investigator, as required 
5.17.2 Immunology and sero-suitability to challenge virus 
Participants must be sero-suitable to take part in the study, i.e. he/she must have no detectable 
pre-existing serum levels of antibodies specific to SARS-CoV-2.  
Serum levels of pre-existing SAR-COV-2 specific antibodies to the Challenge Virus will be 
determined as described in the AP. 
Additional exploratory immunological assays may be performed, as described in Exploratory 
Research. 
5.18 Respiratory Samples 
The following exploratory respiratory sampling procedures will be performed during the study: 
 
Mid turbinate FLOQ swab (or nasopharyngeal FLOQ swab) 
 
Mid-turbinate and/or nasopharyngeal swab for cells for RNA 
 
Throat FLOQ swab 
 
Saliva 
 
Nasosorption  
Sample collection, handling, storage, shipment and analysis of samples from the respiratory tract 
will be performed in accordance with hVIVO SOPs, or as detailed in the Analytical Plan, as 
appropriate. These samples will be collected for: 
 
Viral loads  
 
Respiratory Pathogen Screen  
 
SARS-COv-2 confirmation of infection for intervention treatment  
 
SAR-COV-2 discharge test  
 
Exploratory purposes e.g. immunology  
Tolerance of the procedure may be determined at the screening visit. 
5.18.1 Viral load 
Viral load will be determined by quantitative reverse transcription polymerase chain reaction (qRT-
PCR) and a viral culture assay to investigate the following parameters: 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
107 
 
Infectivity status and rate 
 
viral dynamics (e.g. duration, peak, time to peak) 
5.18.2 Respiratory pathogen screen 
On entry to quarantine, a nasopharyngeal swab or nasal wash will be collected and tested to 
detect the presence of a set of respiratory pathogens, including Covid-19, that 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 Analytical Plan. Additional test may be 
conducted if the results from the first test were invalid to support study eligibility prior to virus 
inoculation, or if a community acquired infection is suspected during quarantine. 
Any additional screening tests will be conducted at the discretion of the CI/PI.  
5.18.3 SARS-CoV-2 confirmation of infection for intervention treatment 
Infection will be determined by quantitative RT-PCR, of mid-turbinate and or throat swab samples 
taken 12 hourly. Intervention treatment can commence, if indicated and available after viral 
detection (≥LLOQ) in two consecutive upper respiratory tract samples by PCR. 
5.18.4 SAR-CoV-2 confirmation of infection endpoint analysis 
Infection will be determined by quantitative RT-PCR, quantitative viral culture and/or culture of 
mid-turbinate and throat swab samples taken 12 hourly. This is detailed in the objectives and 
endpoints. 
5.18.5 SARS-CoV-2 discharge process 
Subjects will remain in the quarantine unit for a minimum of 14 days after inoculation, until the 
following criteria are met: 
1. 2 consecutive swabs with qPCR Ct >33.5 AND negative culture. 
2. Lateral flow tests may be used in place of culture if culture is not available. 
3. A qualitative PCR may be used in place of quantitative PCR, if the latter is not 
available. 
At the PI’s discretion if protracted quarantine is deemed to be causing harm to the 
participant’s mental or physical health and no viable virus is detected by culture or 
a lateral flow test is negative. 
Discharge criteria for non-infected subjects 
1. 2 consecutive swabs with undetectable virus by PCR only prior to discharge. 
If, on the 14th day of residence post challenge the discharge criteria above are met then 
participants will be discharged from the confinement facility at the discretion of the PI.  
Participants will be advised that they should stay in the quarantine unit they meet discharge 
criteria.  
If a participant wishes to leave quarantine after virus inoculation but before discharge criteria are 
met, they will be counselled on risk of transmission, instructed on infection control measures and 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
108 
reminded to isolate within their own home. As part of the counselling, participants will be reminded 
that any household members will also need to self-isolate according to PHE and UK government 
guidelines as potential contacts of a COVID-19 case; that “rescue” or pre-emptive treatment is 
not possible in the community and therefore they will not receive it; and that they must remain in 
close contact with the study team to be monitored for any safety signals. The Health Protection 
Unit local to the participant’s home will be informed and any additional infection control measures 
recommended by them will be implemented. 
In the event that a participant is suspected of becoming unwell or suffers a SAE and requires 
further treatment, the participant will be provided with immediate medical management followed 
by discussion with the PI/CI for possible referral for further assessment in accordance with 
“Criteria for Clinical Escalation of Participants” or elsewhere as appropriate (see Withdrawal 
criteria). NHS Hospitalisation of any subject, will lead to the immediate suspension of the trial. 
The DSMB will be convened to assess the clinical evidence in order to determine whether the 
study may proceed (see Data Safety Monitoring Board).                                                                                       
5.18.6 Post-discharge process 
Self-isolation post-discharge 
 
If viable virus is no longer detectable by culture or lateral flow test following 10 days of 
quarantine after the first positive SARS-CoV-2 PCR test or first day of symptoms consistent 
with COVID-19 (whichever is later), discharged participants will be advised at the PI’s 
discretion that any additional self-isolation post-discharge will be in line with government 
guidelines. 
Self-swabbing post discharge 
 
Weekly combined nose and throat swabs will be arranged for subjects who show persistent 
PCR detectable virus shedding. If swab results raise any concern about infectiousness, e.g. 
PCR value <33.5, then a lateral flow test can be performed. If the lateral flow test is negative 
isolation is not required.  
 
Additional swabs will not be required once a single swab has returned a not detected result. 
Where low level virus can still be detected, participants will be reminded at each contact with the 
study team that they must follow government guidelines regarding infection control (including 
hand-washing and social distancing) and avoid contact with high-risk individuals. 
5.19 Environmental Sampling 
Exploratory environmental sampling may be conducted one day before (Day -1) and up to twice 
daily every day following intranasal inoculation of volunteers with SARS- CoV-2 (from Day 1).  
Daily sampling will entail:  
 
Swabs collected from bedside furniture, door handles, computer keyboards, mobile phone 
and toilet floor in the volunteer quarters. Each day volunteer rooms will undergo a surface 
clean to avoid contamination from the previous day's virus deposition. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
109 
 
 
Air sampling to detect airborne virus will be performed using a variety of devices.  At certain 
time points volunteers may be asked to sing or speak loudly and collect samples before and 
after. Other than generating some noise, the samplers do not have any other impact on study 
participants.  
Following collection, samples will be kept cold and returned to the laboratory for downstream 
processing. This may involve different viral assays such as: 
 
Quantitation of extracted viral RNA using two different RT-PCRs to E gene and polymerase 
gene  
 
Quantitation of infectious material by immunofluorescence: inoculation onto Vero cells, 
overnight incubation and staining of fixed cells with antibody to SARS CoV2 N protein.  N 
positive cells are counted to give a read out of numbers of infectious foci in each sample.  
Room temperature and humidity will be recorded. Baseline room ventilation rates (air changes 
per hour) will be measured. 
5.20 Mask wearing sampling 
As an additional exploratory assessment of virus in exhaled breath, volunteers will be asked to 
wear a single use face mask that has been fitted with a polyvinyl alcohol (PVA, Orbi-Tech, 
Leichlingen, Germany) sampling matrix insert, capable of capturing virus. They will do this on 
Study day -1 and then on a daily basis from Study Day 1 up to a maximum of 3 times a day for 
60 - 90 minutes on each occasion. No hazards have been identified by the manufacturer of the 
PVA material and these face masks have been validated for the detection of M. tuberculosis in 
infected participants (Williams et al., 2020b). They have recently also been successfully 
demonstrated to detect SARS-CoV-2 in exhaled breath (Williams et al., 2020a). Up to five PVA 
strips will be harvested from exposed masks and analysed for virus and virus-related signals. 
5.21 Exploratory research 
The primary, secondary, and tertiary endpoints may be explored in relation to immunological 
levels at baseline and after SARS-CoV-2 challenge. Assays performed on blood and respiratory 
samples may include, but are not limited to:  
 
Humoral immunity / systems serology SARS-CoV-2 (for example: SARS-CoV-2 neutralizing 
titres, ELISAs to IgG, IgM, IgA, sIgA, ADCC) 
 
Proteomic levels and changes (for example, cytokine and chemokines) 
 
Cellular cell quantification and quality of immunity (for example T and B cell frequencies, 
phenotypes and functionality assays, ELISPOTs, ICS, cytokine/chemokine responses) 
 
Transcriptome levels and changes (for example, RNAseq, single cell RNAseq, microarray, 
PCR) 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
110 
 
Human genomics in relation to SARS-CoV-2 susceptibility, infection (e.g. HLA typing, SNPs, 
GWAS) 
 
Viral genomics in relation to SARS-CoV-2 population changes through infection 
 
Microbiome analysis in relation to viral infection, disease and susceptibility (e.g. PCR, NGS, 
16s rRNA) 
Results of these analyses may be reported separately to the final study report. 
5.22 Optional Exploratory Non-Interventional Study of Wearable Device 
Participants may be given the option to take part in a separate ethically-approved exploratory 
non-interventional trial that aims to collect physiological data via a wearable device. Participants 
will have the wearable device study explained to them and a choice to opt into the study, which 
will require them to consent to wear a wearable device (such as a wrist- or arm-band during the 
challenge trial, via an additional informed consent, which will be separately ethically-approved). 
There will be no impact on participants eligibility and/or safety follow-up or treatment in the 
challenge trial. The wearable device will not replace any conventional safety monitoring. All 
subjects will be monitored for adverse events related to the wearable device from signing of the 
wearable device ICF to the end of data capture. An adverse event related to the wearable device 
may lead to discontinuation of the exploratory wearable study, without having an impact on the 
human challenge trial. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
111 
6.  Recording of Adverse Events and Serious Adverse Events 
The PI is responsible for ensuring that all AEs, SAEs and pregnancies are identified, evaluated, 
recorded and reported in a timely manner as per hVIVO’s SOPs, and also for ensuring that the 
medical management (including follow up) of AEs, SAEs and, where appropriate, pregnancy 
symptoms/complications is provided by site staff. 
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 4. 
6.1 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 (Table 1). 
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. 
6.2 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 4. 
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. 
6.2.1 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. Additional Information/clarification may be required to ensure 
accurate completion of safety reports. The follow up reports should include a detailed 
Investigator’s clinical assessment. 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 4). Further 
information on follow-up procedures is provided in Appendix 1. 
6.2.2 Regulatory reporting requirements of SAEs 
Prompt notification by the Investigator (PI) to the CI and 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. 
SAEs will be documented and reported in accordance with hVIVO SOPs: 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
112 
PI will send SAE/pregnancy forms to the delegated Pharmacovigilance (PV) provider within 
24 hours of becoming aware of the event. PI will also inform the CI and Sponsor 
(RGIT.ctimp.team@imperial.ac.uk) at the same time. 
The sponsor ensures compliance with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics 
Committees (IEC), and Investigators.  
An Investigator who receives an investigator safety report describing a SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the sponsor will review and will notify 
the IRB/IEC, if appropriate according to local requirements. 
Further information on regulatory reporting requirements is provided in Appendix 1. 
6.3 Reporting of events related to REGEN-COV 
Any SAEs deemed to be related to REGEN-COV will be reported within 24 hours of investigator 
awareness following hVIVO SOP - P_SOP_Clin_0084. 
Furthermore, we will report to Regeneron the following adverse events of special interest (AESI) 
related to REGEN-COV.: 
 
Grade ≥2 infusion-related reaction or Grade ≥2 hypersensitivity reaction. Where: 
 
i. 
Infusion-related reactions are defined as any relevant adverse events that occurs during 
the infusion or up to day 4. 
ii. 
Hypersensitivity reactions are defined as any relevant adverse event that occurs during 
the infusion or up to study day 29. 
The only data that will be transferred to Regeneron will be restricted solely to safety information 
as outlined above. 
6.3.1 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 4.. 
Additionally, identification of pregnancy in a female participant within 6 months of receipt of 
REGEN-COV will be reported within 24 hours to Regeneron via a standardised reporting form.  
Optional consent for reporting of pregnancy in female partners of male participants within 6 
months of receipt of REGEN-COV will also be sought. Outcomes for all participant pregnancies 
(and consented partner pregnancies) will be reported to Regeneron. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
113 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
6.3.2 Disease-related events and/or disease related outcomes not qualifying as AEs or 
SAEs 
Not applicable. 
6.3.3 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 (Dr. Chris Chiu, Chief Investigator) 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 delegate (hVIVO) is responsible for notifying the REC of the potential serious breach 
within 7 days of becoming aware of it.  
6.4 Safety Oversight Procedures  
6.4.1 Procedures to be followed in the event of abnormal findings 
Eligibility for enrolment in the trial in terms of laboratory findings will be assessed by clinically 
qualified staff. Abnormal clinical findings from medical history, examination or blood tests will be 
assessed as to their clinical significance throughout the trial. Laboratory AEs will be assessed 
using specific toxicity grading scales adapted from the FDA Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (see Appendix 3). 
If a test is deemed clinically significant, it may be repeated, to ensure it is not a single occurrence. 
If a test remains clinically significant, the volunteer will be informed and appropriate medical care 
arranged as appropriate and with the permission of the volunteer. Decisions to exclude the 
volunteer from enrolling in the trial or to withdraw a volunteer from the trial will be at the discretion 
of the Investigator. 
6.4.2 Ongoing and interim safety reviews 
The safety profile will be assessed on an on-going basis by the study Investigators. The CI/PI  
and relevant Investigators (as per the trial delegation log) will be reviewing safety issues and 
SAEs as they arise. The Chief Investigator will be informed of any safety concerns. 
Safety reviews are planned as follows: 
 
After the first 3 volunteers at each dose level (Sentinels), available safety data will be 
reviewed by the PI, CI and relevant investigators, before inoculating further participants 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
114 
 
After each cohort has been challenged, a review will be performed by the chair of Data 
Safety Monitoring Board (DSMB) (or full DSMB at the discretion of the DSMB chair) before 
proceeding with challenge of further volunteers.  
The DSMB will review safety data accumulated after each cohort and evaluate frequency of 
events, safety and infection rate / symptom data. The DSMB will make recommendations to the 
investigators concerning the conduct, continuation or modification of the study.  
6.4.3 Safety holding rules 
Safety holding rules have been developed considering the fact that this is the first study in which 
SARS-CoV-2 virus has been administered experimentally.   
6.4.4 Group holding rules 
Group holding rules below will apply:  
 
Adverse events:  
o If 2 or more individuals suffer the same Grade 3 adverse event persisting at Grade 3 for 
>72 hrs following virus challenge 
 
Laboratory adverse event:  
 
If 2 or more individuals suffer the same Grade 3 laboratory adverse event persisting at 
Grade 3 for >72 hrs following virus challenge 
 
A serious adverse event considered possibly, probably or definitely related to 
inoculation occurs 
 
Withdrawal from the study of 2 or more individuals due to subjectively intolerable 
symptoms considered possibly, probably or definitely related to SARS-CoV-2 
inoculation  
If a holding rule is activated, then further virus inoculations will not occur until a safety review by 
the DSMB, study Sponsor, CI and PI has been conducted and it is deemed appropriate to restart 
challenges. Follow-up visits and procedures, including safety assessments for all study 
participants already challenged with the virus will continue. Intervention treatment will be given as 
planned unless the adverse events in question are deemed possibly, probably or definitely related 
to such treatment. The safety review will consider: 
 
The relationship of the AE or SAE to the virus inoculation, or other possible causes of the 
event. 
 
If appropriate, additional screening or laboratory testing for other volunteers to identify those 
who may develop similar symptoms and alterations to the current Participant Information 
Sheet (PIS)  
 
New, relevant safety information from ongoing research programs on COVID-19. 
 
The ethics committee will also be notified if a holding rule is activated or released.  


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
115 
6.5 Data Safety Monitoring Board 
The Data Safety Monitoring Board (DSMB) will be appointed for this study to periodically review 
and evaluate the accumulated study data for participant safety, study conduct, progress, and 
efficacy and make recommendations concerning the continuation, modification, or termination of 
the trial. Specifically, the DSMB will meet before study start and following the discharge of each 
challenged group. 
The DSMB will operate in accordance with the study-specific charter, which will be established 
before recruitment starts. 
The chair of the DSMB may be contacted for advice and independent review by the Investigator 
or Sponsor in the following situations: 
• 
Following any SAE deemed to be possibly, probably or definitely related to a study 
intervention. 
• 
Any other situation where the Investigator or trial Sponsor feels independent advice or 
review is important. 
The DSMB will review SAEs deemed possibly, probably or definitely related to study interventions. 
The DSMB will be notified within 24 hours of the Investigators’ being aware of their occurrence. 
The DSMB has the power to place the study on hold if deemed necessary following a study 
intervention-related SAE. Additionally, the DSMB will review safety data after each dosing cohort 
to assess the safety of progressing to the next cohort at the same dose, higher dose or lower 
dose. The DSMB is expected to meet approximately every 4 weeks during the period in which 
quarantines are taking place or as required. 
6.6 Trial Steering Committee (also known as Medical Oversight Committee) 
A Trial Steering Committee (TSC) will be convened to provide overall guidance for the project on 
behalf of the Project Sponsor (Imperial College London) and to ensure the project is conducted 
to the rigorous standards set out in the Department of Health’s Research Governance Framework 
for Health and Social Care and the Guidelines for Good Clinical Practice.  It should be noted that 
the day-to-day management of the trial is the responsibility of the Chief Investigator (Chris Chiu). 
The Chief Investigator in conjunction with the Project Delivery Group and the Sponsor’s Project 
Manager is responsible for overseeing Trial management and progress. The TSC will comprise 
at least 3 independent members (including the Chair). The TSC will operate in accordance with 
the study-specific charter, which will be established before recruitment starts. 
6.7 Human Challenge Steering Committee 
Per the collaboration agreement signed by all collaborating partners a Human Challenge Steering 
Committee (HCSC) will be convened to provide overall guidance for the project on behalf of the 
Project Funder (UK Vaccines Taskforce, Department of Business, Energy & Industrial Strategy) 
and Partners to ensure the project is conducted in a timely and high quality manner. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
116 
The study will be terminated if this is recommended by the DSMB and/or TSC following any safety 
review. Additionally, the study will be terminated if data becomes available that raises concern 
about the safety of the study so that continuation would have posed significant new risks to the 
subjects. If the Investigators, DSMB, TSC or any member of the HCSC become aware of such 
data, they will call an extraordinary meeting to discuss the implications and assess the risk to 
study participants in light of the new data, after which the DSMB and TSC will provide a 
recommendation as to whether the study can continue. 
6.8 Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this study.  
6.9 Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
117 
7. Statistical Methods and Planned   
This section describes the statistical analyses that will be performed in this 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). 
7.1 Study Analysis Sets 
The following analysis sets are defined for this study: 
 
Full Analysis Set (FAS) is defined as all subjects that are inoculated with wild-type SARS-
COV-2 challenge virus. The FAS will be considered as the primary analysis set for all 
primary, secondary and exploratory endpoints. 
 
