A Phase I Study to Determine the Safety & Immunogenicity of the Candidate Rift Valley Fever Virus (RVFV) Vaccine ChAdOx1 RVF in UK Healthy Adult Volunteers
Phase: EARLY_PHASE1
Conditions: Rift Valley Fever
Sponsor: University of Oxford

 
 
CONFIDENTIAL 
 
RVF001 Clinical Trial Protocol Version 3.0, 27th Apr 2021                                                                 
©Oxford University    
 
UNIVERSITY OF OXFORD 
 
 
 
 
A phase I study to determine the safety and immunogenicity of the candidate Rift Valley 
Fever Virus (RVFV) vaccine ChAdOx1 RVF in UK healthy adult volunteers 
 
 
Study Reference: RVF001 
Protocol Number: v3.0 
Date: 27th Apr  2021 
 
 
Chief Investigator: Professor A.V.S Hill 
Sponsor: University of Oxford 
Funder: UK BBSRC and MRC/Department of Health through the UK Vaccines Network 
 
REC Number: 20/EE/0262 
EudraCT Number:  2017-004482-27  
IRAS Reference: 246707 
 
 
 
 
 
 
 
 

 
 
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Full Study Title 
A phase I clinical trial to determine the safety and immunogenicity 
of the candidate RVFV vaccine ChAdOx1 RVF in UK healthy adult 
volunteers. 
 
Study Code: RVF001 
EudraCT Number: 2017-004482-27  
IRAS project ID: 246707 
 
Short Study Title 
 
Safety and Immunogenicity of a candidate RVFV vaccine (RVF001) 
 
Chief Investigator 
 
Prof Adrian V.S. Hill 
 
 
 
 
Centre for Clinical Vaccinology and Tropical Medicine 
University of Oxford,  
Churchill Hospital, Old Road, Headington 
Oxford, OX3 7LE 
Email: adrian.hill@ndm.ox.ac.uk 
Trial Sites  
 
 
Centre for Clinical Vaccinology and Tropical Medicine 
Churchill Hospital, Old Road, Headington 
Oxford, OX3 7LE 
 
Sponsoring  Institution 
 
 
University of Oxford 
Clinical Trials and Research Governance  
Boundary Brook House 
Churchill Drive 
Headington 
Oxford  
OX3 7LQ 
Tel: 01865 572224 
Email: ctrg@admin.ox.ac.uk 
 
External Monitor  
 
 
Clinical Trials & Research Governance 
Boundary Brook House 
Churchill Drive 
Headington 
Oxford  
OX3 7LQ  
 
 
  
 

 
 
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Local Safety Monitor  
 
 
 
Dr Brian Angus 
Centre for Clinical Vaccinology and Tropical Medicine 
Churchill Hospital, Old Road, Headington 
Oxford, OX3 7LE 
 
Email: brian.angus@ndm.ox.ac.uk 
 
 
 

 
 
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Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone other 
than the Sponsor, the Investigator Team, HRA, host organisation, members of the Research 
Ethics Committee and other regulatory bodies. This information cannot be used for any 
purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Professor Adrian Hill. 
 
 
 
Statement of Compliance 
The trial will be conducted in compliance with the protocol, the  principles Good Clinical 
Practice Guideline , Medicines for Human Use (Clinical Trial) Regulations 2004 (as amended) 
and all other applicable regulatory requirements.   
 
 
 
Chief Investigator Approval and Agreement 
I have read the trial protocol and agree to conduct the trial in compliance with the protocol, 
the principles of Good Clinical Practice and all applicable regulatory requirements. 
 
I hereby approve this version of the protocol and declare no conflict of interest 
 
 
 
 
Adrian Hill 
 
10/05/2021 
 
 
 
 
 
 
 
 
 
Chief Investigator 
Name 
 
 
 
Signature 
 
 
Date  

 
 
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Modification History 
 
 
 
Version 
Date 
Author(s) 
Modifications 
1.0 
 6th Oct 2020 
Pedro Folegatti, Daniel 
Jenkin, George 
Warimwe, Sarah 
Gilbert, Adrian Hill 
N/A 
1.1 
8th Dec 2020 
Daniel Jenkin, Nguyen 
Tran 
Change of the planned trial period to 
Q1 2021 to Q4 2021. 
Update the number of subjects 
exposed to ChAdOx1 vectored vaccines 
to date in section 3.8 
2.0 
6th Jan 2021 
Daniel Jenkin, Pedro 
Folegatti, Nguyen Tran, 
Alison Lawrie 
(Response to MHRA GNA) 
Clarification of: staggered enrolment 
sequence, inclusion criteria related to 
pregnancy (updated to “at least 3 
months”), temporary postponement 
of vaccination, sponsor responsibilities 
related to completion and submission 
of DSURs and group holding rules. 
Update the list of abbreviations. 
2.1 
28th Jan 2021 
Daniel Jenkin, Nguyen 
Tran 
Section 6.3.1: Inclusion criterion 4 on 
contraception updated to “at least 3 
months from the final vaccination 
procedure”  
3.0 
27th Apr 2021 
Daniel Jenkin, Nguyen 
Tran, Alison Lawrie 
Change of the planned trial period to 
Q2 2021 to Q4 2021. 
Update to  risks and exclusion criteria 
sections regarding reports of 
thrombosis and thrombocytopenia. 