Safety Analysis Set is defined as all subjects that are inoculated with wild-type SARS-
COV-2 challenge virus. The Safety Analysis Set is identical to FAS, and will be used for 
all safety endpoints. 
 
Per Protocol (PP) Analysis Set is defined as all FAS subjects that are sero-suitable, who 
have no major protocol deviations and who complete the quarantine period up to the final 
day of quarantine (study Day 14). The PP Analysis Set will be considered as the secondary 
analysis set for pre-specified primary, secondary and exploratory endpoints. 
Membership of subjects in each analysis set will be determined at a planned data review meeting 
(DRM), prior to any analysis and database lock. 
7.2 Subgroup Analysis 
A ‘Laboratory confirmed infected’ subgroup will be identified and will be presented for certain pre-
specified analyses (as described in this protocol and/or documented in the SAP). The ‘subgroup 
is defined as those subjects that fulfil the following criteria: 
 
Two quantifiable (≥LLOQ) RT-PCR measurements from mid turbinate or throat samples, 
reported on 2 or more consecutive timepoints, starting from 24 hours post-inoculation and 
up to discharge from quarantine. 
The subjects not part of the ‘Laboratory confirmed infected’ (i.e. those that are uninfected) will 
also be presented for certain pre-specified analyses. 
Some pre-specified endpoints will additionally be explored in relation to subsets of symptoms 
from the symptom diary card. 
Additional subgroup analysis may be performed, as detailed in the SAP (e.g., summarizing 
subjects that received a given dose level with a specific intervention treatment or not). 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
118 
7.3 Sample Size 
The primary objective of the study is to identify a safe and infectious dose of wild type SARS-
CoV-2 in healthy volunteers, suitable for future intervention studies. No formal sample size 
calculation has been performed for this early stage dose finding study. However, a sample size 
of up to an expected 30 subjects for a dose level and treatment regimen (made up of 3 cohorts of 
up to an expected 10 subjects, including the dose expansion cohort), with a total of up to 90 
subjects overall, is felt sufficient to meet the primary objective of escalating/expanding the dose 
in a safe manner whilst providing information on the attack rate. 
The initial dose level administered will include a sentinel group of 3 subjects. As described in 
Section 4, if none of the 3 subjects in this initial dose level sentinel group become infected then 
the dose will be escalated, i.e. based on a target attack rate of 70%, the probability of seeing at 
least 1 subject in the 3 sentinel subjects being infected is 97.3%. Hence, if no subjects are infected 
then dose escalation will occur. 
See below for further statistical rationale for the dose escalation/expansion scheme. 
7.4 Cohort and Dose Escalation 
An overview of the cohort and dose escalation scheme is presented in Figure 4. The following 
describes the statistical aspects to support the cohort and dose escalation scheme in relation to 
the first, second and third groups each of an expected 10 subjects (i.e. the first, second and third 
cohorts, respectively) at each dose level. 
To support future studies, a target attack rate of 70% has been deemed desirable and should not 
be below 50%. A two-sided 95% confidence interval (CI) approach will be used for assessing the 
precision of the point estimate for the attack rate. This approach is consistent with previous human 
infection dose escalation studies43.This approach is consistent with previous human infection 
dose escalation studies. Given that sample sizes are relatively small, an exact (Clopper-Pearson) 
confidence interval will be used. The assessment of the early (first and second) cohorts of the 
dose escalation scheme will be based primarily on safety together with clinically relevant fixed 
attack rate criteria. Subject numbers will then be expanded with a third cohort at the selected dose 
level and a 95% CI calculated to obtain a level of precision for the observed attack rate.  
First Cohort: 
For the first cohort, criteria for escalation, de-escalation and expansion, require no further 
statistical justification, i.e. dose expansion, escalation and de-escalation are based on a 
combination of safety and a clinically relevant fixed attack rate criterion. 
Second Cohort: 
For the second cohort, criteria for escalation, de-escalation and expansion are based on 
combination of safety and clinically relevant fixed attack rate criterion. A group size made up of 
subjects from the first and second cohorts will be used to show early indications of the attack rate. 
However, this is not based on statistical considerations. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
119 
Third Cohort (expansion group): 
The dose expansion cohort should only take place when it is believed that an appropriate dose 
has been identified after the completion of the second cohort. Using “≥70% infected” as the 
criterion to expand to the third cohort, is a reasonable criterion to use based on targeting a 70% 
target attack rate, but also reducing the risk of seeing an attack rate of less than 50%, after an 
expected 30 subjects. This is similar to previous human infection dose escalation studies. If 
however an observed ≥70% attack rate after the first 2 cohorts at any dose level has not been 
achieved (even after reaching the highest dose) then expansion could be undertaken at the “most 
promising” dose (providing the attack rate after the second cohort is high enough. So, if a 70% 
attack rate is never reached after the first 2 cohorts at any dose level then the “≥70% infected” 
criterion becomes a “guide”. 
For the level of precision, once say 30 subjects are recruited, and an observed 21 out of 30 (70%) 
subjects are infected then this provides a 95% CI of (51%, 85%), and therefore this provides the 
necessary CI width to have the lower bound above the required 50%. In addition to this, by 
recruiting the third cohort (e.g. 30 subjects in total), this allows for inspection of any variation in 
the attack rate between the 3 cohorts at a particular dose level, and also increases the chance of 
potentially seeing any less frequent adverse events 
7.5 Interim Statistical Analysis 
No formal interim statistical analysis will be performed. However, two analyses are planned to be 
conducted. The primary analysis of study data will be conducted when all data through the Day 
28 post-inoculation are available, monitored, and locked for all subjects. This will be followed by 
a final analysis which will include all study data through to the extended (Day 365) follow-up. 
7.6 Statistical Analysis Plan 
Data will be analysed and reported using SAS® version 9.4 or later.  
No statistical comparison of dose groups is planned. Primary, secondary and exploratory 
endpoints will be analysed descriptively. Continuous variables will be summarised using 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).  A 95% confidence 
interval (CI) may be presented for certain pre-specified endpoints. 
An SAP will be developed and approved prior to any lock of the study database. 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 will 
be described and justified in an amendment to the protocol and/or SAP as appropriate and also 
referenced 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. Any 
required sensitivity analyses will be specified in the SAP. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
120 
Further post-hoc evaluations of any exploratory endpoints may be conducted and reported 
separately.  
7.6.1 Subject Accountability 
The number of subjects receiving Challenge Virus, receiving at least one dose of intervention 
treatment withdrawing from the study (also split by reason for withdrawal), completing the study, 
and the numbers in each analysis set, will be summarised by dose group and across all subjects. 
7.6.2 Protocol deviations 
Subject data will be reviewed for major protocol deviations prior to database lock at a planned 
Data Review Meeting (DRM), and decisions will be documented within the meeting minutes. At 
this meeting, subjects will be reviewed for their inclusion/exclusion from the analysis sets. Protocol 
deviations will be listed. 
7.6.3 Demographic and baseline characteristics 
Descriptive statistics of demographics (age, sex, height, weight, BMI, and ethnicity) will be 
presented by dose group and across all subjects. Medical history information will be listed. Other 
baseline characteristics will be defined in the SAP.  
7.7 Primary Endpoint Analysis 
The primary objective is to identify a safe and infectious dose of wild type SARS-CoV-2 in healthy 
volunteers, suitable for future intervention studies. 
The following primary endpoints will be analysed as follows: 
 
To evaluate the safety of wild type SARS-CoV-2 challenge in healthy subjects the following 
endpoints will be summarised by dose group, as well as the subgroups of infected and 
uninfected, and for all subjects: 
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. 
Additional safety data presentations are also described in Section 5. 
 
To evaluate the infection rate, the laboratory confirmed infection rate will be summarised by 
dose group. 
The laboratory confirmed infection is defined as: Two quantifiable greater than lower limit of 
quantification (≥LLOQ) RT-PCR measurements from mid turbinate and/or, throat samples, 
reported on 2 or more consecutive timepoints, starting from 24 hours post-inoculation and up 
to discharge from quarantine. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
121 
In addition, the laboratory confirmed infection will be assessed using at least two detectable 
(≥LLOD) in place of quantifiable (≥LLOQ) RT-PCR measurements and will be summarised by 
dose group. 
7.8 Secondary Endpoint Analysis  
Secondary endpoints as described in Section 2 will be summarised by dose group as per Section 
7, as appropriate. In addition, subgroup analyses may be performed as per Section 7. Further 
details will be described in the SAP. 
7.9 Exploratory Endpoints  
Exploratory endpoints as described in Section 2 may be summarised by dose group as per 
Section 7, as appropriate. In addition, subgroup analyses may be performed as per Section 7. 
Further details will be described in the SAP. 
7.10 Safety Analysis  
Safety data will be summarised descriptively. 
All Adverse Events (AEs) will be coded using the most current version of the Medical Dictionary 
for Regulatory Activities (MedDRA). Virus Challenge emergent adverse events will be 
summarised by MedDRA system organ class (SOC), preferred term and dose group, for those 
subjects infected and uninfected and for all subjects.  
An AE will be defined as Virus Challenge emergent if the onset date is on or after the date of 
inoculation.  Any AE with an onset date earlier than the date of inoculation will be considered as 
a pre-Virus Challenge AE. If a subject experiences more than one AE with the same preferred 
term, that preferred term will be counted only once within summary presentations. It will be 
assigned the highest severity and the strongest relationship to Virus Challenge among those 
events for the summaries in which those characteristics are considered. Pre-Virus Challenge AEs 
will be identified in a listing.  
Summary presentations will be performed for the number and percentage of subjects reporting 
Virus Challenge emergent: AEs, severity of AEs and AEs related to Virus Challenge. In addition, 
SAEs and AEs directly resulting in withdrawal from the study will be listed. 
Other safety endpoints that will be presented by dose group include laboratory evaluations 
(biochemistry, haematology, coagulation, cardiac enzymes and urine analysis), vital signs 
assessments, 12-lead ECG, Forced Oscillation Technique (FOT) and spirometry. Additionally, 
physical examinations will be listed. 
Concomitant medications will be coded using the most current version of the World Health 
Organization (WHO) Drug Dictionary. A medication will be assigned as being prior to Virus 
Challenge or concomitant with Virus Challenge, based on the start and stop dates of the 
medication and the date of inoculation. If the medication stop date is before the date of inoculation, 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
122 
the medication will be assigned as being prior to Virus Challenge. In all other situations, the 
medication will be assigned as being concomitant with Virus Challenge. Concomitant medications 
will be separately summarised by WHO drug class, generic name and dose group.  Prior 
medications will be identified in a listing. If a subject has separate periods of taking specific 
medications, then that medication is only counted once within the specific period of observation 
(i.e. prior or concomitant) where it is taken. 
Further details of the safety analyses will be documented in the SAP. 
 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
123 
8. Appendices: Supporting Documentation and Operational 
Considerations 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
8.1.1 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 
 
The protocol, protocol amendments, ICF and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the Chief Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. These will be reviewed by Sponsor prior to submission. 
 
The sponsor delegate, hVIVO, will be responsible for the following: 
 
 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures.  
 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC.  
 
Provide Gilead and Regeneron with necessary information to facilitate safety reporting 
related to Remdesivir and REGEN-COV respectively  
 
Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies 
(if applicable), and all other applicable local regulations 
 
8.1.2 Financial disclosure 
Investigators and co-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. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
124 
8.1.3 Funding 
This study is funded by the UK Vaccines Taskforce and Department of Business, Energy and 
Industrial Strategy. They are acting as sole funders and the contract and agreement are in place.  
The investigators will not receive any additional payment above their normal salaries.  Participants 
will be given a donation of up to £4565 to compensate for the time and inconvenience of taking 
part in the study (including at least 16-day quarantine). This was calculated using the NIHR 
formula and national living wage. It is similar to the market rate for in-patient human infection 
challenge studies. These expenses will be paid in line with standard hVIVO procedures. Where 
participants have an extended quarantine stay beyond Day 14 post-inoculation, the additional 
days will be reimbursed on a pro rata basis according to the number of days they additionally 
attended. Where participants have completed the confinement period but fail to attend further 
follow-up appointments, they will be reimbursed on a pro rata basis according to the number of 
visits they have attended. This will be detailed fully in the PIS. 
8.1.4 Informed Consent Process 
Before any study specific procedures are attempted, study physician will again discuss the study 
and study procedures with the potential participant and answer any questions. After that, 
participants will be asked to read, sign and date the full study ICF in the presence of the study 
doctor or nurse, who will also sign the consent form.  A copy of the consent will be given to the 
participant and another copy will be filed in their medical notes. 
The Investigator will obtain a signed screening ICF from each participant before any screening or 
study specific procedures are performed as described in section 2. 
Potential participants will be sent a copy of the Screening ICF when their Screening Visit is 
arranged and at least one day prior to the visit, and will be encouraged to read it prior to their 
appointment. Upon arrival at the Screening Visit the Screening ICF is discussed, and they will be 
given the opportunity to ask any questions, and may take the information sheet away to consider 
their participation. Participants will be informed that a further discussion with the full study PIS/ICF 
will be scheduled at a later point (if necessary) and that they will be free to withdraw at any point 
before or after that. 
All participants will be required to have a good understanding of English and the Investigator will 
be responsible for ensuring that the subject understands the information contained in the ICFs. 
Once they have confirmed that the subject has understood the study, including the benefits and 
risks of participation, the subject and the Investigator can sign and date the ICF.  
The ICF must be signed and dated by the subject and countersigned by the Investigator (whoever 
conducted the consent discussion). A copy of the ICF will be given to the subject, and the original 
will be held in the full study TMF. The consent process will be documented in line with hVIVO 
SOPs, which require that documented and signed evidence must be available to confirm staff 
obtaining consent are trained and passed as competent, prior to independently obtaining consent. 
The Investigator will document the consent process in the subject notes and progress notes as 
applicable. This documentation will include details of capacity assessment, discussion with 
subject, and when/how consent has been obtained. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
125 
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 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.  
8.1.5 Confidentiality 
The Chief Investigator will preserve the confidentiality of participants taking part in the study and 
is registered under the Data Protection Act. 
8.1.6 Data protection 
Participants will be assigned a unique 6-digit subject number by hVIVO Any participant records 
or datasets that are transferred to the sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent.  
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 or by 
appropriate IRB/IEC members. 
8.1.7 Indemnity 
Imperial College London holds negligent harm and non-negligent harm insurance policies which 
apply to this study. In addition, hVIVO and the Royal Free Hospital hold negligent harm insurance 
policies which apply to this study.  
8.1.8 Sponsor 
Imperial College London will act as the sponsor for this study.  Delegated responsibilities will be 
assigned to hVIVO and the Royal Free Hospital taking part in this study.  
8.1.9 Audits 
The study may be subject to audit by Imperial College London under their remit as sponsor and 
other regulatory bodies to ensure adherence to GCP and the UK Policy Framework for Health 
and Social Care Research.  


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
126 
8.1.10 Sample and data storage and usage 
Samples of tissue, cells and fluids will be stored according to Imperial College London and hVIVO 
SOPs as appropriate. Samples will be anonymised with participant identification numbers only 
and the anonymisation key kept in a separate locked location accessible only to the clinical study 
team. Samples may be used for further assays or in other ethically approved studies. Samples 
and data may be shared with UK and international collaborators in studies that have been 
approved by local ethics committees and subject to a valid Materials Transfer Agreement. Data 
and samples sent outside the UK will be pseudonymised with no patient identifiable data 
transferred. Data and all appropriate documentation will be stored for a minimum of 10 years after 
the completion of the study, including the follow-up period according to Imperial College London 
policy. 
8.1.11 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 (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 CI/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. 
8.1.12 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.  
The Investigator must permit study-related monitoring, audits, IRB/IEC 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. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
127 
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. No records may be destroyed during the retention 
period without the written approval of the Sponsor. No records may be transferred to another 
location or party without written notification to the Sponsor. 
8.1.13 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 can be found in the Source Data Agreement. 
8.1.14 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 CI, 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 CI 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. In addition, 
the site must conduct final disposition of all unused intervention treatment in accordance with the 
Sponsor's procedures for the study. 
Termination of the clinical trial may also be initiated by the REC.  
8.1.15 Study management and governance 
The study will be registered on https://clinicaltrials.gov/. 
This study is part of the Human Challenge Programme overseen by the Vaccine Taskforce and 
funded by the Department of Business, Energy and Industrial Strategy (BEIS) of Her Majesty’s 
Government. The programme is overseen by the Hu cman Challenge Steering Committee, which 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
128 
reports into the Human Challenge Board. The Human Challenge board in turn reports to the 
Vaccine Taskforce Steering Group. overseen  
The Human Challenge Steering Committee is the projects operational governing and advisory 
committee in relation to the scope, budget and timelines of the project. It has operational 
oversight, governance and decision-making rights of the study with respect to scope, timelines 
and budget. It has no authority with respect to decisions concerning medical or safety aspects of 
the subjects in the study.  
The Medical Oversight Committee (also known as the TSC) is an independent committee with 
representatives appointed by the sponsor. The Medical Oversight Committee shall have authority 
with respect to decisions concerning the delivery of the protocol or any medical or clinical aspects 
of the project and/or any subjects of the study. The Medical Oversight Committee may provide 
information to the study Delivery team or the HCSC via their sponsor Chair. 
The Study Delivery Team is responsible for the projects operational management and has day-to 
day responsibility for the management of the project but with no authority with respect to medical 
or safety aspects of the study. The study delivery team reports to the HCSC on performance 
against the service agreements and study milestones.  
8.1.16 Publication policy 
By signing the study protocol, the CI/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 collaboration partners. 
In order to allow the use of the information derived from this clinical study, the CI/PI understands 
that he has an obligation to provide complete test results and all data developed during this study 
to the Sponsor. 
If the study is to be published, the Sponsor and collaboration partners may jointly prepare and co-
author manuscript(s) that could result from the clinical trial. In the case the Sponsor acts as fully 
responsible for the publication, the Sponsor agrees to allow the partners time to review all 
manuscripts and abstracts prior to submission for publication. All proposed publications that 
discuss or disclose any part of the Study Data will be submitted to the Human Challenge Steering 
Committee (HCSC) and will be subject to the prior approval of the Human Challenge Steering 
Committee, or its successor The Sponsor also reserves the right to delete any confidential 
information from any proposed manuscripts prior to submission for publication. Confirmation of 
study specific arrangements can be found in the partnership collaboration agreement. 
The expectation is that after analysis aggregated anonymised data from this study will be widely 
distributed in the medical and scientific community.  Facilitated with presentations at local, 
national and international meetings, we hope to publish widely in the medical literature.  In 
addition, we will work with public engagement and involvement groups and the media department 
at Imperial College and the collaboration partners to publicise research that is of public interest.  
No personal data from the participants will be published.  
 