 
 
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Table of Contents  
1. 
SYNOPSIS ................................................................................................................ 10 
2. 
ABBREVIATIONS ...................................................................................................... 12 
3. 
BACKGROUND & RATIONALE ................................................................................... 14 
3.1 
Impact of Rift Valley Fever and the need for a vaccine ....................................... 14 
3.2 
Progress towards a RVFV  vaccine ..................................................................... 15 
3.3 
Gn and Gc glycoproteins as a vaccine antigen .................................................... 15 
3.4 
Adenovirus-vectored Vaccines .......................................................................... 16 
3.5   
ChAdOx1 .......................................................................................................... 17 
3.6   
Development of ChAdOx1 RVF .......................................................................... 17 
3.7   
Preclinical Studies ............................................................................................. 17 
3.7.1   
Efficacy and Immunogenicity ............................................................................. 17 
3.8   
Previous clinical experience .............................................................................. 21 
3.9 
Rationale .......................................................................................................... 25 
3.10   Vaccine Development Strategy ......................................................................... 25 
4.  
OBJECTIVES AND ENDPOINTS ............................................................................... 26 
4.1 
Primary Objective ............................................................................................. 26 
4.1.1 
Primary Outcome Measures .............................................................................. 26 
4.2 
Secondary Objective ......................................................................................... 26 
4.2.1 
Secondary Outcome Measures .......................................................................... 26 
5.  
STUDY OVERVIEW ................................................................................................ 28 
5.1  
Rationale for Selected Doses ............................................................................. 28 
5.2  
Study Groups .................................................................................................... 29 
5.2.1 
Duration of study ............................................................................................... 29 
5.2.2 
Definition of Start and End of Trial .................................................................... 29 
5.3 
Potential Risks for volunteers ............................................................................ 29 
5.4 
Known Potential Benefits .................................................................................. 31 
6. 
RECRUITMENT AND WITHDRAWAL OF TRIAL VOLUNTEERS ...................................... 32 
6.1 
Volunteers ........................................................................................................ 32 
6.2 
Informed consent ............................................................................................. 32 
6.3 
Inclusion and exclusion criteria ......................................................................... 33 
6.3.1 
Inclusion Criteria ................................................................................................ 33 
6.3.2 
Exclusion Criteria................................................................................................ 34 
6.3.3 
Effective contraception for female volunteers of childbearing potential ......... 35 
6.3.4 
Prevention of ‘Over Volunteering’ ..................................................................... 36 
6.3.5 
Criteria for postponement of vaccination ......................................................... 36 
6.3.6 
Withdrawal of Volunteers .................................................................................. 36 
6.4 
Compliance with Dosing Regime ....................................................................... 37 
6.5 
Pregnancy ......................................................................................................... 37 

 
 