 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
129 
Appendix 2: Clinical Laboratory Tests 
 
The tests detailed in Table 12 will be performed The Doctor’s Laboratory (TDL). 
 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 3 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. 
 
Pregnancy Testing.  
Table 12 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) 
D-dimer 
Biochemistry 
Sodium 
Potassium 
Glucose (random) 
HbA1c (only required at screening) 
Albumin 
Chloride 
Bicarbonate 
Calcium 
Uric acid 
Total protein 
Creatinine 
eGFR  
Total, direct, and indirect bilirubin 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
130 
Laboratory 
Assessments 
Parameters 
Inorganic phosphate 
Blood urea nitrogen 
C-reactive protein (CRP) 
Gamma glutamyl transferase 
Alkaline phosphatase (ALP) 
Alanine transaminase (ALT) 
Lactate dehydrogenase (LDH) 
Aspartate transaminase (AST) 
Urea. 
Thyroid function 
Thyroid Stimulating Hormone (TSH) 
Thyroxine 
Cardiac enzymes 
Creatine Kinase (CK) 
CK-MB 
Troponin (T) 
High sensitivity 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 abnormal results) 
Other 
screening/eligibility 
tests 
Follicle stimulating hormone (FSH)* 
Total cholesterol (and full lipid profile at Investigator’s 
discretion) 
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) 
*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 investigative sites or other 
blinded personnel until the study has been unblinded. 
 
 
 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
131 
Appendix 3: Toxicity Grading Scale for Lab AEs 
Toxicity Grading Scale for Lab 
AEs 
Lab 
Range 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Sodium 
Elevated 
mmol/L
145 
146-147 
148-149 
150-155 
>155 
Sodium 
Low 
mmol/L
135 
132-134 
130-131 
125-129 
<125 
Potassium 
Elevated 
mmol/L
5.1 
5.2-5.3 
5.4-5.5 
5.6-6.5 
>6.5 
Potassium 
Low 
mmol/L
3.5 
3.2-3.3 
3.0-3.1 
2.5-2.9 
<2.5 
Urea 
Elevated 
mmol/L
1.7-8.3 
8.4-9.3 
9.4-11.0 
>11.0 
Requires 
Dialysis 
Creatinine 
(Female) 
Elevated 
µmol/L 
49-92 
101-138 
139-276 
>277 
Requires 
Dialysis 
Creatinine 
(Male) 
Elevated 
µmol/L 
66-112 
123-168 
169-336 
>336 
Requires 
Dialysis 
Bilirubin 
Normal 
LFTs 
µmol/L 
0-20 
22-30 
31-40 
41-60 
>60 
Bilirubin 
Abnormal 
LFTs 
µmol/L 
0-20 
22-25 
26-30 
31-35 
>35 
ALP 
(Female) 
Elevated 
IU/L 
104 
114-208 
209-312 
313-1040 
>1040 
ALP (Male) 
Elevated 
IU/L 
129 
142-258 
259-387 
388-1290 
>1290 
ALT 
(Female) 
Elevated 
IU/L 
35 
39-88 
89-175 
176-350 
>350 
ALT (Male) 
Elevated 
IU/L 
50 
55-125 
126-250 
251-500 
>500 
AST 
(Female) 
Elevated 
IU/L 
31 
34-78 
79-155 
156-310 
>310 
AST (Male) 
Elevated 
IU/L 
37 
41-93 
94-185 
186-370 
>370 
Albumin 
Low 
g/L  
34-50 
28-31 
25-27 
<25 
- 
 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
132 
 
 
 
 
 
 
Lab 
Range 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Haemoglobin 
Absolute 
Male 
g/L 
130 – 170 
115-125 
100-114 
85-99 
<85 
Haemoglobin 
Absolute 
Female 
g/L 
115 – 155 
105-113 
90-104 
80-89 
<80 
Haemoglobin 
Decrease 
from 
Baseline 
 
 
n/a 
0-15 
16-20 
21-50 
>50 
White Blood 
Cells  
Elevated 
10^9/L 
3.0 – 10.0 
11.5-15.0 
15.01-20 
20.01-25 
>25 
White Blood 
Cells 
Low 
10^9/L 
3.0 – 10.0 
2.0-3.5 
1.5-1.99 
1.0-1.49 
<1.0 
Platelets 
Low 
10^9/L 
150 – 400 
125-140 
100-124 
25-99 
<25 
Neutrophils 
Low 
10^9/L 
2.0 – 7.5 
1.5-1.99 
1.0-1.49 
0.5-0.99 
<0.5 
Lymphocytes
Low 
10^9/L 
1.2 – 3.65 
0.75-0.99 
0.3-0.74 
0.25-0.29 
<0.25 
Eosinophils 
Elevated 
10^9/L 
0.0 – 0.4 
0.65-1.5 
1.51-5.00 
>5.00 
Hyper-
eosinophilia


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
133 
Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting 
 
8.4.1 Adverse event 
AE Definition 
An AE is any untoward medical occurrence in a volunteer, which may occur during or after 
administration of an intervention and does not necessarily have a causal relationship with the 
intervention. An AE can therefore be any unfavourable and unintended sign (including any 
clinically significant abnormal laboratory finding or change from baseline), symptom or disease 
temporally associated with the study intervention, whether or not considered related to the study 
intervention. 
 
Events Meeting the AE Definition 
 
Exacerbation of a pre-existing illness. 
 
Increase in frequency or severity of a pre-existing eVISodic condition. 
 
A condition detected or diagnosed after inoculum administration even though it may 
have been present prior to the start of the study. 
 
A complication that occurs during a hospitalisation. 
Events NOT Meeting the AE Definition 
 
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion); 
the condition that leads to the procedure is an AE. 
 
Pre-existing disease or conditions present or detected prior to start of Challenge Virus 
inoculation that does not worsen (including screening findings such as abnormal 
laboratory results). 
 
Hospitalisation for elective surgery, social and/or convenience admissions provided 
they are arranged before the start of Challenge Virus administration. 
 
Over-administration of either the challenge virus or concomitant medication without any 
signs or symptoms. 
 
An uncomplicated pregnancy or an induced elective abortion to terminate a pregnancy 
without medical reason. 
 
Typical/normal viral symptoms on symptom diary cards. 
8.4.2 Serious adverse event 
SAE Definition  


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
134 
An SAE is an AE that results in any of the following outcomes, whether or not considered related 
to the study intervention. 
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 hospitalisation 
 
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 hospitalization or fulfils 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. 
 
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 
 
The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. 
 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhoea, 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: 
 
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. 
 
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. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
135 
8.4.3 Potential adverse events related to SARS-CoV-2 infection 
Following viral challenge, pyrexia (or febrile illness) is expected and presumed to represent virus 
infection consequent to viral challenge. Additionally, symptoms including headache, malaise, 
rhinorrhoea, nasal congestion, sneezing, sore throat, and cough may occur as features of upper 
respiratory tract symptoms. These would not be captured as an AE except those that meet the 
definitions below, or if they are deemed to be clinically significant (in the opinion of the 
Investigator) to be classed as an AE, or require intervention (e.g. medication except paracetamol) 
(see Withdrawal criteria). All unexpected (in the opinion of the Investigator) symptoms will be 
captured as AEs. Symptoms lasting longer than 12 weeks post-inoculation and consistent with 
“long COVID” (such as fatigue, neurological symptoms and anosmia, see Background “Potential 
long-term complications of COVID-19 and “long COVID”) will be classed as AEs. 
Criteria for classing expected symptoms and signs as AEs are: 
 
Temperature Grade 2 or higher for >48 hours 
 
Headache Grade 3 or higher 
 
Cough Grade 3 or higher 
Any clinical events set out in Withdrawal criteria that require a participant to be withdrawn from 
the study or pause in the study are defined as SAEs. 
 
8.4.4 Recording, assessment and follow-up of AE and/or SAE 
8.4.4.1 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 are reported, whether spontaneously volunteered by a subject 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:  
 
How are you feeling? 
 
Have you had any medical problems since your last visit/assessment?  
 
Have you taken any new medicines, other than those given to you in this study, since 
your last visit/assessment? 
Following the reporting of AEs and concomitant medication, the Investigator should assess the 
subject’s eligibility to continue in the study.  
The PI will record all relevant information regarding an AE/SAE in the source documents and 
evaluate AEs using the following guidelines:  


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
136 
 
Description of events (if the event consists of a cluster of signs and symptoms, a 
diagnosis should be recorded) 
 
Seriousness 
 
Severity (or grade) 
 
Onset date and time 
 
Frequency 
 
Date and time of resolution (or ‘continuing’ if unresolved) 
 
Action taken  
 
Concomitant medication 
 
Clinical outcome 
 
Relationship or causality (Intervention treatment/ 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.  
8.4.4.2 Assessment 
Description 
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 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
137 
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. 
Direct 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. 
Spirometry 
A 15% drop in a spirometry value (compared to baseline, and confirmed by a repeat on the 
same day) may be judged a Grade 1 (mild) AE. However, due to variability in participants’ ability 
to perform these tests with adequate technique, the Investigator and/or SME will use his/her 
clinical judgement to assess whether abnormal spirometry readings are consistent with a true 
drop and whether an AE should be raised. 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 a spirometry reading on repeat assessment has returned to normal an AE will not be raised. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
138 
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 SME 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).   
8.4.4.3 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 PI will use the grading scale for AEs as a reference when collecting, reporting and clarifying 
database queries of AEs and SAEs.  
The severity of an AE that does not appear in the grading scale for AEs should be determined 
according to the definitions in Table 13. 
Table 13 Classification of Adverse Event Severity 
Grade 
Definition 
Grade 0 
Absent 
Grade 1 
Mild level of discomfort, and does not interfere with regular activities 
Grade 2 
Moderate level of discomfort that intermittently interferes with regular activities 
Grade 3 
Severe: Significant level of discomfort and prevents regular activities 
Grade 4 
Potentially life threatening  
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. It is important to distinguish between 
serious and severe AEs. An AE of severe intensity needs not necessarily be considered serious. 
For example, a migraine headache that incapacitates a participant for many hours may be severe, 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
139 
whereas a stroke that results in a limited degree of disability may be considered mild but should 
be reported as a SAE. 
 
 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
140 
Table 14 Severity grading criteria for physical observations 
Vital Signs 
Grade 1 
(mild) 
Grade 2 
(moderate) 
Grade 3 
(severe) 
Grade 4 
Potentially 
Life 
threatening 
Fever (tympanic) 
37.9°C - 
38.4°C 
38.5°C – 
38.9°C 
39.0°C - 
40°C 
> 40°C 
Tachycardia (bpm)* 
101 – 115 
116 – 130 
>130 
A&E visit or 
hospitalisation for 
arrhythmia  
Bradycardia (bpm)** 
45-49 
40-44 
<40 
A&E visit or 
hospitalisation for 
arrhythmia 
Systolic hypertension 
(mmHg) 
141 – 150 
151 – 155 
≥155 
A&E visit or 
hospitalization for 
malignant hypertension 
Diastolic hypertension 
(mmHg) 
91 – 95 
96 – 100 
>100 
A&E visit or 
hospitalization for 
malignant hypertension 
Systolic hypotension 
(mmHg)*** 
85 – 89 
80 – 84 
<80 
A&E visit or 
hospitalization for 
hypotensive shock 
Respiratory Rate –
breaths per minute 
17 – 20 
21-25 
>25 
Intubation 
*Taken after 5 minutes at rest **When resting heart rate is between 50 – 100 beats per minute. 
Use clinical judgement when characterising bradycardia among some healthy subject 
populations, for example, conditioned athletes. ***Only if symptomatic (e.g. dizzy/ light-headed) 
8.4.4.4 Frequency 
The frequency of the AE should be categorised as one of the following: 
 
Single 
 
Intermittent 
 
Continuous 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
141 
8.4.4.5 Assessment of causality 
For every AE, an assessment of the relationship of the event to the administration of the challenge 
virus will be undertaken by the PI.  An interpretation of the causal relationship of the challenge 
virus to the AE in question will be made, based on the type of event; the relationship of the event 
to the time of challenge virus administration; and the known biology of the challenge virus (Table 
9). Alternative causes of the AE, such as the natural history of pre-existing medical conditions, 
concomitant therapy, other risk factors and the temporal relationship of the event to challenge 
virus will be considered and investigated. Causality assessment will take place during planned 
safety reviews, interim analyses (e.g. if a holding or stopping rule is activated) and at the final 
safety analysis, except for SAEs, which should be assigned by the reporting investigator 
immediately. 
 
The Investigator is obligated to assess the relationship between challenge virus and each 
occurrence of each AE/SAE. 
 
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. 
 
The Investigator will use clinical judgment to determine the relationship. 
 
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. 
 
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. 
 
There may be situations in which an SAE has occurred, and the Investigator has minimal 
information to include in the initial report to PV lead 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. 
 
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. 
 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements – AE/SAE related to the challenge virus will be reported to the REC. 
 
The relationship of an AE to the challenge virus will be categorised as shown in 
 
 
 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
142 
Table 15 Classification of Adverse Event Relationship 
Classification 
Definition 
Not related 
The AE is related to an aetiology other than the  challenge virus 
(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 challenge virus and likely to 
be related to factors other than challenge virus 
Possibly related 
There is an association between the AE and the administration of 
the challenge virus, and there is a plausible mechanism for the AE 
to be related to the challenge virus, 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 challenge 
virus 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 challenge virus seems likely. 
Definitely related 
 
A definite causal relationship exists between the AE and the 
administration of the challenge virus, and other conditions do not 
appear to explain the AE. 
 
Unless an AE is ‘definitely related’ to the challenge virus, a causal relationship to one of the 
following should be considered, and full details provided on the AE reporting form as appropriate. 
 
Study procedures 
 
Concomitant medication 
 
Other 
8.4.4.6 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 study intervention. In addition, 
the Investigator will describe whether any treatment was given for the AE. 
The Investigator will classify the action taken with regard to the AE. The action taken should be 
classified according to the following categories and full details provided as appropriate: 
 
None 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
143 
 
Non-drug therapy given 
 
Concomitant medication taken 
 
Study intervention dose not changed 
 
Study intervention dose adjusted 
 
Study intervention administration temporarily interrupted 
 
Study intervention administration permanently discontinued 
 
N/A Study intervention not administered  
 
Participant withdrawn 
 
Participant hospitalised 
 
Other 
8.4.4.7 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 16. 
Table 16 Classification of Adverse Event Outcome 
Classification 
Definition 
Resolved 
Resolution of the AE with no residual signs or symptoms 
Resolved with sequelae 
Resolution of the AE with residual signs or symptoms 
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). 
8.4.4.8 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: 
 
Resolved (return to normal or baseline values), or 
 
Stabilised, or 
 
Judged by the PI/Investigator to be no longer clinically significant, or 
 
An alternative explanation has been provided. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
144 
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. 
8.4.5 Reporting of SAEs 
Prompt notification and assessment of SAEs to ethics committee(s) where necessary for this 
study will be the responsibility of the sponsor delegate (hVIVO). Contact details are detailed in 
Table 17 
Annual safety/progress reports and final Study report will be generated and submitted to relevant 
ethics committee(s). This will be the responsibility of hVIVO as described in Section 6. 
Notification should be made: 
 
In a detailed written SAE form report within 24 hours of the Investigator becoming aware 
of the event.  
All reports should be directed to the pharmacovigilance mailbox. 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. 
Table 17 Contact Details for Reporting SAEs 
Contact  
Details 
Pharmacovigilance reporting email 
hvivo-clinical@arriello.com 
Pharmacovigilance phone number 
reporting  
+370 37 247 987  
SAE e-mail address:  
hvivo-clinical@arriello.com 
and 
RGIT.ctimp.team@imperial.ac.uk 
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 CI and 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.  


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
145 
The Investigator will also provide additional information, including a copy of the following 
documents (where applicable): 
 
Copies of test results, as available  
 
Hospital discharge summary (as soon as it is available to the PI) 
 
Autopsy report (as soon as it is available to the PI). 
The Investigator must report SAEs 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. 
8.4.6 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 REC for the 
appropriate action to be taken. 
8.4.7 Post-study AEs and SAEs 
All SAEs that occur during the study must be reported by the Investigator to the SME as soon as 
possible, in accordance with hVIVO’s SOPs, and at the latest within 24 hours of becoming aware 
of the event.  
8.4.8 Pregnancy 
If a female participant or partner of a male participant becomes pregnant during [specify time 
period], this must be reported by the Investigator to the medical monitor 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 pharmacovigilance 
department 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.  
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. 
 
A complete evaluation will be documented in the source data to permit transfer to the 
clinical database.  


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
146 
 
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.  
 
hVIVO in consultation with the participant will keep the participant’s GP informed.  
 
All cases of foetal drug exposure via the parent as a study participant will be reported to 
the Sponsor and the REC.  
 
 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
147 
Appendix 5: Normal Ranges 
Vital Signs 
 
Vital sign Parameters 
Lower limit 
Higher limit 
Units 
Tympanic temperature 
(above 37.8 classed as 
pyrexia) 
35.5 
37.8 
°C 
Oxygen saturation 
Normal is ≥ 95 
% 
Respiratory rate 
10 
17 
breaths per minute 
Heart rate 
50 
100 
beats per minute 
Systolic BP 
90 
140 
mmHg 
Diastolic BP 
50 
90 
mmHg 
 
ECG 
ECG Parameters 
Lower limit 
Higher limit 
Units 
HR 
50 
100 
bpm 
QRS 
60 
120 
ms 
PR interval 
120 
220 
ms 
QT 
320 
450 
ms 
QTc 
Normal for females is < 470  
ms 
Normal for males is < 450 
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 base value  
litres  
 
 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
148 
Appendix 6: Abbreviations 
ADA 
Anti-Remdesivir Antibody 
ADCC 
Antibody-Dependent Cellular Cytotoxicity 
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 Aminotransferase 
AST 
Aspartate Transaminase 
AUC 
Area Under the Curve 
BP 
Blood Pressure 
BD 
Twice Daily 
BMI 
Body Mass Index 
cGMP 
Current Good Manufacturing Practices 
CK 
Creatine Kinase 
CHIM 
Controlled human infection model  
CI 
Chief Investigator  
CIOMS 
Council for International Organizations of Medical Sciences 
CMI 
Cell Mediated Immunity 
COPD 
Chronic Obstructive Pulmonary Disease 
CRF 
Case Report Form 
CRP 
C-reactive Protein 
CTL 
Cytotoxic T cell 
COVID-19 
Coronavirus Disease 19 
CYP450 
Cytochrome 450 
DBP 
Diastolic blood pressure 
DNA 
Deoxyribonucleic acid 
DMID 
Division of Microbiology and Infectious Disease 
DRM 
Data review meeting 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram  
ELISA 
Enzyme-linked Immunosorbent Assay 
ERS 
European Respiratory Society  
FAS 
Full Analysis Set 
FEV 
Forced Expiratory Volume 
FEV1 
Forced Expiratory Volume in One Second 
FOT 
Forced oscillation technique 
FSH 
Follicle Stimulating Hormone 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
149 
FVC 
Forced Vital Capacity 
GAD 
Generalised Anxiety Disorder 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GMP 
Good Manufacturing Practice 
GP 
General Practitioner  
HAV 
Hepatitis A 
HbA1c 
Haemoglobin A1c 
HBV 
Hepatitis B 
HCV 
Hepatitis C 
HIV 
Human Immunodeficiency Virus 
HVC 
Human Viral Challenge  
IB  
Investigator Brochure  
ICF 
Inform Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committees 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G  
IgM 
Immunoglobulin M  
IM 
Intramuscular 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Boards 
IUD 
Intrauterine Device  
IV 
Intravenous 
LRT 
Lower Respiratory Tract 
MCH 
Mean Corpuscular Haemoglobin 
MCHC 
Mean Corpuscular Haemoglobin Concentration 
MCID 
Minimal Clinically Important Difference 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MOI 
Monoamine Oxidase Inhibitors 
NIMP 
Non-Investigational Medicinal Product 
NPS 
Nasopharyngeal Swab 
PBMC 
Peripheral Blood Mononuclear Cell  
PCA 
Principal Component Analysis 
PCR 
Polymerase Chain Reaction 
PEF 
Peak Expiratory Flow 
PFM 
Peak flow meter 
PFU 
Plaque Forming Unit 
PHQ 
Patient Health Questionnaire 
PI 
Principal Investigator* 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
150 
PIS 
Participant Information Sheet 
PK  
Pharmacokinetic 
PP 
Per Protocol 
PT 
Prothrombin Time 
QDS 
Four Times Daily 
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  
SAR-COV-2  
Severe Acute Respiratory Syndrome Coronavirus 2 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SBP 
Systolic blood pressure 
SoA 
Schedule of Activities  
SOC 
System Organ Class 
SOP 
Standard Operating Procedure  
SpO2 
Peripheral arterial oxygen saturation 
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 
UPSIT 
University of Pennsylvania smell identification test 
URT 
Upper Respiratory Tract 
WBC 
White Blood Cell 
WHO 
Word Health Organisation 
β-HCG 
β-human chorionic gonadotrophin 
* Delegation Log will list all investigators / study physicians delegated by PI to perform study 
activities.  
 
 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
151 
9. References 
Bagga, B., Woods, C.W., Veldman, T.H., Gilbert, A., Mann, A., Balaratnam, G., Lambkin-Williams, R., 
Oxford, J.S., McClain, M.T., Wilkinson, T., et al. (2013). Comparing influenza and RSV viral and disease 
dynamics in experimentally infected adults predicts clinical effectiveness of RSV antivirals. Antiviral therapy 
18, 785-791. 
Beigel, J.H., Tomashek, K.M., Dodd, L.E., Mehta, A.K., Zingman, B.S., Kalil, A.C., Hohmann, E., Chu, H.Y., 
Luetkemeyer, A., Kline, S., et al. (2020). Remdesivir for the Treatment of Covid-19 - Final Report. The New 
England journal of medicine, NEJMoa2007764. 
Berlin, D.A., Gulick, R.M., and Martinez, F.J. (2020). Severe Covid-19. The New England journal of 
medicine. 
Berry, D., Berry, S., Hale, P., Isakov, L., Lo, A., Siah, K.W., and Wong, C.H. (2020). A Cost/Benefit Analysis 
of Clinical Trial Designs for COVID-19 Vaccine Candidates. medRxiv, 2020.2009.2015.20195495. 
Bost, P., Giladi, A., Liu, Y., Bendjelal, Y., Xu, G., David, E., Blecher-Gonen, R., Cohen, M., Medaglia, C., 
Li, H., et al. (2020). Host-Viral Infection Maps Reveal Signatures of Severe COVID-19 Patients. Cell 181, 
1475-1488.e1412. 
Brouwer, P.J.M., Caniels, T.G., van der Straten, K., Snitselaar, J.L., Aldon, Y., Bangaru, S., Torres, J.L., 
Okba, N.M.A., Claireaux, M., Kerster, G., et al. (2020). Potent neutralizing antibodies from COVID-19 
patients define multiple targets of vulnerability. Science 369, 643-650. 
Buckland, M.S., Galloway, J.B., Fhogartaigh, C.N., Meredith, L., Provine, N.M., Bloor, S., Ogbe, A., Zelek, 
W.M., Smielewska, A., Yakovleva, A., et al. (2020). Treatment of COVID-19 with remdesivir in the absence 
of humoral immunity: a case report. Nat Commun 11, 6385. 
de Graaf, H., Ibrahim, M., Hill, A.R., Gbesemete, D., Vaughan, A.T., Gorringe, A., Preston, A., Buisman, 
A.M., Faust, S.N., Kester, K.E., et al. (2020). Controlled Human Infection With Bordetella pertussis Induces 
Asymptomatic, Immunizing Colonization. Clinical infectious diseases : an official publication of the 
Infectious Diseases Society of America 71, 403-411. 
DeVincenzo, J.P., McClure, M.W., Symons, J.A., Fathi, H., Westland, C., Chanda, S., Lambkin-Williams, 
R., Smith, P., Zhang, Q., Beigelman, L., et al. (2015). Activity of Oral ALS-008176 in a Respiratory Syncytial 
Virus Challenge Study. New England Journal of Medicine 373, 2048-2058. 
DeVincenzo, J.P., Whitley, R.J., Mackman, R.L., Scaglioni-Weinlich, C., Harrison, L., Farrell, E., McBride, 
S., Lambkin-Williams, R., Jordan, R., Xin, Y., et al. (2014). Oral GS-5806 activity in a respiratory syncytial 
virus challenge study. The New England journal of medicine 371, 711-722. 
DeVincenzo, J.P., Wilkinson, T., Vaishnaw, A., Cehelsky, J., Meyers, R., Nochur, S., Harrison, L., Meeking, 
P., Mann, A., Moane, E., et al. (2010). Viral load drives disease in humans experimentally infected with 
respiratory syncytial virus. American journal of respiratory and critical care medicine 182, 1305-1314. 
Docherty, A.B., Harrison, E.M., Green, C.A., Hardwick, H.E., Pius, R., Norman, L., Holden, K.A., Read, 
J.M., Dondelinger, F., Carson, G., et al. (2020). Features of 20 133 UK patients in hospital with covid-19 
using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ 
369, m1985. 
Eyal, N., Lipsitch, M., and Smith, P.G. (2020). Human Challenge Studies to Accelerate Coronavirus Vaccine 
Licensure. The Journal of infectious diseases 221, 1752-1756. 
Gbesemete, D., Barker, M., Lawrence, W.T., Watson, D., de Graaf, H., and Read, R.C. (2020). Exploring 
the acceptability of controlled human infection with SARSCoV2—a public consultation. BMC medicine 18, 
209. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
152 
Goldman, J.D., Lye, D.C.B., Hui, D.S., Marks, K.M., Bruno, R., Montejano, R., Spinner, C.D., Galli, M., Ahn, 
M.Y., Nahass, R.G., et al. (2020). Remdesivir for 5 or 10 Days in Patients with Severe Covid-19. The New 
England journal of medicine. 
Grifoni, A., Weiskopf, D., Ramirez, S.I., Mateus, J., Dan, J.M., Moderbacher, C.R., Rawlings, S.A., 
Sutherland, A., Premkumar, L., Jadi, R.S., et al. (2020). Targets of T Cell Responses to SARS-CoV-2 
Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell 181, 1489-1501.e1415. 
Guvenel, A., Jozwik, A., Ascough, S., Ung, S.K., Paterson, S., Kalyan, M., Gardener, Z., Bergstrom, E., 
Kar, S., Habibi, M.S., et al. (2020). Epitope-specific airway-resident CD4+ T cell dynamics during 
experimental human RSV infection. The Journal of clinical investigation 130, 523-538. 
Habibi, M.S., Thwaites, R.S., Chang, M., Jozwik, A., Paras, A., Kirsebom, F., Varese, A., Owen, A., 
Cuthbertson, L., James, P., et al. (2020). Neutrophilic inflammation in the respiratory mucosa predisposes 
to RSV infection. Science 370. 
Harrison, E.M.e.a. (2020). Ethnicity and Outcomes from COVID-19: The ISARIC CCP-UK Prospective 
Observational Cohort Study of Hospitalised Patients. The Lancet. 
Hayden, F.G., Treanor, J.J., Fritz, R.S., Lobo, M., Betts, R.F., Miller, M., Kinnersley, N., Mills, R.G., Ward, 
P., and Straus, S.E. (1999). Use of the Oral Neuraminidase Inhibitor Oseltamivir in Experimental Human 
InfluenzaRandomized Controlled Trials for Prevention and Treatment. JAMA 282, 1240-1246. 
He, X., Lau, E.H.Y., Wu, P., Deng, X., Wang, J., Hao, X., Lau, Y.C., Wong, J.Y., Guan, Y., Tan, X., et al. 
(2020). Temporal dynamics in viral shedding and transmissibility of COVID-19. Nature medicine 26, 672-
675. 
Helleberg, M., Niemann, C.U., Moestrup, K.S., Kirk, O., Lebech, A.-M., Lane, C., and Lundgren, J. (2020). 
Persistent COVID-19 in an Immunocompromised Patient Temporarily Responsive to Two Courses of 
Remdesivir Therapy. The Journal of infectious diseases 222, 1103-1107. 
Horby, P., Lim, W.S., Emberson, J.R., Mafham, M., Bell, J.L., Linsell, L., Staplin, N., Brightling, C., 
Ustianowski, A., Elmahi, E., et al. (2020). Dexamethasone in Hospitalized Patients with Covid-19 - 
Preliminary Report. The New England journal of medicine. 
Humeniuk, R., Mathias, A., Cao, H., Osinusi, A., Shen, G., Chng, E., Ling, J., Vu, A., and German, P. 
(2020). Safety, Tolerability, and Pharmacokinetics of Remdesivir, An Antiviral for Treatment of COVID-19, 
in Healthy Subjects. Clin Transl Sci 13, 896-906. 
Iwasaki, A., and Yang, Y. (2020). The potential danger of suboptimal antibody responses in COVID-19. 
Nature reviews. Immunology 20, 339-341. 
Jiang, L., Tang, K., Levin, M., Irfan, O., Morris, S.K., Wilson, K., Klein, J.D., and Bhutta, Z.A. (2020). COVID-
19 and multisystem inflammatory syndrome in children and adolescents. The Lancet. Infectious diseases 
20, e276-e288. 
Jones, S., Evans, K., McElwaine-Johnn, H., Sharpe, M., Oxford, J., Lambkin-Williams, R., Mant, T., Nolan, 
A., Zambon, M., Ellis, J., et al. (2009). DNA vaccination protects against an influenza challenge in a double-
blind randomised placebo-controlled phase 1b clinical trial. Vaccine 27, 2506-2512. 
Jozwik, A., Habibi, M.S., Paras, A., Zhu, J., Guvenel, A., Dhariwal, J., Almond, M., Wong, E.H., Sykes, A., 
Maybeno, M., et al. (2015). RSV-specific airway resident memory CD8+ T cells and differential disease 
severity after experimental human infection. Nat Commun 6, 10224. 
Kuiper, V.P., Rosendaal, F.R., Kamerling, I.M.C., Visser, L.G., and Roestenberg, M. (2020). Assessment 
of risks associated with SARS-CoV-2 experimental human infection studies. Clinical Infectious Diseases. 
Lam, M.H., Wing, Y.K., Yu, M.W., Leung, C.M., Ma, R.C., Kong, A.P., So, W.Y., Fong, S.Y., and Lam, S.P. 
(2009). Mental morbidities and chronic fatigue in severe acute respiratory syndrome survivors: long-term 
follow-up. Archives of internal medicine 169, 2142-2147. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
153 
Lambkin-Williams, R., Gelder, C., Broughton, R., Mallett, C.P., Gilbert, A.S., Mann, A., He, D., Oxford, J.S., 
and Burt, D. (2016). An Intranasal Proteosome-Adjuvanted Trivalent Influenza Vaccine Is Safe, 
Immunogenic & Efficacious in the Human Viral Influenza Challenge Model. Serum IgG & Mucosal IgA Are 
Important Correlates of Protection against Illness Associated with Infection. PloS one 11, e0163089. 
Long, Q.-X., Tang, X.-J., Shi, Q.-L., Li, Q., Deng, H.-J., Yuan, J., Hu, J.-L., Xu, W., Zhang, Y., Lv, F.-J., et 
al. (2020). Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections. Nature 
medicine 26, 1200-1204. 
Maxwell (2020). Living with Covid19. 
McClain, M.T., Henao, R., Williams, J., Nicholson, B., Veldman, T., Hudson, L., Tsalik, E.L., Lambkin-
Williams, R., Gilbert, A., Mann, A., et al. (2016). Differential evolution of peripheral cytokine levels in 
symptomatic and asymptomatic responses to experimental influenza virus challenge. Clinical and 
experimental immunology 183, 441-451. 
Miller, M.R., Hankinson, J., Brusasco, V., Burgos, F., Casaburi, R., Coates, A., Crapo, R., Enright, P., van 
der Grinten, C.P., Gustafsson, P., et al. (2005). Standardisation of spirometry. The European respiratory 
journal : official journal of the European Society for Clinical Respiratory Physiology 26, 319-338. 
Nabavi, N. (2020). Long covid: How to define it and how to manage it. BMJ 370, m3489. 
Ngai, J.C., Ko, F.W., Ng, S.S., To, K.W., Tong, M., and Hui, D.S. (2010). The long-term impact of severe 
acute respiratory syndrome on pulmonary function, exercise capacity and health status. Respirology 
(Carlton, Vic.) 15, 543-550. 
Nguyen-Van-Tam, J.S., Killingley, B., Enstone, J., Hewitt, M., Pantelic, J., Grantham, M.L., Bueno de 
Mesquita, P.J., Lambkin-Williams, R., Gilbert, A., Mann, A., et al. (2020). Minimal transmission in an 
influenza A (H3N2) human challenge-transmission model within a controlled exposure environment. PLoS 
pathogens 16, e1008704. 
Pan, H., Peto, R., Karim, Q.A., Alejandria, M., Henao-Restrepo, A.M., García, C.H., Kieny, M.-P., 
Malekzadeh, R., Murthy, S., Preziosi, M.-P., et al. (2020). Repurposed antiviral drugs for COVID-19 –interim 
WHO SOLIDARITY trial results. medRxiv, 2020.2010.2015.20209817. 
Plotkin, S.A., and Caplan, A. (2020). Extraordinary diseases require extraordinary solutions. Vaccine 38, 
3987-3988. 
Polack, F.P., Thomas, S.J., Kitchin, N., Absalon, J., Gurtman, A., Lockhart, S., Perez, J.L., Pérez Marc, G., 
Moreira, E.D., Zerbini, C., et al. (2020). Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. 
New England Journal of Medicine. 
Quanjer, P.H., Weiner, D.J., Pretto, J.J., Brazzale, D.J., and Boros, P.W. (2014). Measurement of FEF25-
75% and FEF75% does not contribute to clinical decision making. The European respiratory journal : official 
journal of the European Society for Clinical Respiratory Physiology 43, 1051-1058. 
Roberts, A., Lamirande, E.W., Vogel, L., Jackson, J.P., Paddock, C.D., Guarner, J., Zaki, S.R., Sheahan, 
T., Baric, R., and Subbarao, K. (2008). Animal models and vaccines for SARS-CoV infection. Virus Res 
133, 20-32. 
Rogers, T.F., Zhao, F., Huang, D., Beutler, N., Burns, A., He, W.-t., Limbo, O., Smith, C., Song, G., Woehl, 
J., et al. (2020). Isolation of potent SARS-CoV-2 neutralizing antibodies and protection from disease in a 
small animal model. Science 369, 956-963. 
Sakurai, A., Sasaki, T., Kato, S., Hayashi, M., Tsuzuki, S.-I., Ishihara, T., Iwata, M., Morise, Z., and Doi, Y. 
(2020). Natural History of Asymptomatic SARS-CoV-2 Infection. The New England journal of medicine 383, 
885-886. 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
154 
Salje, H., Tran Kiem, C., Lefrancq, N., Courtejoie, N., Bosetti, P., Paireau, J., Andronico, A., Hozé, N., 
Richet, J., Dubost, C.L., et al. (2020). Estimating the burden of SARS-CoV-2 in France. Science 369, 208-
211. 
Shrestha, D.B., Budhathoki, P., Syed, N.-i.-H., Rawal, E., Raut, S., and Khadka, S. (2020). Remdesivir: A 
potential game-changer or just a myth? A systematic review and meta-analysis. Life Sciences, 118663. 
Spiegelhalter, D. (2020). Use of “normal” risk to improve understanding of dangers of covid-19. BMJ 370, 
m3259. 
Stanojevic, S., Wade, A., Stocks, J., Hankinson, J., Coates, A.L., Pan, H., Rosenthal, M., Corey, M., 
Lebecque, P., and Cole, T.J. (2008). Reference ranges for spirometry across all ages: a new approach. 
American journal of respiratory and critical care medicine 177, 253-260. 
Sudre, C.H., Murray, B., Varsavsky, T., Graham, M.S., Penfold, R.S., Bowyer, R.C., Pujol, J.C., Klaser, K., 
Antonelli, M., Canas, L.S., et al. (2020). Attributes and predictors of Long-COVID: analysis of COVID cases 
and their symptoms collected by the Covid Symptoms Study App. medRxiv, 2020.2010.2019.20214494. 
Tenforde, M.W. (2020). Symptom Duration and Risk Factors for Delayed Return to Usual Health Among 
Outpatients with COVID-19 in a Multistate Health Care Systems Network — United States, March–June 
2020. MMWR Morb. Mortal. Wkly. Rep 69. 
Tillett, R.L., Sevinsky, J.R., Hartley, P.D., Kerwin, H., Crawford, N., Gorzalski, A., Laverdure, C., Verma, 
S.C., Rossetto, C.C., Jackson, D., et al. (2020). Genomic evidence for reinfection with SARS-CoV-2: a case 
study. The Lancet Infectious Diseases. 
van Doremalen, N., Lambe, T., Spencer, A., Belij-Rammerstorfer, S., Purushotham, J.N., Port, J.R., 
Avanzato, V.A., Bushmaker, T., Flaxman, A., Ulaszewska, M., et al. (2020). ChAdOx1 nCoV-19 vaccine 
prevents SARS-CoV-2 pneumonia in rhesus macaques. Nature 586, 578-582. 
van Kampen, J.J.A., van de Vijver, D.A.M.C., Fraaij, P.L.A., Haagmans, B.L., Lamers, M.M., Okba, N., van 
den Akker, J.P.C., Endeman, H., Gommers, D.A.M.P.J., Cornelissen, J.J., et al. (2020). Shedding of 
infectious virus in hospitalized patients with coronavirus disease-2019 (COVID-19): duration and key 
determinants. medRxiv, 2020.2006.2008.20125310. 
Wang, Y., Zhang, D., Du, G., Du, R., Zhao, J., Jin, Y., Fu, S., Gao, L., Cheng, Z., Lu, Q., et al. (2020). 
Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre 
trial. Lancet 395, 1569-1578. 
Watson, J.M., Francis, J.N., Mesens, S., Faiman, G.A., Makin, J., Patriarca, P., Treanor, J.J., Georges, B., 
and Bunce, C.J. (2015). Characterisation of a wild-type influenza (A/H1N1) virus strain as an experimental 
challenge agent in humans. Virology journal 12, 13-13. 
Whittaker, E., Bamford, A., Kenny, J., Kaforou, M., Jones, C.E., Shah, P., Ramnarayan, P., Fraisse, A., 
Miller, O., Davies, P., et al. (2020). Clinical Characteristics of 58 Children With a Pediatric Inflammatory 
Multisystem Syndrome Temporally Associated With SARS-CoV-2. Jama 324, 259-269. 
WHO_Solidarity_Trial_Consortium (2020). Repurposed Antiviral Drugs for Covid-19 — Interim WHO 
Solidarity Trial Results (Dec). New England Journal of Medicine. 
Wilkinson, T.M., Li, C.K., Chui, C.S., Huang, A.K., Perkins, M., Liebner, J.C., Lambkin-Williams, R., Gilbert, 
A., Oxford, J., Nicholas, B., et al. (2012). Preexisting influenza-specific CD4+ T cells correlate with disease 
protection against influenza challenge in humans. Nature medicine 18, 274-280. 
Williams, C., Pan, D., Decker, J., Wisniewska, A., Sze, S., Fletcher, E., Haigh, R., Abdulwhhab, M., Bird, 
P., Holmes, C., et al. (2020a). COVID-19: Exhaled virus detected by Face Mask Sampling provides new 
links to disease severity and potential infectivity. medRxiv, 2020.2008.2018.20176693. 
Williams, C.M., Abdulwhhab, M., Birring, S.S., De Kock, E., Garton, N.J., Townsend, E., Pareek, M., Al-
Taie, A., Pan, J., Ganatra, R., et al. (2020b). Exhaled Mycobacterium tuberculosis output and detection of 