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7. 
CLINICAL PROCEDURES ............................................................................................ 38 
7.1 
Study procedures .............................................................................................. 38 
7.2 
Observations .................................................................................................... 38 
7.3 
Blood Tests and Urinalysis................................................................................. 38 
7.4 
Study visits ....................................................................................................... 39 
7.4.1 
Screening visit .................................................................................................... 39 
7.4.2 
Day 0: Enrolment and Vaccination Visit ............................................................ 40 
7.4.3 
Subsequent visits:  days 2, 7, 14, 28, 56 and 84 ................................................ 42 
7.4.4 COVID-19 Study Considerations .............................................................................. 43 
8. 
INVESTIGATIONAL PRODUCTS .................................................................................. 45 
8.1. 
 Manufacturing and Presentation ...................................................................... 45 
8.1.1 
Description of ChAdOx1 RVF .............................................................................. 45 
8.1.2 
ChAdOx1 RVF formulation and packaging ......................................................... 45 
8.2 
 Supply ............................................................................................................. 45 
8.3  
Storage ............................................................................................................. 45 
8.4  
Administration of Investigational Medicinal Products ........................................ 45 
8.5 Minimising environmental contamination with genetically modified organisms 
(GMO) ........................................................................................................................ 46 
9. 
ASSESSMENT OF SAFETY .......................................................................................... 47 
9.1 
Definitions ........................................................................................................ 47 
9.1.1 
Adverse Event (AE) ............................................................................................. 47 
9.1.2 
Adverse Reaction (AR) ....................................................................................... 47 
9.1.3 
Unexpected Adverse Reaction ........................................................................... 47 
9.1.4 
Serious Adverse Event (SAE) .............................................................................. 47 
9.1.5 
Serious Adverse Reaction (SAR) ......................................................................... 48 
9.1.6 
Suspected Unexpected Serious Adverse Reaction (SUSAR) .............................. 48 
9.2 
Foreseeable Adverse Reactions: ........................................................................ 48 
9.3 
Expected Serious Adverse Events ...................................................................... 48 
9.4 
Causality Assessment ........................................................................................ 48 
9.5 
Reporting Procedures for All Adverse Events (see SOP VC027) ........................... 49 
9.5.1 
Reporting Procedures for Serious AEs (see SOP OVC005 Safety Reporting) ..... 50 
9.5.2 
Reporting Procedures for SUSARS ..................................................................... 50 
9.5.3 
Development Safety Update Report .................................................................. 50 
9.6 
Assessment of severity ..................................................................................... 50 
9.7 
Procedures to be followed in the event of abnormal findings ............................ 52 
9.8 
Local Safety Monitor ......................................................................................... 52 
9.8.1 
Interim Safety Reviews ...................................................................................... 53 
9.9 
Safety Stopping/Holding Rules .......................................................................... 53 
9.9.1 
Group holding rules ........................................................................................... 53 
10.  
STATISTICS ........................................................................................................... 55 

 
 
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11.  
DATA MANAGEMENT ........................................................................................... 56 
11.1 Data Handling ................................................................................................... 56 
11.2 Record Keeping ................................................................................................. 56 
11.3 Source Data and Case Report Forms (CRFs) ....................................................... 56 
11.4 Data Protection ................................................................................................ 57 
11.5 Data Quality ..................................................................................................... 57 
11.6 Archiving .......................................................................................................... 57 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES ................................ 58 
12.1 Investigator procedures .................................................................................... 58 
12.2 Monitoring ....................................................................................................... 58 
12.3 Protocol deviation ............................................................................................ 58 
12.4 Audit & inspection ............................................................................................ 58 
13. 
SERIOUS BREACHES .......................................................................................... 59 
14.  
ETHICS AND REGULATORY CONSIDERATIONS ....................................................... 60 
14.1 Declaration of Helsinki ...................................................................................... 60 
14.2 Guidelines for Good Clinical Practice ................................................................. 60 
14.3 Approvals ......................................................................................................... 60 
14.4 Volunteer Confidentiality .................................................................................. 60 
15.  
FINANCING AND INSURANCE ................................................................................ 61 
15.1  Financing ......................................................................................................... 61 
15.2  Insurance ......................................................................................................... 61 
15.3  Compensation .................................................................................................. 61 
16. 
CONTRACTUAL ARRANGEMENTS .......................................................................... 61 
17. 
PUBLICATION POLICY ........................................................................................... 62 
18. 
DEVELOPMENT OF A NEW PRODUCT/PROCESS OR THE GENERATION OF 
INTELLECTUAL PROPERTY ............................................................................................... 62 
19. 
REFERENCES ......................................................................................................... 63 
 
 
 
 

 
 
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1. SYNOPSIS 
 
Trial Title 
A phase I study to determine the safety and immunogenicity of the 
candidate RVFV vaccine ChAdOx1 RVF in UK healthy volunteers. 
 
Trial Centre 
 
Centre for Clinical Vaccinology & Tropical Medicine, University of Oxford, 
Churchill Hospital, Old Road, Headington, Oxford, OX3 7LE 
 
Trial Identifier 
 
RVF001 
 
Clinical phase  
 
I  
 
Study Design 
 
Open–labelled, non-randomised, dose escalation, first-in-human, single 
centre, phase I clinical trial 
 
Population 
 
Healthy adults aged 18 – 50 years 
 
Planned Sample Size 
 
 
 
 
 
 
15 volunteers 
Group 
Dose of ChAdOx1 RVF 
Group 1 (n=3) 
5 x 109 vp 
Group 2 (n=6) 
2.5 x 1010 vp 
Group 3 (n=6) 
5 x 1010 vp 
 
 
Follow-up duration 
 
12 weeks post  vaccine administration 
 
Planned Trial Period 
 
Q2 2021 to Q4 2021 
 
Primary Objective 
 
To assess the safety profile of the candidate vaccine ChAdOx1 RVF in 
healthy adult volunteers 
 
Secondary Objective 
 
 
To assess the immunogenicity of the candidate vaccine ChAdOx1 RVF in 
healthy adult volunteers 
 

 
 
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Investigational 
Products 
ChAdOx1 RVF, a replication-deficient simian adenoviral vector encoding 
the envelope glycoproteins (Gn/Gc) of the Rift Valley Fever Virus.   
 