CONFIDENTIAL 
COVHIC001 Protocol Final V7.0
 
COVHIC001 HVO-vCS-003 SARS-CoV-2 Characterisation Study 
Protocol Final v7.0 09Nov2021 
IRAS ID 292098 
 
 
 
 
 
 
155 
subclinical disease by face-mask sampling: prospective observational studies. The Lancet. Infectious 
diseases 20, 607-617. 
Williamson, B.N., Feldmann, F., Schwarz, B., Meade-White, K., Porter, D.P., Schulz, J., Doremalen, N.v., 
Leighton, I., Yinda, C.K., Pérez-Pérez, L., et al. (2020). Clinical benefit of remdesivir in rhesus macaques 
infected with SARS-CoV-2. bioRxiv, 2020.2004.2015.043166. 
Wölfel, R., Corman, V.M., Guggemos, W., Seilmaier, M., Zange, S., Müller, M.A., Niemeyer, D., Jones, 
T.C., Vollmar, P., Rothe, C., et al. (2020). Virological assessment of hospitalized patients with COVID-2019. 
Nature 581, 465-469. 
 

SAP_001.pdf: 






















o
o
o
o


o
Figure 1: Group and Dose Escalation Scheme
Starting dose 10^1 TCID50
Sentinel group (n=3) 
If no pausing rules at 14 days then 
continue to
total n of up to 10
(Includes Remdesivir)
Low dose 10^1 TCID50
Planned n=10 (up to 20)
(with or without treatment)
Low dose 10^1 TCID50
Planned n=10 (up to 20)
Adaptive (see Criteria for 3rd
expansion group)
(with or without treatment)
Low/Medium dose 10^2 TCID50
Sentinel group (n=3) 
If no pausing rules at 7 days then 
continue to
total n of up to 10
(with or without treatment)
Low/Medium dose 10^2 TCID50
Planned n=10 (up to 20) 
(with or without treatment)
Low/Medium dose 10^2 TCID50
Planned n=10 (up to 20)
Adaptive (see Criteria for 3rd
expansion group)
(with or without treatment)
Medium dose 10^3 TCID50
Sentinel group (n=3) 
If no pausing rules at 7 days then 
continue to
total n of up to 10 
(with or without treatment)
Medium dose 10^3 TCID50
Planned n=10 (up to 20)
(with or without treatment)
Medium dose 10^3 TCID50
Planned n=10 (up to 20)
Adaptive (see Criteria for 3rd
expansion group)
(with or without treatment)
If cohort <40% infected*, 
or if sentinel 0% infected**
infected*
If cumulative < 70% infected***
If cumulative < 70% infected***
If cumulative < 70% infected***
If cumulative < 70% infected***
infected*
infected*
If cohort <40% infected*, 
or if sentinel 0% infected**
Low dose 10^0 TCID50
Planned n=10 (up to 20)
(with or without treatment)
Low dose 10^0 TCID50
Planned n=10 (up to 20)
(with or without treatment)
Low dose 10^0 TCID50
Planned n=10 (up to 20)
Adaptive (see Criteria for 3rd
expansion group)
(with or without treatment)
infected*
If cumulative < 70% infected***
If cumulative < 70% infected***




Table 1: Schedule of Activities








Table 2: Key notes for SoA








o
o
o
o
o
o
o


o
o
.
o
o
o
o
o
o
o
o
o
o
o
o
o
o


o
o
o
o
o
o
o


o
o
o
o
o
o
o
o
o
o
o
o
o
o
o
o


o
o




















o
o
o
o
o
o
o
o
















Table 3: Olfactory index of absolute dysfunction based on UPSIT scores
Index
Female
Male
Anosmia
Score < 19
Score < 19
Severe Microsmia
19 <= Score < 26
19 <= Score < 26
Microsmia
26 <= Score < 31
26 <= Score < 30
Mild Microsmia
31 <= Score < 35
30 <= Score < 34
Normosmia
Score >= 35
Score >= 34












Parameter
n
xx
xx
Mean (SD)
xx.x (xx.xx)
xx.x (xx.xx)
%CV
xx.x
xx.x
SE
xx.xx
xx.xx
Median
xx.x
xx.x
Q1, Q3
xx.x, xx.x
xx.x, xx.x
Min, Max
xx, xx
xx, xx
CONFIDENTIAL
hVIVO Services Ltd.
Page x of y
HVO-vCS-003
Table x.x
Title (
(Day 28) 
)
Analysis set
Source Data: Listing 16.2.x {Source data footnote only appears for tables, where x references relevant listing 
number}
Program: xxxxxxxxx
Output: xxxxxxx
Date: xxxxxxxxx


























Table 14.1.1
Subject Disposition
All Subjects
All Subjects
(N=xx)
n
(%)
Enrolled
XX
Safety Analysis Set [1]
XX
(XX.X)
Full Analysis Set [2]
XX
(XX.X)
PP Analysis Set [3]
XX
(XX.X)
Received at least one dose of Remdesivir
XX
(XX.X)
Did not receive Remdesivir
XX
(XX.X)
Completed Day 28 Visit [4]
XX
(XX.X)
Completed Study [5]
XX
(XX.X)
Early Withdrawal [6]
XX
(XX.X)
Reason for Withdrawal
Withdrawal by Subject
XX
(XX.X)
XX
(XX.X)
Non-compliance with study requirements
XX
(XX.X)
Termination of study by sponsor
XX
(XX.X)
Adverse Event or Serious Adverse Event
XX
(XX.X)
Death
XX
(XX.X)
Pregnancy
XX
(XX.X)
Lost to follow-up
XX
(XX.X)
Other
XX
(XX.X)
[1] Safety Analysis Set = all subjects who were inoculated with wild-type SARS-COV-2 Challenge virus.
[2] Full Analysis Set = all subjects who were inoculated with wild-type SARS-COV-2 Challenge virus.
[3] Per Protocol (PP) Analysis Set = all subjects who were inoculated, had no major protocol deviations and completed the quarantine period (up to Day 14).
[4] Completed Day 28 Visit = Completed up to and including study visit Day 28.
[5] Completed Study = Completed up to and including study visit Day 360.
[6] Early Withdrawal = Withdrew from the study prior to Day 360 visit.
Note: Percentages are based on the number of enrolled subjects.


Table 14.1.2
Demography
Safety Analysis Set
All Subjects
(N=xx)
Sex
   Male
n (%) 
XX (XX.X)
   Female
n (%)
XX (XX.X)
Age at Screening (years)
n
XX
Mean (SD)
XX.X (XX.XX)
SE
XX.XX
Median
XX.X
Q1, Q3
XX.X, XX.X
Min, Max
XX, XX
BMI at Screening 
n
XX
Mean (SD)
XX.X (XX.XX)
SE
XX.XX
Median
XX.X
Q1, Q3
XX.X, XX.X
Min, Max
XX, XX
[Repeat for Height and Weight at screening]
Race
Asian
n (%)
XX (XX.X)
Black or African American
n (%)
XX (XX.X)
White
n (%)
XX (XX.X)
Hawaiian or Pacific Islander
n (%)
XX (XX.X)
Native Indian or Alaskan
n (%)
XX (XX.X)
Other
n (%)
XX (XX.X)
Ethnicity
Hispanic or Latino
n (%)
XX (XX.X)
Not Hispanic or Latino
n (%)
XX (XX.X)
Note: Percentages are based on the number of non-missing observations.
BMI=Body Mass Index.
Programming Note: If there are any subjects for whom sex and/or race and/or ethnicity is missing then include a missing row along with the n and %.


Table 14.1.3
Substance Use History
Safety Analysis Set
All Subjects
(N=xx)
Smoking History
   Never Smoked
n (%)
XX (XX.X)
   Current Smoker
n (%)
XX (XX.X)
   Previous Smoker
n (%)
XX (XX.X)
Alcohol History
   Never 
n (%)
XX (XX.X)
   Current User
n (%)
XX (XX.X)
   Previous User
n (%)
XX (XX.X)
   
      Note: Percentages are based on the Safety Analysis Set.
      Programming note: If any categorical parameters have missing values for certain subjects, then include a missing value category.


Table 14.1.4.1
Concomitant Medications up from Viral Challenge to Day 28
Safety Analysis Set
Drug Class (L2)/
    WHO Drug Preferred Base Name [1]
All Subjects
        (N=xx)
      n
%      
Number of Subjects with any Medication
XX
(XX.X)   
Drug Class 1
XX
(XX.X)  
    WHO Drug Name 1
XX
(XX.X)  
    WHO Drug Name 2
XX 
(XX.X)  
Drug Class 2
XX
(XX.X)  
    WHO Drug Name 1
XX
(XX.X)  
    WHO Drug Name 2
XX
(XX.X)  
[1] All medications will be coded using the WHO Drug Dictionary Global version 2021 (March 1, 2021).
    
Concomitant medications correspond to medications where the medication start date will not be later than Day 28 post-viral challenge and the medication stop date is not 
before the date of viral challenge.
Table shows distinct number of subjects with each WHO Drug name/Drug Class.
Percentages are based on the Safety Analysis Set.
Table template should also be used for Table 14.1.4.2.


Table 14.2.1.1
qRT-PCR-confirmed (>=LLOQ) SARS-Cov-2 Infection (Variant 1, Day 2 to Discharge) by Mid-Turbinate and Throat Samples
Full Analysis Set
Sample Type
All Subjects
(N=xx)
    n (%)
    95% CI
Mid-Turbinate and/or Throat
    XX (XX.X)
(X.XX, X.XX)
Note: LLOQ=Lower Limit of Quantification.
Note: Clopper-Pearson 95% CI 
This table template should be used for Table 14.2.1.2, 14.2.2.1, 14.2.2.2, 14.2.3.1.1, 14.2.3.1.2, 14.2.3.2.1, 14.2.3.2.2 


Table 14.2.4.1.1.1
Viral Load AUC (Day 2 to Discharge) by Mid-Turbinate or Throat Samples qRT-PCR
Full Analysis Set
Remdesivir
(N=xx)
No Remdesivir
(N=xx)
Viral Load AUC
(hours*Log10 copies/mL)
Infected
(N=xx)
Uninfected
(N=xx)
All
(N=xx)
Infected
(N=xx)
Uninfected
(N=xx)
All
(N=xx)
All Subjects
(N=xx)
Mid-Turbinate
n
         XX
    XX
    XX
    XX
    XX
    XX
    XX
Mean (SD)
         XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
%CV
         XX.X
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
SE
         XX.XX
    XX.XX
    XX.XX
    XX.XX
    XX.XX
    XX.XX
    XX.XX
Median
         XX.X
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
Q1, Q3
         XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
Min, Max
         XX, XX
    XX, XX
    XX, XX
    XX, XX
    XX, XX
    XX, XX
    XX, XX
95% CI
        (XX.X, XX.X)
   (XX.X, XX.X)
   (XX.X, XX.X)
   (XX.X, XX.X)
   (XX.X, XX.X)
   (XX.X, XX.X)
   (XX.X, XX.X)
Throat
n
         XX
    XX
    XX
    XX
    XX
    XX
    XX
Mean (SD)
         XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
%CV
         XX.X
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
SE
         XX.XX
    XX.XX
    XX.XX
    XX.XX
    XX.XX
    XX.XX
    XX.XX
Median
         XX.X
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
Q1, Q3
         XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
Min, Max
         XX, XX
    XX, XX
    XX, XX
    XX, XX
    XX, XX
    XX, XX
    XX, XX
95% CI
        (XX.X, XX.X)
   (XX.X, XX.X)
   (XX.X, XX.X)
   (XX.X, XX.X)
   (XX.X, XX.X)
   (XX.X, XX.X)
   (XX.X, XX.X)
Note %CV is derived for the AUC, based on the log10 copies/mL
This table layout will also be used for tables 14.2.4.1.1.2, 14.2.4.1.2.1, 14.2.5.1.1.1, 14.2.5.1.1.2, 


Table 14.2.4.2.1
Peak Viral Load (Day 2 to Discharge) by Mid-Turbinate and Throat Samples qRT-PCR
Full Analysis Set
Remdesivir
(N=xx)
No Remdesivir
(N=xx)
Peak Viral Load 
(log 10 copies / mL)
Infected
(N=xx)
Uninfected
(N=xx)
All
(N=xx)
Infected
(N=xx)
Uninfected
(N=xx)
All
(N=xx)
All Subjects
(N=xx)
Mid-Turbinate
n
         XX
    XX
    XX
    XX
    XX
    XX
    XX
Mean (SD)
         XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
%CV
         XX.X
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
SE
         XX.XX
    XX.XX
    XX.XX
    XX.XX
    XX.XX
    XX.XX
    XX.XX
Median
         XX.X
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
Q1, Q3
         XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
Min, Max
         XX, XX
    XX, XX
    XX, XX
    XX, XX
    XX, XX
    XX, XX
    XX, XX
Throat
n
         XX
    XX
    XX
    XX
    XX
    XX
    XX
Mean (SD)
         XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
%CV
         XX.X
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
SE
         XX.XX
    XX.XX
    XX.XX
    XX.XX
    XX.XX
    XX.XX
    XX.XX
Median
         XX.X
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
Q1, Q3
         XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
Min, Max
         XX, XX
    XX, XX
    XX, XX
    XX, XX
    XX, XX
    XX, XX
    XX, XX
This table template will be used for Table 14.2.4.2.2, 14.2.5.2.1, 14.2.5.2.2


Table 14.2.4.3.1.1
Duration of SARS-CoV-2 (Day 2 to Discharge) by Mid-Turbinate and Throat Samples qRT-PCR, Kaplan-Meier Analysis
Full Analysis Set
Remdesivir
(N=xx)
No Remdesivir
(N=xx)
All Subjects
(N=xx)
Sample Type
Time (days)
n
N#
Kaplan-Meier 
Estimate
n
N#
Kaplan-Meier 
Estimate
n
N#
Kaplan-Meier 
Estimate
Mid-Turbinate
Xx
xx
xx
0.xxx
xx
xx
0.xxx
xx
xx
0.xxx
Xx
xx
xx
0.xxx
xx
xx
0.xxx
xx
xx
0.xxx
Xx
xx
xx
0.xxx
xx
xx
0.xxx
xx
xx
0.xxx
Xx
xx
xx
0.xxx
xx
xx
0.xxx
xx
xx
0.xxx
Xx
xx
xx
0.xxx
xx
xx
0.xxx
xx
xx
0.xxx
Xx
xx
xx
0.xxx
xx
xx
0.xxx
xx
xx
0.xxx
Xx
xx
xx
0.xxx
xx
xx
0.xxx
xx
xx
0.xxx
Xx
xx
xx
0.xxx
xx
xx
0.xxx
xx
xx
0.xxx
Xx
xx
xx
0.xxx
xx
xx
0.xxx
xx
xx
0.xxx
    Q1 (days)
xx.x
xx.x
xx.x
Median (days)
xx.x
xx.x
xx.x
Q3 (days)
xx.x
xx.x
xx.x
Throat
Xx
xx
xx
0.xxx
xx
xx
0.xxx
xx
xx
0.xxx
Xx
xx
xx
0.xxx
xx
xx
0.xxx
xx
xx
0.xxx
Xx
xx
xx
0.xxx
xx
xx
0.xxx
xx
xx
0.xxx
Xx
xx
xx
0.xxx
xx
xx
0.xxx
xx
xx
0.xxx
Xx
xx
xx
0.xxx
xx
xx
0.xxx
xx
xx
0.xxx
Xx
xx
xx
0.xxx
xx
xx
0.xxx
xx
xx
0.xxx
Xx
xx
xx
0.xxx
xx
xx
0.xxx
xx
xx
0.xxx
Xx
xx
xx
0.xxx
xx
xx
0.xxx
xx
xx
0.xxx
Xx
xx
xx
0.xxx
xx
xx
0.xxx
xx
xx
0.xxx
    Q1 (days)
xx.x
xx.x
xx.x
Median (days)
xx.x
xx.x
xx.x
Q3 (days)
xx.x
xx.x
xx.x
Note: N is the number of subjects in the Full Analysis Set. n is the number of subjects with a confirmed undetectable assessment after their peak 
measure, by the end of the period. N# is the number of subjects at risk.
Note: Day 1 is the first day of detectable viral load, not study Day 1.
This table layout will also be used for tables 14.2.4.3.1.2, 14.2.5.3.1.1, 14.2.5.3.1.2
Programming note: Q1, the median and Q3 are derived from the Kaplan-Meier analysis.


Table 14.2.4.4.1
Incubation of SARS-CoV-2 (Day 2 to Discharge) by Mid-Turbinate and Throat Samples qRT-PCR
Full Analysis Set
Incubation 
(Days)
All Subjects
(N=xx)
Mid-Turbinate
n
    XX
Mean (SD)
    XX.X (XX.XX)
%CV
    XX.X
SE
    XX.XX
Median
    XX.X
Q1, Q3
    XX.X, XX.X
Min, Max
    XX, XX
Throat
n
    XX
Mean (SD)
    XX.X (XX.XX)
%CV
    XX.X
SE
    XX.XX
Median
    XX.X
Q1, Q3
    XX.X, XX.X
Min, Max
    XX, XX
Note: Incubation is defined as the time from viral challenge to the first quantifiable sample.
This table template will be used for Table 14.2.4.4.2, 14.2.5.4.1, 14.2.5.4.2


Table 14.2.6.1.1
Sum Total Symptom Score (Day 1 to Day 14) 
Full Analysis Set
Remdesivir
(N=xx)
No Remdesivir
(N=xx)
Sum Total Symptom Score
Infected
(N=xx)
Uninfected
(N=xx)
All
(N=xx)
Infected
(N=xx)
Uninfected
(N=xx)
All
(N=xx)
All Subjects
(N=xx)
n
         XX
    XX
    XX
    XX
    XX
    XX
    XX
Mean (SD)
         XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
GM
         XX.X
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
%CV
         XX.X
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
SE
         XX.XX
    XX.XX
    XX.XX
    XX.XX
    XX.XX
    XX.XX
    XX.XX
Median
         XX.X
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
Q1, Q3
         XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
Min, Max
         XX, XX
    XX, XX
    XX, XX
    XX, XX
    XX, XX
    XX, XX
    XX, XX
95% CI [1]
        (XX.X, XX.X)
   (XX.X, XX.X)
   (XX.X, XX.X)
   (XX.X, XX.X)
   (XX.X, XX.X)
   (XX.X, XX.X)
   (XX.X, XX.X)
Note %CV is derived for the TSS based on the unlogged data.
[1] 95% CI is derived by back-transforming the 95% CI obtained based on the logged data.
This table layout will also be used for tables 14.2.6.1.2, 14.2.6.2.1, 14.2.6.2.2
Programming note: Add an appropriate footnote to show the geometric mean calculation used.


Table 14.2.6.3.1
Peak Total Symptom Score (Day 1 to Day 14) 
Full Analysis Set
Remdesivir
(N=xx)
No Remdesivir
(N=xx)
Peak Total Symptom 
Score
Infected
(N=xx)
Uninfected
(N=xx)
All
(N=xx)
Infected
(N=xx)
Uninfected
(N=xx)
All
(N=xx)
All Subjects
(N=xx)
n
         XX
    XX
    XX
    XX
    XX
    XX
    XX
Mean (SD)
         XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
GM
         XX.X
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
%CV
         XX.X
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
SE
         XX.XX
    XX.XX
    XX.XX
    XX.XX
    XX.XX
    XX.XX
    XX.XX
Median
         XX.X
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
Q1, Q3
         XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
Min, Max
         XX, XX
    XX, XX
    XX, XX
    XX, XX
    XX, XX
    XX, XX
    XX, XX
Note %CV is derived for the TSS based on the unlogged data.
This table layout will also be used for tables 14.2.6.3.2, 14.2.6.4.1, 14.2.6.4.2
Programming note: Add an appropriate footnote to show the geometric mean calculation used.


Table 14.2.7.1.1
Proportion of Subjects for each Symptom Definition (Day 0 to Day 14) 
Full Analysis Set
Remdesivir
(N=xx)
No Remdesivir
(N=xx)
Endpoint Definition
Infected
(N=xx)
Uninfected
(N=xx)
All
(N=xx)
Infected
(N=xx)
Uninfected
(N=xx)
All
(N=xx)
All Subjects
(N=xx)
      n (%)
      n (%)
      n (%)
      n (%)
      n (%)
      n (%)
      n (%)
Grade 1 or Higher on Any Occasion
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
Grade 2 or Higher on Any Occasion
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
Grade 3 or Higher on Any Occasion
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
Grade 1 or Higher on Two Separate 
Occasions 
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
Grade 2 or Higher on Two Separate 
Occasions 
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
This table template should be used for table 14.2.7.1.2


Table 14.2.7.2.1
Incidence of Virus Illness Outcomes 
Full Analysis Set
Remdesivir
(N=xx)
No Remdesivir
(N=xx)
Number of subjects with 
illness
Infected
(N=xx)
Uninfected
(N=xx)
All
(N=xx)
Infected
(N=xx)
Uninfected
(N=xx)
All
(N=xx)
All Subjects
(N=xx)
URTI Incidence (%) 
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
LRTI Incidence (%) 
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
SI Incidence (%) 
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
FI Incidence (%) 
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
    XX (XX.X)
Note: Percentages are based on the Full Analysis Set. 
URTI = Upper Respiratory Tract Illness, LRTI = Lower Respiratory Tract Illness, SI = Systemic Illness, FI = Febrile Illness
This table template should be used for table 14.2.7.2.2


Table 14.2.8.1
UPSIT Score Summary 
Full Analysis Set
Remdesivir
(N=xx)
Sum Total 
Symptoms 
Score
Infected
(N=xx)
Uninfected
(N=xx)
All
(N=xx)
Visit
Absolute
Change from 
Baseline
Absolute
Change from 
Baseline
Absolute
Change from 
Baseline
Day -1
n
    XX
    XX
    XX
Mean (SD)
    XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
GM
    XX.X
    XX.X
    XX.X
%CV
    XX.X
    XX.X
    XX.X
SE
    XX.XX
    XX.XX
    XX.XX
Median
    XX.X
    XX.X
    XX.X
Q1, Q3
    XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
Min, Max
    XX, XX
    XX, XX
    XX, XX
Baseline 
(Day 0 Pre-Challenge)
n
    XX
    XX
    XX
Mean (SD)
    XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
GM
    XX.X
    XX.X
    XX.X
%CV
    XX.X
    XX.X
    XX.X
SE
    XX.XX
    XX.XX
    XX.XX
Median
    XX.X
    XX.X
    XX.X
Q1, Q3
    XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
Min, Max
    XX, XX
    XX, XX
    XX, XX
Day 1
n
    XX
    XX
    XX
    XX
    XX
    XX
Mean (SD)
    XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
    XX.X (XX.XX)
GM
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
%CV
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
SE
    XX.XX
    XX.XX
    XX.XX
    XX.XX
    XX.XX
    XX.XX
Median
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
    XX.X
Q1, Q3
    XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
    XX.X, XX.X
Min, Max
    XX, XX
    XX, XX
    XX, XX
    XX, XX
    XX, XX
    XX, XX
[Repeat for Day 2 to Day 14, Day 28, Day 90, Day 180, Day 270, Day 360]
Programming Note: Repeat the above for No Remdesivir (Infected, Uninfected, All)


Table 14.2.8.2
UPSIT: Shift Table of Olfactory Index of Absolute Dysfunction
Full Analysis Set
Remdesivir
(N=xx)
Infected
(N=xx)
Visit 
Olfactory Index of 
Absolute Dysfunction [1]
Baseline Olfactory Index of Absolute Dysfunction [1]
0
1
2
3
4
Day 1
   0
n (%)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
   1
n (%)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
   2
n (%)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
   3
n (%)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
   4
n (%)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
    Missing
n (%)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
Day 2
   0
n (%)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
   1
n (%)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
   2
n (%)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
   3
n (%)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
   4
n (%)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
    Missing
n (%)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
[Repeat for Day 3 to Day 14, Day 28, Day 90, Day 180, Day 
270, Day 360]
[ Repeat for each Dose Group ]
[1] 0 = Normosmia, 1 = Mild Microsmia, 2 = Microsmia, 3=Severe Microsmia, 4 = Anosmia
Programming Note: Repeat the above for Remdesivir (Uninfected, All) No Remdesivir (Infected, Uninfected, All) and All Subjects


Table 14.3.1.1
Overall Viral-Challenge Emergent Adverse Events up to Day 28
Safety Analysis Set
Infected
(N=xx)
Uninfected
(N=xx)
All Subjects
(N=xx)
Remdesivir
(N=xx)
No Remdesivir
(N=xx)
      n
(%)
      n
(%)
      n
(%)
      n
(%)
      n
(%)
Number of Events
XX
XX
XX
XX
XX
Number of Subjects with any Adverse Event
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
    Mild
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
    Moderate
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
    Severe
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
Number of Subjects with any Serious Adverse Event
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
Number of Subjects with any Related Adverse Event
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
Number of Subjects with any Adverse Event Leading to Withdrawal from the Study
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
The AEs summarised here are those that occurred from Viral Challenge until Day 28 visit. 
If a subject experiences more than one event, then the event with the worst severity or strongest relationship is included in the relevant level of summarisation.
Percentages are based on the safety analysis set.
.   
Subject withdrew from the study due to an adverse event.
Percentages are based on the safety analysis set.
This table layout will also be used for Tables 14.3.2.1, 14.3.5.1
Programming note: Adapt footnotes to the appropriate AE groupings.
Programming Note: adapt footnotes for time period covered by the table as appropriate.


Table 14.3.1.2
Viral-Challenge Emergent Adverse Events up to Day 28 by SOC and PT
Safety Analysis Set
System Organ Class/
Infected
(N=xx)
Uninfected
(N=xx)
All Subjects
(N=xx)
Remdesivir
(N=xx)
No Remdesivir
(N=xx)
    Preferred Term [1]
      n
(%)
      n
(%)
      n
(%)
      n
(%)
      n
(%)
Number of Events
XX
XX
XX
XX
XX
Number of Subjects with any adverse event
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
System Organ Class 1
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
    Preferred Term 1
    Preferred Term 2
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
System Organ Class 2
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
    Preferred Term 1
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
    Preferred Term 2
XX
(XX.X)
XX
XX
XX
(XX.X)
(XX.X)
(XX.X)
XX
(XX.X)
[1] MedDRA Version 24.0.
The AEs summarised here are those that occurred from viral challenge until Day 28 visit..
Table shows distinct number of subjects with events for each system organ class/preferred term.
Percentages are based on the safety analysis set.
      
The table template should be used for Table 14.3.1.4, 14.3.1.5, 14.3.2.2, 14.3.2.4, 14.3.2.5, 14.3.5.2, 14.3.5.4, 14.3.5.5


Table 14.3.1.3
Viral-Challenge Emergent Adverse Events up to Day 28 by SOC and PT and severity
Safety Analysis Set
Infected
(N=xx)
Uninfected
(N=xx)
All Subjects
(N=xx)
Remdesivir
(N=xx)
No Remdesivir
(N=xx)
      n
(%)
      
n
(%)
      n
(%)
      
n
(%)
      n
(%)
System Organ Class 1
XX
XX
XX
XX
XX
     Mild
        Moderate
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
      Severe
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
Preferred Term 1
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
     Mild
         Moderate
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
       Severe
     
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
Preferred Term 2
     Mild
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
XX
(XX.X)
         Moderate
XX
XX
XX
XX
XX
XX
XX
XX
XX
XX
       Severe
XX
XX
XX
XX
XX
XX
XX
XX
XX
XX
[1] MedDRA Version 24.0.
This table shows distinct number of subjects with events for each system organ class/preferred term/severity.
If a subject experienced a specific event more than once then the event with the worst severity is summarised.
Note: Percentages are based on the safety analysis set.
This table template should be used for table 14.3.2.3, 14.3.5.3


Table 14.3.3
Listing of Subjects with Serious Adverse Events
Safety Analysis Set
Subject
MedDRA SOC /
Preferred Term [1] /
    Adverse Event (verbatim)
Start Date 
/ Time 
(Study Day)
Stop Date / 
Time 
(Study Day)
Relationship 
to Viral 
Challenge
Severity
VE [2]
[1] MedDRA Version 24.0
[2] VE = Viral Challenge Emergent. An AE occurring on or after the date of viral challenge


Table 14.3.4
Listing of Subjects with Adverse Events Directly Resulting in Withdrawal from the Study
Safety Analysis Set
Subject
MedDRA SOC /
Preferred Term [1] /
    Adverse Event (verbatim)
Start Date / Time 
(Study Day)
Stop Date / Time 
(Study Day)
Relationship to Viral Challenge
Severity
VE [2]
[1] MedDRA Version 24.0
[2] VE = Viral Challenge Emergent. An AE occurring on or after the date of viral challenge


Table 14.3.6.1.1
Haematology: Platelet Count Summary
Safety Analysis Set
Platelet Count 
(X10^9/L)
All Subjects
(N=xx)
Absolute
Change 
from 
Baseline
Screening
n
xx
Mean
xx.x
SD
xx.xx
%CV
xx.xx
SE
xx.xx
Median
xx.x
Q1
xx.x
Q3
xx.x
Min
xx
Max
xx
Admission
n
xx
Mean
xx.x
SD
xx.xx
%CV
xx.xx
SE
xx.xx
Median
xx.x
Q1
xx.x
Q3
xx.x
Min
xx
Max
xx
Baseline 
(Day 0 Pre-Challenge)
n
xx
Mean
xx.x
SD
xx.xx
%CV
xx.xx
SE
xx.xx
Median
xx.x
Q1
xx.x
Q3
xx.x
Min
xx
Max
xx
Day 1
n
xx
xx
Mean
xx.x
xx.x
SD
xx.xx
xx.xx
%CV
xx.xx
xx.xx
SE
xx.xx
xx.xx
Median
xx.x
xx.x
Q1
xx.x
xx.x
Q3
xx.x
xx.x
Min
xx
xx
Max
xx
xx
[Repeat for each timepoint]


This table template should be used for Table 14.3.6.1.2 
14.3.6.1.7, Table 14.3.7.1.1 
14.3.7.1.2, Table 14.3.8, 14.3.9.1, 14.3.9.2
Baseline should be updated for each set of parameters 
Haematology, Biochemistry and Cardiac Enzymes this should be Day 0 pre-Challenge. For Thyroid function and Coagulation 
this should be Admission. 