Dose per 
Administration 
 
ChAdOx1 RVF 5 x 109 vp  
ChAdOx1 RVF 2.5 x 1010 vp  
ChAdOx1 RVF 5 x 1010 vp  
 
Form 
 
Liquid (all finished products) 
 
Route 
Intramuscularly (IM) into the deltoid region of the arm  
 
 
 

 
 
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2. ABBREVIATIONS 
 
AE 
 
  Adverse event 
AR 
 
 
  Adverse reaction 
CBF  
 
 
  Clinical Biomanufacturing Facility 
CCVTM 
 
  Centre for Clinical Vaccinology and Tropical Medicine 
ChAdOx1 
 
  Chimpanzee Adenovirus Ox1 
ChAdOx1 RVF 
Recombinant Chimpanzee Adenovirus Ox1 encoding the envelope                         
glycoproteins of RVFV    
CI 
 
 
  Chief Investigator 
CRF 
 
 
  Case Report Form or Clinical Research Facility 
CTRG  
 
  Clinical Trials Research Governance 
DSUR  
 
  Development Safety Update Report 
EC 
 
 
 
Ethics committee 
ELISA  
 
 
Enzyme linked immunosorbent assay 
ELISpot 
 
 
Enzyme linked immunospot assay 
FBC  
 
 
Full blood count 
GCP  
 
 
Good Clinical Practice 
GMO  
 
 
Genetically modified organism 
GMP  
 
 
Good Manufacturing Practice 
HBsAg 
 
 
Hepatitis B surface antigen 
HCG  
 
 
Human Chorionic Gonadotrophin 
HCV  
 
 
Hepatitis C virus 
HIV  
 
 
Human Immunodeficiency virus 
HLA  
 
 
Human leukocyte antigen 
IB 
 
 
 
Investigators Brochure 
ICH  
 
 
International Conference on Harmonisation 
IM 
 
 
 
Intramuscular 
IMP  
 
 
Investigational Medicinal Product 
LSM  
 
 
Local Safety Monitor 
MHRA 
 
 
Medicines and Healthcare products Regulatory Agency 
MVA  
 
 
Modified Vaccinia Virus Ankara 
OIE  
 
 
World Organisation for Animal Health 
PFU  
 
 
Plaque Forming Units 
PIS 
 
 
 
Participant information sheet 
QP 
 
 
 
Qualified Person 
RVF  
 
 
Rift Valley Fever 
RVFV  
 
 
Rift Valley Fever Virus 

 
 
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SAE  
 
 
Serious Adverse Event 
SAR  
 
 
Serious Adverse Reaction 
SFU  
 
 
Spot forming units 
SOP  
 
 
Standard Operating Procedure 
SUSAR 
 
 
Suspected Unexpected Serious Adverse Reaction 
TMF 
 
 
 Trial Master File 
vp 
 
 
 Viral particles 
WHO  
 
 World Health Organisation 
 
 
 

 
 
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3.   
BACKGROUND & RATIONALE 
3.1 
Impact of Rift Valley Fever and the need for a vaccine  
Rift Valley Fever Virus (RVFV) is a negative-stranded RNA Phlebovirus in the Bunyaviridae 
family known to be the causative agent of Rift Valley Fever (RVF), an emerging mosquito-
borne zoonotic infectious viral disease first described in the early 1930s (1). RVF affects 
primarily ruminants and it is characterised by high mortality rates (>90%) amongst young 
sheep, goats and cattle and increased abortion episodes in pregnant animals (2). The disease 
has serious implications for livestock agriculture and trade and is listed as a notifiable disease 
by the World Organization for Animal Health (OIE). Although primarily restricted to Africa, the 
virus can be transmitted by numerous different mosquito species that are more widely 
distributed than RVFV itself (1), leading to concerns of disease spread as has occurred in the 
Arabian Peninsula and Madagascar (3, 4). Humans can get infected through either infectious 
mosquito bites or contact with virus-contaminated tissues and fluid (5, 6). In humans, RVFV 
infection usually presents as an acute self-limiting febrile illness, but severe manifestations 
including haemorrhagic fever and encephalitis may also occur. Previous outbreaks in East 
Africa and Saudi Arabia reported case fatality rates of 30% and long-term sequela (e.g. 
impaired vision) were observed in some of the survivors (7, 8).  
Outbreaks of the disease are episodic and closely linked to climate variability, especially  
prolonged heavy rains and flooding that facilitates RVFV transmission by vector mosquitoes 
(9). It is thought that successive and overlapping swarms of different mosquitos infect and  
increase infection rates in ruminants with subsequent transmission to humans, resulting in 
epidemics (10). Human epidemics during RVF outbreaks in eastern Africa (Kenya, Tanzania, 
Somalia, Sudan and Madagascar) involved 478 deaths in 1998, 1107 reported cases with 350 
deaths in 2006 and 2007, and 1174 cases with 241 deaths in 2008 (11). More recently, the 
Ministry of Health of Niger reported 105 suspected cases in 2016, including 28 deaths of RVF 
in humans in the Tahoua region (12), and an RVF outbreak is currently ongoing in South 
Sudan. The high levels of human morbidity and mortality during these outbreaks underscores 
the urgency of developing comprehensive surveillance, response and control programmes, 
especially since there is growing evidence for inter-epidemic transmission of RVFV (13, 14). In 
Uganda, three RVF outbreaks have been reported; one in 1968 (15), 2016 (16), and there is 
currently an ongoing outbreak reported since November 2017 (17). There is also evidence of 
RVF endemicity on livestock farms in Uganda (18), Kenya, Rwanda, and other countries in 
eastern Africa.  
RVFV is an emerging global health threat listed as a select agent with significant potential for 
international spread and use in bioterrorism, hence it has been prioritised for vaccine 
research and development by the World Health Organisation (WHO), the National Institute 
of Allergy and Infectious Diseases (NIAID) and the UK Vaccine Research & Development 
Network (UKVRDN) (19). Live and inactivated RVFV vaccines are available for livestock, but no 
licensed vaccines or anti-viral therapies are currently available for humans (20). 
 

 
 
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3.2 
Progress towards a RVFV  vaccine 
Vaccination continues to be the most effective way to control RVF (21). The widely used live 
attenuated RVFV vaccines (e.g. Smithburn vaccine) in livestock elicit high titre neutralizing 
antibody and provide durable cross-strain protection after a single vaccination and have 
therefore been valuable for the control of RVFV in endemic areas. However, vaccination of 
pregnant animals can result in abortions and fetal malformations due to residual virulence, 
making their general use in humans very unlikely (21, 22). A formalin-inactivated 
investigational RVFV vaccine, TSI-GSD-200, has previously been evaluated in humans and 
found to be safe but poorly immunogenic, requiring three primary immunizations and a 
booster dose to generate and maintain neutralizing antibody responses (23, 24). An 
investigational live RVFV vaccine, MP-12, has shown better immunogenicity in humans than 
TSI-GSD-200, but as with the vaccine used in livestock, it could lead to post-vaccination 
viremia potentially causing teratogenic effects or abortion (25).  
Development and licensure of safe, highly immunogenic and efficacious RVFV vaccines for 
humans is clearly an unmet need for this neglected public health threat. The use of vaccine 
platforms with a well-established human safety profile is an attractive strategy for this 
purpose (20). Recovery from natural RVFV infection results in long-lived cross-strain immunity 
conferred by neutralizing antibodies against the viral envelope glycoproteins, Gn and Gc, 
which are conserved across different viral isolates (26, 27). Thus, whilst the neutralizing 
antibody titre threshold required for protection against RVFV infection is currently unknown, 
development of vaccines that elicit antibody titres within the range induced by natural 
infections is a very attractive way forward. 
 
3.3 
Gn and Gc glycoproteins as a vaccine antigen 
Bunyaviruses are enveloped viruses which harbor a tripartite, single stranded RNA genome 
with negative polarity. The tri-partite viral genome consists of a small (S), medium (M) and 
large (L) RNA genome segments. The L-segment of the genome encodes for the viral 
polymerase, the M-segment for the viral glycoproteins, Gn and Gc, and the S-segment for the 
nucleocapsid (N) protein (28). 
The Gn and Gc are the two major structural glycoproteins involved in virus–cell attachment 
and membrane fusion and are the only targets for neutralizing antibodies (29). Phleboviruses 
use their envelope proteins, Gn and Gc, for entry into target cells and for assembly of progeny 
particles in infected cells. Binding of Gn and Gc to cell surface factors promotes viral 
attachment and uptake into cells, and exposure to endosomal low pH induces Gc-driven 
fusion of the viral and the vesicle membranes. Moreover, Gn and Gc facilitate virion 
incorporation of the viral genome via their intracellular domains and Gn and Gc interactions 
allow the formation of a highly ordered glycoprotein lattice on the virion surface (28). 
Gn and Gc are synthesized as a precursor polyprotein, GnGc, in the secretory pathway of 
infected cells. Gn and Gc are separated by proteolytic cleavage but may remain non-