Table 14.3.6.2
Haematology Parameters: Toxicity Grade Shift Table
Safety Analysis Set
All Subjects
(N=xx)
Parameter
Visit
    Toxicity Grade [1]
Baseline Toxicity Grade
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Parameter 1
Day 1
    Grade 0
n (%)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
    Grade 1
n (%)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
    Grade 2
n (%)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
    Grade 3
n (%)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
    Grade 4
n (%)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
     Missing
n (%)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
Day 2
    Grade 0
n (%)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
    Grade 1
n (%)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
    Grade 2
n (%)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
    Grade 3
n (%)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
    Grade 4
n (%)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
     Missing
n (%)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
Day 3
    Grade 0
n (%)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
    Grade 1
n (%)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
    Grade 2
n (%)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
    Grade 3
n (%)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
    Grade 4
n (%)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
     Missing
n (%)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
X (X.XX)
[Repeat for visits Day 4-Day 14, Day 28, Day 90, Day 
180, Day 270 Day 360] 
[Repeat for each Haematology parameter for which 
toxicity grade available] 
     [Repeat for each dose group]
[1] Grade 0=None, Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Potentially life-threatening.
Note: Baseline is Day 0 Pre-Challenge
Programming Note: If toxicity criteria available for parameter and toxicity grade missing (and aval not missing) then assume toxicity grade is 0 (none).
Toxicity criteria and grades are shown in Appendix 1.
This table template should be used for Table 14.3.7.2 


Table 14.3.10.1
Vital Signs: Heart Rate Summary
Safety Analysis Set
Heart Rate 
(BPM)
All Subjects
(N=xx)
Absolute
Change 
from 
Baseline
Screening
n
xx
Mean
xx.x
SD
xx.xx
%CV
xx.xx
SE
xx.xx
Median
xx.x
Q1
xx.x
Q3
xx.x
Min
xx
Max
xx
Admission
n
xx
Mean
xx.x
SD
xx.xx
%CV
xx.xx
SE
xx.xx
Median
xx.x
Q1
xx.x
Q3
xx.x
Min
xx
Max
xx
Baseline 
(Day 0 Pre-
Challenge)
n
xx
Mean
xx.x
SD
xx.xx
%CV
xx.xx
SE
xx.xx
Median
xx.x
Q1
xx.x
Q3
xx.x
Min
xx
Max
xx
Day 1
n
xx
xx
Mean
xx.x
xx.x
SD
xx.xx
xx.xx
%CV
xx.xx
xx.xx
SE
xx.xx
xx.xx
Median
xx.x
xx.x
Q1
xx.x
xx.x
Q3
xx.x
xx.x
Min
xx
xx
Max
xx
xx


[Repeat for 
each 
timepoint]
This table template should be used for Table 14.3.10.2 
14.3.10.5, 14.3.11


Table 14.3.12.1
Spirometry: FEV1 Summary
Safety Analysis Set
All Subjects
(N=xx)
Absolute
Change from 
Baseline
Screening
n
         XX
Mean (SD)
         XX.X (XX.XX)
%CV
         XX.X
SE
         XX.XX
Median
         XX.X
Q1, Q3
         XX.X, XX.X
Min, Max
         XX, XX
Admission
n
         XX
Mean (SD)
        XX.X (XX.XX)
%CV
XX.X
SE
XX.XX
Median
         XX.X
Q1, Q3
         XX.X, XX.X
Min, Max
         XX, XX
Day 0 
(Pre-Challenge)
n
         XX
Mean (SD)
        XX.X (XX.XX)
%CV
XX.X
SE
XX.XX
Median
         XX.X
Q1, Q3
         XX.X, XX.X
Min, Max
         XX, XX
Day 1
n
         XX
      XX
Mean (SD)
        XX.X (XX.XX)
      XX.X 
(XX.XX)
%CV
XX.X
      XX.X
SE
XX.XX
      XX.XX
Median
         XX.X
      XX.X
Q1, Q3
         XX.X, XX.X
      XX.X, XX.X
Min, Max
         XX, XX
      XX, XX
This table template will be used for Table 14.3.12.2 
14.3.12.6


Listing 16.2.1.1
Subject Disposition
Subject
Informed Consent
Date / Time
Eligible [1]
Quarantine 
Admission
Date
Viral 
Challenge
Date / Time
Discharge
Date
(Study Day)
Completed 
Day 28 Visit
Completed 
Study [2]
Date of
Completion/
Withdrawal
(Study Day)
Reason for
Withdrawal
xxxxxx
ddmmyyyy /hh:mm
Yes/No
ddmmyyyy 
ddmmyyyy 
/ 
hh:mm
ddmmyyyy 
Yes / No
Yes / No
ddmmyyyy (xx)
xxxxxxxxxxxxxxxxxxxxxxxxxx
xxxxxxx
[1] Corresponds to eligibility criteria review at Day 0 Pre-Challenge.      
[2] Completed Study = Participating in the study up to and including Day 360 (Follow-up)                                                                     


Listing 16.2.1.2
Failed Inclusion and Exclusion Criteria
Subject
Reason for Exclusion
xxxxxx
xxxxxxxxxxxxxxxxxxxx
Programming note: Listing not required if no subjects fail the criteria.


Listing 16.2.2
Protocol Deviations
Subject
Deviations 
Reported
Date Occurred
(Study Day)
Deviation 
Category [a]
Other, Specify
Deviation 
Description
Corrective 
Action
Serious 
Breach
xxxxxx
Yes/No
ddmmyyyy (xx)
n
xxxx
xxxxxxxxxx
Xxxxxxxxxx
Yes/No
[a] 
Deviation categories: Informed Consent procedure [1] / Subject error [2] / Inclusion/exclusion criteria [3] / Investigational product [4] / Visit window [5] / Concomitant 
medication/therapy [6] / Study procedure/assessment window [7] / SAE reporting [8] / Study procedure/assessment performance [9] / Missing assessment/sample [11] / Other [12]


Listing 16.2.3
Subject Analysis Sets
Subject
Full Analysis Set [1]
Per Protocol 
Analysis Set [2]
Safety 
Analysis Set [3]
Laboratory Confirmed 
Infection [4]
Received Remdesivir 
[5]
xxxxxx
Yes / No
Yes / No
Yes / No
Yes / No
Yes / No
[1] Safety Analysis Set = all subjects who were inoculated with wild-type SARS-COV-2 Challenge virus.
[2] Full Analysis Set = all subjects who were inoculated with wild-type SARS-COV-2 Challenge virus.
[3] Per Protocol (PP) Analysis Set = all subjects who were inoculated, had no major protocol deviations and completed the quarantine period (up to Day 14).
[4] Laboratory Confirmed Infection =
-PCR measurements from mid turbinate or throat samples, reported on 2 or more consecutive timepoints, starting from 
Day 2 up to Quarantine discharge.
[5] Received at least one dose of Remdesivir


Listing 6.2.4.1
Demographics
Subject
Age at 
Time of 
screening 
(years)
Sex
Ethnicity
Race
Visit
Date
Height
(cm)
Weight 
(kg)
BMI 
(kg/m^2)
Comments
xxxxxx
xx
Male / 
Female
xxxxxxxxxx
xxxxxxxx
Screening / Admission
ddmmyyyy
xxx
xx.xx
xx
xxxxxxxxxxxxxxxxxx
Note: NA = Not Applicable. Results for height, weight and BMI are shown for all visits.                                      


Listing 16.2.4.2
Reproductive Status and Contraception Use
Subject
Preg [1]
Child
Bearing 
Potential
Date of 
Last Period
HSAC
[2]
Become 
HSAC
[3]
Agree not
To Donate
Sperm
SAC [4]
Become 
SAC
[5]
Agree to Use
Contraception
Methods [6]
Comment
xxxxxx
Yes / No  
Yes / No 
ddmmmyyyy
Yes / No
Yes / No
Yes / No
Yes / No
Yes / No
Yes / No
x, x
xxxxxxxxxxxxxxx
[1] Breast Feeding/Pregnant Recently/Planning Pregnancy
[2] HSAC = Heterosexually Active (female)
[3] Should subject become Heterosexually Active, agree to use Contraception
[4] SAC = Sexually Active (male)
[5] Should subject become Sexually Active, agree to use Contraception
[6] 1 Oral, injected or implanted hormonal methods of contraception (minimum 2 weeks prior to admission).
    2 An intrauterine device (IUD) or intrauterine system (IUS), or bilateral tubal ligation.
    3 Male Sterilisation
    4 Barrier Methods 
Condom with spermicide 
    5 Other method.


Listing 16.2.4.3
Smoking History
Subject
Smoking History
Start Date
Stop Date
Exposure to 
household smoke
Uses 
e-cigarettes
Category
Amount
Years
Comments
xxxxxx
xxxxxxxxxxx
ddmmyyyy
ddmmyyyy
Yes / No
Yes / No
Number of cigarettes smoked per day
xx
xx
xxxxxxxxxxx
Number of cigars smoked per day
xx
xx
xxxxxxxxxxx
Number of cigarillos smoked per day
xx
xx
xxxxxxxxxxx
Number of pipe bowls smoked per day
xx
xx
xxxxxxxxxxx
Tobacco smoked per week (grams)
xx
xx
xxxxxxxxxxx
Pack years
xx
xx
xxxxxxxxxxx
Note: Comments are collected for the combined smoking, alcohol and drugs of abuse module and hence may relate to any of these parameters.
      * Date estimated.


Listing 16.2.4.4
Alcohol Use
Subject
Alcohol Use History
Weekly alcohol intake (units)
Willing to refrain from alcohol intake
Comments
xxxxxx
Never / 
Current User /
Previous User 
xx
Yes / No
xxxxxxxxxxx
Note: Comments are collected for the combined smoking, alcohol and drugs of abuse module and hence may relate to any of these parameters.


Listing 16.2.4.5
Recreational Drug Use and Abuse
Subject
Current or
Recent User
Start Date
Stop Date /
Ongoing
Recreational 
drug(s) used
Volume / amount of
Consumption
Route of 
Administration
Willing to refrain from 
use?
Comments
xxxxxx
Yes / No
ddmmyyyy
ddmmyyyy
xxxxxxxxxxxxx
xxxxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxx
Yes / No
xxxxxxxxxxx
Note: Comments are collected for the combined smoking, alcohol and drugs of abuse module and hence may relate to any of these parameters.
      * Date estimated.


Listing 16.2.4.6
QCovid Risk Assessment
Subject
Visit
Date / Time
Death Risk (Abs)
Death Risk 
Hospital Risk (Abs)
Hospital Risk 
Comment
xxxxxx
xxxxx
ddmmyyyy / hh:mm
x.xxxxx
xxxxxx
x.xxxxx
xxxxxx
xxxxxxx


Listing 16.2.4.7
Screening Questionnaires
Subject
Visit
Date / Time
Questionnaire
Score
Comment
xxxxxx
xxxxx
ddmmyyyy / hh:mm
GAD-7 / PHQ-9
xxxxxx
xxxxxxx


Listing 16.2.4.8
Medical History
Subject
Med Hist Line
MedDRA SOC /
Preferred Term [1] /
     Medical Condition
Start Date
End Date
Frequency
Ongoing
Concomitant medication
Taken for this condition?
xxxxxx
xxx
Xxxxxxxxxx
ddmmyyyy
ddmmyyyy
Single Episode /
Intermittent / 
Continuous / 
Other
Yes / No
Yes / No
[1] MedDRA Version 24.0.
Note: * Date estimated.


Listing 16.2.4.9
Prior and Concomitant Medications
Subject
Drug Class (L2) /
WHO Drug Preferred Base Name [1] / 
    Medication (verbatim)
Start Date /  
Time
(Study Day)
End Date / 
Time
(Study Day)  
Ongoing
Indication / 
AE / 
Med History Line
Dose / 
Dose Units
Freq [2] / 
Route [3]
P / C28 / C [4]
xxxxxx
xxxxxxxxx
ddmmyyyy /
hh:mm
(xx)
ddmmyyyy /
hh:mm
(xx)
Yes / No
xxxxxxxx /
AE / 
MHn
xxx
xxx /
xxx
P / C28 / C
[1] WHO Drug Dictionary Global version 2021 (March 1, 2021).
[2] OD = Once a day, BD = Twice a day, PRN = As needed, TDS = Three times a day, QDS = Four times a day, CTS = Continuous.                                                                 
[3] A = Aural, IM = Intramuscular, INH = Inhalation, IUD = Intrauterine Device, IV = Intravenous, N = Nasal, O = Ocular, PO = Oral, PR = Rectal, PV = Vaginal,
     SC = Subcutaneous, SL = Sublingual, TOP = Topical.  
[4] P=Prior, C28=Concomitant up to Day 28 post-viral challenge, C=Concomitant other.
Note: * Date/Time estimated.
If the medication stop date is before the date of viral challenge, the medication will be assigned as being prior to         
Viral challenge. In all other cases, the medication is assigned as being concomitant with viral challenge.              
Programming notes: Update footnotes 2 and 3 to reflect codes used in actual data.


Listing 16.2.5.1
Inoculation Administration
Subject
Administration 
Date / Time
Administered 
Intranasally?
Administered in 
Both Nostrils?
Administration 
Successful?
Titre of 
Virus 
Change in 
Health? [1]
Comments
xxxxxx
ddmmyyyy / hh:mm
Yes / No
Yes / No
Yes / No
xxxxx
Yes / No
xxxxxxxxxxx
[1] Subjects were monitored for 30 minutes post inoculum administration.


Listing 16.2.5.2
Remdesivir Administration
Subject
Dosing Reason [1]
Administration 
Date / Time 
(study day)
Dose Number
Full Dose 
Administered?
Adverse 
Reaction
Completed 
Dosing 
Schedule
Date of 
Discontinuatio
n
Number of 
Doses 
Administered
Reason for 
Discontinuation
xxxxxx
Infection / 
Symptoms
ddmmyyyy / hh:mm
x
Yes / No
Yes / No
Yes / No
dmmyyyy
x
xxxxxxxxxxxxxxxxxxxxxxx
[1] Infection = Confirmation of SARS-COV-2 infection at two consecutive time points.
Symptoms = Immediately after symptoms, signs or investigations suggestive of COVID-19.
Note: Remdesivir only administered during Cohort 1.


Listing 16.2.5.3
Antibodies
Subject
Sample Collection
Date / Time 
(Study Day)
Visit
Presence of SARS-
CoV-2
Comments
xxxxxx
ddmmyyyy / 
hh:mm 
(xx)
xxxxx
Xxxxx
xxxxxxxxxxxx


Listing 16.2.6.1
Viral Load by Mid-Turbinate or Throat Sample Results
Subject
Sample Collection
Date / Time 
(Study Day)
Sample Type
Assessment
qRT-PCR Virus Titre
(Log10 Copies/mL)
Viral Culture 
(Log10 FFU/mL)
Qualitative
Viral Culture
Comments
xxxxxx
ddmmyyyy / 
hh:mm 
(xx)
Mid-Turbinate 
/ Throat
1 / 2
Xxxxx
xxxxx
Negative / 
Positive 
xxxxxxxxxxxx
The Limit of Detection and Lower limit of Quantification will be shown in the footnote.


Listing 16.2.6.2.1
Viral Load by Mid-Turbinate or Throat Sample qRT-PCR Derivations
Subject
Sample Type
AUC (Day 1 to Day 14)
(hours*Log10 Copies/mL)
Peak Viral Load (Day 
1 to Day 14)
(Log10 Copies/mL)
Duration of
SARS-CoV-2
(days)
Incubation of
SARS-CoV-2
(days)
At Least Two Positive 
Measurement (>=LLOQ)
(Day 1 to Day 14)
xxxxxx
Mid-Turbinate 
/ Throat /
Mid-Turbinate 
or Throat
XX.XX
XX.XX
XX
XX
Yes / No


Listing 16.2.6.2.2
Viral Load by Mid-Turbinate or Throat Sample Viral Culture Derivations
Subject
Sample Type
AUC (Day 1 to Day 14)
(hours*Log10 PFU/mL)
Peak Viral Load (Day 1 to Day 
14)
(Log10 PFU/mL)
Duration of
SARS-CoV-2
(days)
Incubation of
SARS-CoV-2
(days)
At Least One Positive Measurement 
(>=LLOQ)
(Day 1 to Day 14)
xxxxxx
Mid-Turbinate 
/ Throat
/ Mid-Turbinate 
or Throat
XX.XX
XX.XX
XX
XX
Yes / No


Listing 16.2.7.1.1
Symptom Diaries 
Individual Symptoms 
Subject
Visit
Diary Card Completion
Date / Time 
(Study Day)
Assessment
Type
Sign
Grade
VAS
xxxxxx
xxxxxx
ddmmyyyy /
hh:mm
(xx)
1 / 2 / 3
LRTI
Cough
x
Shortness of Breath
X
Chest Tightness
X
Wheeze
X
URTI
Runny Nose
X
Stuffy Nose
X
Sneezing
X
Sore Throat
X
Earache
Eye Soreness
X
Hoarse Voice
X
SI
Headache
X
Malaise
X
Muscle/Joint ache
X
Chilliness/Feverishness
X
Dizziness
X
Blisters
X
Diarrhoea
X
Rashes
X


Listing 16.2.7.1.2
Symptom Diaries 
Qualitative
Subject
Visit
Date 
(Study Day)
Do you have a Cold? [1] Global Change Since Yesterday [2]
Confusion, disorientation, or drowsiness [3] Loss of appetite [4]
xxxxxx
xxxxxx
ddmmyyyy (xx)
Yes / No
Very much better / Somewhat better /
A little better / The same / 
A little worse /
Somewhat worse / Very much worse
Yes / No
Yes / No
[1] Do you have a cold?
[2
Note: [2] is only answered if subject answers yes to [1]
Note: [1] and [2] are asked in the morning and [3] and [4] are asked in the evening.


Listing 16.2.7.1.3
Individual Total Symptom Scores 
Subject
Diary Card Completion
Date / Time 
(Study Day)
Assessment
Total Symptom 
Score
Daily Total 
Symptom Score
xxxxxx
ddmmyyyy /
hh:mm
(xx)
1 / 2 / 3
xx
                                         
Programming Note: Daily total symptom score will be one score per day, shown on the top row for each day.


Listing 16.2.7.1.4
Total Symptom Score Derivations
Subject
Sum Total
Symptom Score
(Day 1 to Day 14)
Total 
Symptom Score AUC 
(Day 1 to Day 14)
Peak Total 
Symptom Score 
(Day 1 to Day 14)
Peak Daily Total  
Symptom Score 
(Day 2 to Day 13)
xxxxxx
XX
XX
XX
XX


Listing 16.2.7.2.1
Symptoms Grade Derivations
Subject
Grade 1 or Higher
on Any Occasion
Grade 1 or Higher
on Two Separate Occasions
Grade 2 or Higher
on Any Occasion
Grade 2 or Higher
on Two Separate Occasions
Grade 3 or Higher
on Any Occasion
xxxxxx
Yes / No
Yes / No
Yes / No
Yes / No
Yes / No


Listing 16.2.7.2.2
Illness and Symptomatic Infection Derivations
Subject
Subject has qRT-PCR 
confirmed (>=LLOQ) 
symptomatic 
infection (Variant 
1)?
Subject has Culture-
lab-confirmed 
(>=LLOQ) symptomatic 
infection?
Subject has
URTI?
Subject has 
LRTI?
Subject has 
SI?
Subject has 
FI?
xxxxxx
Yes / No
Yes / No
Yes / No
Yes / No
Yes / No
Yes / No
URTI = Upper Respiratory Tract Illness, LRTI = Lower Respiratory Tract Illness, SI = Systemic Illness, FI = Febrile Illness


Listing 16.2.8.1
UPSIT 
Subject
UPSIT Test Completion
Date / Time 
(Study Day)
Result
Olfactory 
Index of 
Absolute 
Dysfunction
xxxxxx
ddmmyyyy /
hh:mm
(xx)
xx
                                         


Listing 16.2.9.1
Adverse Events (Part 1)
Subject
AE Line
MedDRA SOC /
Preferred Term [1] / 
    Adverse event (verbatim)
Start Date / 
Time
(Study Day)
Stop Date / Time /
(Study Day)
Severity
VE [2]
xxxxxx
xxxxxxxxx
ddmmyyyy / hh:mm
(xx)
ddmmyyyy / hh:mm
(xx)
Mild /
Moderate /
Severe /
Life-Threatening
Yes / Blank
                                                   
[1] MedDRA Version 24.0.                                                 
[2] VE = Viral Challenge Emergent. An adverse event is Viral Challenge Emergent if the start date is at or after the Viral Challenge.
Note: * Date/Time estimated.
Programming note:
Only subjects with AEs will be shown in this listing.