 
 
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covalently associated. The cleavage step is executed by a cellular enzyme, signal peptidase, 
during import of the GnGc precursor into the endoplasmic reticulum (ER). In the ER, Gn and 
Gc are decorated with N-linked glycans of the high-mannose type, which can be processed 
into hybrid and complex forms upon import of Gn and Gc into the Golgi apparatus. The Golgi 
apparatus is the site of bunyavirus budding and this process is facilitated by Gn and Gc, which 
play a key role in particle morphogenesis and genome incorporation. Finally, infectious 
particles decorated with Gn and Gc are released from the infected cell by exocytosis (28). 
The roles of Gn and Gc in viral entry into host cells and membrane fusion make them a perfect 
target for vaccine development.  
 
3.4 
Adenovirus-vectored Vaccines 
Adenoviruses are attractive vectors for human vaccination. They possess a stable genome so 
that inserts of foreign genes are not deleted and they can infect large numbers of cells without 
any evidence of insertional mutagenesis.  
Replication defective adenovirus can be engineered by deletion of genes from the E1 locus, 
which is required for viral replication, and these viruses can be propagated easily with good 
yields in cell lines expressing E1 from AdHu5 such as human embryonic kidney cells 293 (HEK 
293 cells) (30). 
Previous mass vaccination campaigns in over 2 million adult US military personnel using orally 
administered live human adenovirus serotype 4 and 7 have shown good safety and efficacy 
data (31). Human adenoviruses are under development as vectors for malaria, HIV, 
tuberculosis and hepatitis C vaccines, amongst others. They have been used extensively in 
human trials  (32-36) with excellent safety profile mainly as vectors for HIV vaccines. 
A limiting factor to widespread use of human adenovirus as vaccine vectors has been the level 
of anti-vector immunity present in humans where adenovirus is a ubiquitous infection. The 
prevalence of immunity to human adenoviruses prompted the consideration of simian 
adenoviruses as vectors, as they exhibit hexon structures homologous to human 
adenoviruses (37). Simian adenoviruses are not known to cause pathological illness in humans 
and the prevalence of antibodies to chimpanzee origin adenoviruses is less than 5% in humans 
residing in the US (38).  
In chimpanzee adenoviruses, the E1 locus can be deleted to render viruses replication 
deficient and allow transcomplementation on an E1 AdHu5 complementing cell line (39). 
Whilst they exhibit hexon structures homologous to that of human adenoviruses (40), the 
lack of sequence homology at the E1 flanking sequence prevents homologous recombination 
and production of replication competent virus (41) 
Chimpanzee adenoviral vectors can be manufactured cost-effectively and are now in clinical 
development as possible vaccines against malaria, HIV, tuberculosis, influenza, hepatitis C, 
RSV, Cancer and Ebola (42-47). 
 

 
 
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3.5   
ChAdOx1 
ChAdOx1 is a novel recombinant chimpanzee adenovirus designed as a vaccine vector, 
developed by The Jenner Institute at the University of Oxford. This viral vector has been used 
by researchers at the University of Oxford to produce a number of vaccines expressing a range 
of different antigens. 
ChAdOx1 is produced from a replication-deficient (E1 and E3 deleted) simian adenovirus and 
it has been described by Dicks et al (48). The vector was constructed in a bacterial artificial 
chromosome (BAC) to facilitate genetic manipulation of genomic clones with improved 
stability and flexibility. Cellular immunogenicity of recombinant E1 E3-deleted ChAdOx1 was 
comparable to that of other species E derived chimpanzee adenovirus vectors including 
ChAd63, the first simian adenovirus vector to enter clinical trials in humans. The E1 region is 
essential for viral replication, hence the ability to delete E1 renders the new vector 
immediately replication incompetent. The deletion of the non-essential adenovirus E3 region 
increases the insert capacity of the new vector by approximately 5kb. It is known that the 
proteins encoded by the E4 region of adenoviruses interact with E1 during viral replication, 
and the imperfect interaction between the gene products of the AdHu5 E1 gene produced by 
HEK293 cells and simian E4 gene products has been found to result in impaired viral 
replication in this cell line, and consequently lower virus yields. In ChAdOx1, Ad5 E4Orf4 has 
been inserted to replace the homologous simian virus coding sequence, resulting in improved 
viral replication during vaccine production. Since no replication of the virus takes place after 
immunization, this replacement has no effect on immunogenicity of the viral vector. Insertion 
of recombinant antigens at the E1 locus is performed using Gateway® site specific 
recombination technology (Invitrogen). 
 
3.6   
Development of ChAdOx1 RVF 
ChAdOx1 RVF encodes the RVFV envelope glycoproteins that are antigenically conserved 
targets of protective neutralising antibodies. A genomic clone of ChAdOx1 RVF was prepared 
by Gateway® recombination between an entry plasmid containing the coding sequence for 
RVFV Gn and Gc (Genbank accession number DQ380208, bases 411–3614) and the E1-and E3-
deleted ChAdOx1 destination vector. The vector encoded the 1,067 amino acid Gn and Gc 
RVF viral polyprotein under the control of the human cytomegalovirus major immediate early 
promoter. 
3.7   
Preclinical Studies 
3.7.1   Efficacy and Immunogenicity 
An initial efficacy and immunogenicity study of ChAdOx1 RVF has been conducted previously 
in mice (49). A single-dose immunisation with ChAdOx1 RVF was shown to elicit high-titre 
neutralizing antibodies and confer protection against a lethal viral challenge eight weeks post-
immunization. The vaccine also elicited T cells responses assessed by interferon gamma (IFNγ) 
production by splenocytes obtained from mice as measured by enzyme-linked immunospot 

 
 
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assay (ELISpot). Intracellular cytokine staining assay of peripheral blood mononuclear cells 
(PBMCs) sampled two weeks post-vaccination revealed a robust CD8+ T cell response mainly 
comprising cells staining positive for IFNγ or tumor necrosis factor alpha (TNFα) or both these 
cytokines (49).  
The vaccine has been further tested in target animals in disease-endemic settings in Kenya 
(sheep, goats and cattle) and Saudi Arabia (dromedary camels) (50). Immunogenicity and 
protective efficacy against RVFV challenge were the primary endpoints. Sheep, goats and 
cattle aged 4–6 months were sourced from local commercial farms in Kenya and pre-screened 
for previous exposure to RVFV. Groups of seronegative animals were then immunized 
intramuscularly with 109 infectious units (iu) ChAdOx1 RVF alone (group 1), 109 iu ChAdOx1 
RVF mixed with the saponin-based Matrix-QTM adjuvant (group 2) or placebo comprising 
phosphate buffered saline (PBS; group 3). A fourth comparator group received the licensed 
live Smithburn RVFV livestock vaccine widely used in Africa (group 4). Four weeks later all 
animals were challenged by subcutaneous inoculation of 107 plaque-forming units (pfu) of 
the same batch of a heterologous virulent RVFV strain and monitored for 14 days after which 
they were culled. The primary endpoint for efficacy was development of viraemia as 
measured by qRT-PCR in whole blood sampled daily over the monitoring period.  All sheep, 
goats and cattle in the placebo group developed viraemia. No viraemia could be detected 
among any of the ChAdOx1 RVF vaccinees in all three species (Fig. 1). The licensed Smithburn 
vaccine was also protective, but one goat and one calf receiving this vaccine developed 
viraemia post-challenge. In all three species ChAdOx1 RVF vaccination elicited high-titre 
neutralizing antibody, comparable to the licensed Smithburn vaccine (Fig. 2a). Similar 
neutralizing antibody titres were observed in parallel ChAdOx1 RVF immunogenicity studies 
in sheep and cattle in the UK, and remained high at 3 months post-vaccination (51). Matrix-
Q™ adjuvant had no effect on the antibody response elicited by ChAdOx1 RVF in any of the 
livestock species (Fig. 2a), as opposed to what was previously seen in mice (52), highlighting 
the importance of evaluating candidate vaccine regimens in target species. Significant post-
challenge boosting of neutralizing antibody titres was observed in all three species 
independent of vaccine allocation (Fig. 2c) (20). 
 
 

 
 
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Figure 1. ChAdOx1 RVF vaccination protects sheep, goats and cattle against RVFV challenge. 
Kaplan-Meier plots are used to infer vaccine-mediated protection using the primary endpoint 
of qRT-PCR detection of viraemia over a 14-day period following challenge (a, sheep; d, goats; 

 
 
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g, cattle). Peak viraemia levels for each species are shown as relative plaque-forming units 
(pfu; bars represent means), estimated by extrapolation from a standard curve generated 
using serial dilutions of RNA isolated from the challenge virus and assayed using the same 
method as the test samples (b, sheep; e, goats; h, cattle). Rectal temperature data measured 
at the same time of day during post-challenge monitoring are shown by vaccine allocation (c, 
sheep; f, goats; i, cattle), presented as means and standard errors (20). 
 
Six of seven camels immunised with ChAdOx1 RVF in Saudi Arabia mounted a neutralizing 
antibody response detectable at day 28 post-vaccination (Fig. 2b) and the remaining ChAdOx1 
RVF vaccinee had seroconverted by the next sampling time point (day 56 post-vaccination) 
(20).  
 