Listing 16.2.9.2
Adverse Events (Part 2)
Subject
MedDRA SOC /
Preferred Term [1] / 
    Adverse event (verbatim)
Start Date / 
Time
(Study Day)
Relationship To:[2]
Virus
Medication
Procedure
Other
Other 
Details
xxxxxx
xxxxxxxxx
ddmmyyyy / hh:mm
(xx)
[1] MedDRA Version 24.0
[2] NA = Not Assessed by PI; 1 = Not used in this trial/study; 2 = Not Related; 3 = Unlikely Related; 4 = Possibly Related; 5 = Probably Related; 6 = Definitely Related.
Note: * Date/Time estimated.
Programming note:
Only subjects with AEs will be shown in this listing.


Listing 16.2.9.3
Adverse Events (Part 3)
Subject
MedDRA SOC /
Preferred Term [1] / 
    Adverse event (verbatim)
Start Date / 
Time
(Study Day)
Freq 
[2]
Outcome [3]
Action
Taken 
Remdesivir 
[4]
Action Taken
Other
[5]
Action Taken
Details
xxxxxx
xxxxxxxxx
ddmmyyyy / hh:mm
(xx)
x
x
x
xxxxxxxxxxxx
           
[1] MedDRA Version 24.0
[2] Freq = Frequency. For frequency categories, C = Continuous, I = Intermittent, S = Single Episode.        
[3] Outcome: 1 = Resolved; 2 = Resolved with Sequelae; 3 = Ongoing; 4 = Fatal; 5 = Unknown.        
[4] Action Taken: 1 = Study intervention (Remdesivir) dose not changed; 2 = Study intervention (Remdesivir) dose adjusted; 3 = Study intervention (Remdesivir) administration 
temporarily interrupted; 4 = Study intervention (Remdesivir) permanently discontinued; 5 = N/A, Study intervention (Remdesivir) not administered
[5] Action Taken: 1 = None; 2 = Non-drug therapy given; 3 = Concomitant medication taken; 4 = Subject withdrawn; 5 = Subject hospitalized; 6 = Other
Note: * Date/Time estimated.
Programming note: Only subjects with AEs will be shown in this listing.


Listing 16.2.9.4
Adverse Events (Part 4)
Subject
MedDRA SOC /
Preferred Term [1] / 
    Adverse event (verbatim)
Start Date / 
Time
(Study Day)
SAE
Reason 
for SAE
Comments
xxxxxx
xxxxxxxxx
ddmmyyyy / hh:mm
(xx)
Yes / No
xxxxxx
xxxxxxxxxxxx
[1] MedDRA Version 24.0.
Note: * Date/Time estimated.


Listing 16.2.10.1
Blood Sample Collection
Treatment
Group
Participant
Visit
Sample Collection
Date / Time 
(Study Day)
Sample Type(s) [1]
Clinically
Significant 
Result?
Adverse 
Event 
associated 
with 
Procedure?
Comments
xxxxxxx
xxxxxx
xxxxx
ddmmyyyy / 
hh:mm
(xx)
x x x x x x
Yes / No
Yes / No
xxxxxxxxxxxxxxx
* see Time and Events Schedule.       
[1] 1 = Biochemistry, 2 = Cardiac enzymes, 3 = Haematology, 4 = Coagulation, 5 = Thyroid function test,
6 = HIV, hepatitis A, B, & C, 7 = Serum pregnancy test, 8 = Serum FSH, 9, Haemaglobin, 10 = Lipid Profile, 
11 = Plasma Markers, 12 = Antibodies, 13 = Paxgene, 14 = PBMC


Listing 16.2.10.2
Haematology
Subject
Visit
Sample Collection
Date / Time 
(Study Day)
Parameter
Result
Change from
Baseline
Units
Lower 
Limit
Upper
Limit
Flag
Toxicity Grade
Comments
xxxxxx
xxxx
ddmmyyyy 
hh:mm
(xx)
Basophils (%)
x.xx
x.xx
%
x.xx
x.xx
L / H
0 / 1 / 2 / 3 / 4
xxxxxxxxxxxxxxxxxxxx
Basophils (abs)
x.xx
x.xx
X10^9/L
x.xx
x.xx
Eosinophils (%)
x.xx
x.xx
%
x.xx
x.xx
Eosinophils (abs)
x.xx
x.xx
X10^9/L
x.xx
x.xx
Haematocrit
x.xx
x.xx
%
xx
xx
Haemoglobin
xxx
xxx
g/L
xxx
xxx
Lymphocytes (%)
x.xx
x.xx
%
x.xx
x.xx
Lymphocytes (abs)
x.xx
x.xx
X10^9/L
x.xx
x.xx
MCH
x.xx
x.xx
pg
xx.x
xx.x
MCHC
xxx
xxx
g/L
xxx
xxx
MCV
x.xx
x.xx
fL
xx.x
xx.x
Monocytes (%)
x.xx
x.xx
%
xx.x
xx.x
Monocytes (abs)
x.xx
x.xx
X10^9/L
xx.x
xx.x
Neutrophils (%)
x.xx
x.xx
%
xx.x
xx.x
Neutrophils (abs)
x.xx
x.xx
X10^9/L
xx.x
xx.x
Platelets
xxx
xxx
X10^9/L
xx.x
xx.x
RBC Count
x.xx
x.xx
X10^12/L
x.xx
x.xx
Reticulocytes (%)
x.xx
x.xx
%
x.xx
x.xx
Reticulocytes (abs)
xx.x
xx.x
X10^9/L
xx.x
xxx.x
WBC Count
x.xx
x.xx
X10^9/L
x.x
xx.x
Note: Flag: L = below lower limit, H = above upper limit. Toxicity Grade: 0=None, 1=Mild, 2=Moderate, 3=Severe, 4=Potentially life-threatening
Same listing template will be used for 16.2.10.3, 16.2.10.4, 16.2.10.5, 16.2.10.6


Listing 16.2.10.7.1
Other Laboratory Tests: TDL (Part 1)
Subject
Visit
Sample Collection
Date / Time
(Study Day)
HIV 1 and HIV 2 
antibodies
HBSAg
HAIgM
Hepatitis C
FSH
(IU/L)
Beta HCG (quantitative)
(IU/L)
xxxxxx
xxxx
ddmmyyyy 
hh:mm
(xx)
Positive / Negative
Positive / Negative
Positive / Negative
Positive / Negative
xx
xx
Note: L=Low, H=High, ND=Not Done.
Normal Ranges to be displayed in footnote, if available.


Listing 16.2.10.7.2
Other Laboratory Tests: TDL (Part 2)
Subject
Visit
Sample Collection
Date / Time
(Study Day)
Parameter
Result
Units
Comments
xxxxxx
xxxx
ddmmyyyy 
hh:mm
(xx)
xxxxxxxx
xxx
xxx
xxxxxxxxxx
Programming note: Any other collected TDL lab parameters (that are not contained within previous laboratory listings) will be recorded in this listing (e.g. Globulin, Hematocrit, 
MPV, RDW, CKMB, Blood film, Globulin).
Note: L=Low, H=High.
Normal Ranges to be displayed in footnote.


Listing 16.2.10.8.1
Other Laboratory Tests: Urine Pregnancy
Subject
Visit
Test Date / Time
(Study Day)
Subject
has data
Result
Comments
xxxxxx
xxxx
ddmmyyyy / 
hh:mm
(xx)
Yes / No / NA - Male
Positive / Negative
xxxxxxxxxxxxxxxxxx


Listing 16.2.10.8.2
Other Laboratory Tests: Drugs of Abuse Screen 
Treatment 
Group
Subject
Visit
Sample Collection
Date / Time
(Study Day)
Test 
Performed 
Time
Drug
Result
Comments
xxxxxxx
xxxxxx
xxxx
ddmmmyyyy 
hh:mm
(xx)
hh:mm
Cocaine
Positive / 
Negative /
Not done
Cannabinoids
Positive / 
Negative /
Not done
Methadone
Positive / 
Negative /
Not done
Ecstasy
Positive / 
Negative /
Not done
Opiates
Positive / 
Negative /
Not done
Benzodiazepines
Positive / 
Negative /
Not done
Barbituates
Positive / 
Negative /
Not done
Amphetamine
Positive / 
Negative /
Not done
Methamphetamine
Positive / 
Negative /
Not done
Tricyclic
Positive / 
Negative /
Not done


Listing 16.2.10.8.3
Other Laboratory Tests: Urine Cotinine
Subject
Visit
Test Performed
Date / Time
(Study Day)
Result
Comments
xxxxxx
xxxx
ddmmyyyy /
hh:mm
(xx) 
Positive / Negative 
xxxxxxxxxxxxxxxxx


Listing 16.2.10.8.4
Other Laboratory Tests: Alcohol Breath Test
Subject
Visit
Test Date / Time
(Study Day)
Result
Comments
xxxxxx
xxxx
ddmmyyyy / hh:mm
(xx)
Positive / Negative 
xxxxxxxxxxxxxxxxx


Listing 16.2.10.9.1
Urinalysis
Subject
Visit
Sample Collection
Date / Time
(Study Day)
Test Performed Time
Parameter
Result [1]
xxxxxx
xxxx
ddmmyyyy /
hh:mm
(xx)
hh:mm
Appearance
Bilirubin
Blood 
Dip
Blood 
Haemolysed / Non-Haemolysed
Colour
Glucose
Ketones
Leukocytes
Nitrite
Protein
Specific Gravity
Urobilinogen
pH
Interpretation
Sent for Microscopy
Comments
[1] NCS = Not clinically significant, CS = Clinically significant.
Programming note: The physician interpretation and microscopy (Yes/No) will be shown as an additional row at the end of each assessment, with the interpretation/microscopy 
outcome shown in the result column.
Programming note: for Blood parameter there is a Haemolysed/Non-Haemolysed as well as a result.


Listing 16.2.10.9.2
Urinalysis (TDL): Microscopy
Subject
Visit
Sample Collection
Date / Time
(Study Day)
Urine 
RBC
Urine 
WBC
Cellular 
casts
Granular 
casts
Hyaline 
casts
Urine 
culture
xxxxxx
xxxx
ddmmyyyy / 
hh:mm
(xx)
xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxxxx
Note: ND=Not Done.
Note: A=Abnormal


Listing 16.2.10.10.1
Vital Signs
Subject
Visit
Date
Assessment
Time Started
Supine
Collection
Time
Parameter
Result [1]
Change from 
Baseline
Units
Comments
xxxxxx
xxxx
ddmmyyyy
1 / 2 / 3 / 4
hh:mm
hh:mm
Systolic BP
xxx
xxx
mmHg
Diastolic BP
xx
xx
mmHG
Heart Rate
xx
xx
bpm
Rep. Rate
xx
xx
breaths/min
SpO2
xx
xx
%
Interpretation
xxxxxxxx
xxxxxxx
[1] NCS = Not clinically significant, CS = Clinically significant.
Note: Comments and Interpretation relate to the complete vital signs module and hence can relate to temperature as well. 
Programming note: The physician interpretation will be shown as an additional row at the end of each assessment, with the interpretation outcome shown in the result column.


Listing 16.2.10.10.2
Temperature
Subject
Visit
Date
Assessment
Collection
Time
Tympanic 
Temperature 
(deg C)
Baseline
Change from 
Baseline
>=37.9 deg C?
Comments
xxxxxx
xxxx
ddmmyyyy
1 / 2 / 3 / 4
hh:mm
xx.x
xx.xx
xx.xx
Yes / Blank
xxxxxxx
                                                                                                                  
Note: Comments relate to the complete vital signs module and hence relate to one or more vital signs parameters.                    


Listing 16.2.11
ECG
Subject
Visit
Date
Time Started 
in Resting Position
Time Performed
Parameter
Result [1]
Change 
from 
Baseline
Units
Comments
xxxxxx
xxxx
ddmmyyyy
hh:mm
hh:mm
HR
xxx
xxx
bpm
xxxxxx
PR
xxx
xxx
ms
QRS
xxx
xxx
ms
QT
xxx
xxx
ms
QTc
xxx
xxx
ms
QTcB
xxx
xxx
ms
QTcF
xxx
xxx
ms
RR
xxx
xxx
ms
Interpretation
Normal /
Abnormal NCS / 
Abnormal CS
[1] NCS = Not clinically significant, CS = Clinically significant.
Programming note: The physician interpretation will be shown as an additional row at the end of each assessment, with the interpretation outcome shown in the result column.


Listing 16.2.12
Spirometry
Subject
Visit
Date
Best 
Spirometry Time
Parameter
Result [1]
Change from 
Baseline
Units
Comments
xxxxxx
xxxx
ddmmyyyy
hh:mm
FEV1 (abs)
x.xx
x.xx
L
FEV1 (% Pred)
xx
xx
%
FEV1/FVC Ratio (abs)
xx
xx
FEV1/FVC Ratio (% Pred)
xx
xx
%
FVC (abs)
x.xx
x.xx
L
FVC (% Pred)
xx
xx
%
FEV1 decreased by > 15% from baseline
Yes / No
Interpretation
Normal /
Abnormal NCS / 
Abnormal CS
[1] NCS = Not clinically significant, CS = Clinically significant.
Programming note: The physician interpretation will be shown as an additional row at the end of each assessment, with the interpretation outcome shown in the result column.
                                                             


Listing 16.2.13
FOT
Subject
Age / Sex / 
Weight / Height
Test Date 
(Study Day)
Parameter
Units
Variation
Time
Reference
Result
SD
CV
Z-Score
%Predicted
xxxxxx
xx / 
xxx / 
xxx / 
xxx
ddmmmyyyy 
(xx)
R5 /
R20 /
R5-20 / 
X5 / 
X5 in ex / 
Fres / 
AX / 
VT
xxx
Mean / 
M1 / 
M2 / 
M3
hh:mm:ss
x.xx
x.xx
x.xx
x.xx
x.xx
x.xx
Programming Note: The reference, SD, CV and z-score will only be displayed for the mean row of the listing.
                                                              


Listing 16.2.14
Chest X-ray
Subject
Visit
Date
Time Performed
Interpretation
Comments
xxxxxx
xxxx
ddmmyyyy
hh:mm
Normal /
Abnormal NCS / 
Abnormal CS
xxxxxxxx
[1] NCS = Not clinically significant, CS = Clinically significant.


Listing 16.2.15
Lung CT Scan
Subject
Visit
Date
Time Performed
Interpretation
Comments
xxxxxx
xxxx
ddmmyyyy
hh:mm
Normal /
Abnormal NCS / 
Abnormal CS
xxxxxxxx
[1] NCS = Not clinically significant, CS = Clinically significant.


Listing 16.2.16
Echocardiogram
Subject
Visit
Date
Time Performed
Interpretation
Comments
xxxxxx
xxxx
ddmmyyyy
hh:mm
Normal /
Abnormal NCS / 
Abnormal CS
xxxxxxxx
[1] NCS = Not clinically significant, CS = Clinically significant.


Listing 16.2.17.1
Physical Examination 
System Review
Subject
Visit
Date / Time 
(Study Day)
Physical Type
Parameter
Finding
Comments
xxxxxx
xxxx
ddmmyyyy hh:mm 
(Study Day)
Directed / Complete
General Appearance
Normal /
Abnormal Not Clinically Significant /
Abnormal Clinically Significant /
Not Done
Eyes
Ears
Nose
Throat
Head and Neck
Cranial Nerves/Nervous System
Musculoskeletal
Skin
Cardiovascular
Abdomen/GI System
Respiratory System
Chest 
Auscultation
Chest 
Vocal Resonance
Chest 
Percussion
Other Findings


Listing 16.2.17.2
Physical Examination 
Upper Respiratory Exam
Subject
Visit
Date / Time 
(Study Day)
Assessment
Level [1]
Comments
xxxxxx
xxxx
ddmmyyyy hh:mm 
(Study Day)
Nasal Discharge - Left
Nasal Discharge 
Right
Otitis 
Left
Otitis 
Right
Pharyngitis
Sinus Tenderness 
Left
Sinus Tenderness 
Right
New Wheezes, Rhonchi 
Left
New Wheezes, Rhonchi 
Right
[1] Nasal Discharge: 0 = None, 1 = Clear, serous; scant but slightly increased, 2 = Clear to white, obvious increased volume, + / - minor blood      
    streaks on tissue, 3 = Frankly prudent (yellow or green), or gross blood.      
    Otitis: 0 = None, 1 = Dulled tympanic membrane, 2 = Inflamed, injected tympanic membrane, 3 = Retracted or bulging tympanic membrane,   
    obvious air, fluid level.
    Pharyngitis: 0 = None, 1 = Mild and / or patchy erythema, 2 = Marked and / or confluent erythema, 3 = Erythema and purulent exudate.         
    Sinus Tenderness: 0 = None, 1 = Mild tenderness, 2 = Moderate tenderness, 3 = Severe tenderness or overlying erythema.                            
    New Wheezes, Rhonchi: 0 = None, 1 = Mild wheezes or rhonchi, 2 = Scattered wheezes or rhonchi, 3 = Widespread wheezes.


Listing 16.2.18
Visit Dates
Subject
Visit
Date
Source of Unscheduled Visit Comments
Comments
xxxxxx
xxxx
ddmmyyyy
xxxxxxxxxx
xxxxxxxxxxxxx
column in this listing.




Table 4: Toxicity Grade Criteria for Values Below Normal Range (Chemistry)
Table 5:Toxicity Grade Criteria for Values Above Normal Range (Chemistry)


Table 6: Toxicity Grade Criteria for Values Below Normal Range (Haematology)
Table 7: Toxicity Grade Criteria for Values Above Normal Range (Haematology)