 

 
 
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Figure 2. ChAdOx1 RVF elicits high-titre RVFV neutralizing antibody. For each species means 
and standard errors of RVFV neutralizing antibody titres measured 28 days post-vaccination 
are shown in (a) and titres measured 14 days post-challenge are shown in (c). Pooled pre-
challenge (b) and post-challenge (d) neutralizing antibody data from vaccinees (ChAdOx1 RVF 
groups and Smithburn group) are shown, with each point representing an animal and bars 
representing the means and standard errors. Neutralizing antibody titres measured 28 days 
post-ChAdOx1 RVF immunization in dromedary camels are shown in (b). All analyses are by 
the Kruskal-Wallis test, with Dunn’s correction for multiple comparisons between groups. 
ns=not statistically significant (p > 0.05). The dashed line represents the detection limit of the 
assay (20). 
 
 
3.8   
Previous clinical experience 
This will be the first-in-human study using ChAdOx1 RVF. However, ChAdOx1 vectored 
vaccines expressing different inserts have previously been used over 8000  healthy volunteers 
taking part in clinical trials conducted by the University of Oxford in the UK and overseas. 
ChAdOx1 vectored vaccines encoding antigens from Influenza, Tuberculosis, Prostate Cancer, 
Malaria, MERS-CoV, Chikungunya, Meningitis B and Zika have entered clinical testing as part 
of multiple phase I clinical trials, as summarised in table 1.  
None of the studies mentioned reported serious adverse events associated with the 
administration of ChAdOx1, which was shown to have a good safety profile.

 
 
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RVF001 Clinical Trial Protocol Version 3.0, 27th Apr 2021                                                                 
©Oxford University    
 
Table 1. Clinical experience with ChAdOx1 viral vector vaccines. 
Country 
Trial 
Vaccine 
Age 
Route 
Dose 
Number of 
Volunteers 
(Received ChAdOx1) 
Publication / Registration Number 
UK 
FLU004 
ChAdOx1 NP+M1 
18-50 
IM 
5x108 vp 
3 
Antrobus et al, 2014. Molecular Therapy.  
DOI: 10.1038/mt.2013.284 
5x109 vp 
3 
2.5x1010 vp 
3 
5x1010 vp 
6 
UK 
FLU005 
ChAdOx1 NP+M1 
MVA NP+M1 (week 8) 
18-50 
IM 
2.5x1010 vp 
12 
Coughlan et al, 2018. EBioMedicine 
DOI: 10.1016/j.ebiom.2018.02.011 
DOI: 10.1016/j.ebiom.2018.05.001 
ChAdOx1 NP+M1 
MVA NP+M1 (week 52) 
18-50 
IM 
2.5x1010 vp 
12 
MVA NP+M1 
ChAdOx1 NP+M1 (week 8) 
18-50 
IM 
2.5x1010 vp 
12 
MVA NP+M1 
ChAdOx1 NP+M1 (week 52) 
18-50 
IM 
2.5x1010 vp 
9 
ChAdOx1 NP+M1 
>50 
IM 
2.5x1010 vp 
12 
ChAdOx1 NP+M1 
MVA NP+M1 (week 8) 
>50 
IM 
2.5x1010 vp 
12 
UK 
TB034 
ChAdOx1 85A 
18-50 
IM 
5x109 vp 
6 
Wilkie et al, 2020 Vaccine 
DOI: 10.1016/j.vaccine.2019.10.102 
2.5x1010 vp 
12 
ChAdOx1 85A 
MVA85A (week 8) 
18-50 
IM 
2.5x1010 vp 
12 
ChAdOx1 85A  
(x2, 4weeks apart) 
MVA85A (at 4 months) 
18-50 
IM 
2.5x1010 vp 
12 
Switzerland 
TB039 
(ongoing) 
ChAdOx1 85A 
18-55 
Aerosol 
1x109 vp 
3  
Clinicaltrials.gov: 
NCT04121494 
Aerosol 
5x109 vp 
3  
Aerosol 
1x1010 vp 
11  
Aerosol/IM 
1x1010 vp 
15 
Uganda 
 
ChAdOx1 85A 
18-49 
IM 
5x109 vp 
6 
Clinicaltrials.gov: 

 
 
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Country 
Trial 
Vaccine 
Age 
Route 
Dose 
Number of 
Volunteers 
(Received ChAdOx1) 
Publication / Registration Number 
TB042 
(ongoing) 
2.5 x1010 
6 
NCT03681860 
UK 
VANCE01 
ChAdOx1.5T4 
MVA.5T4 
18 – 75 
IM 
2.5x1010 vp 
34  
Clinicaltrials.gov: 
NCT02390063 
UK 
ADVANCE 
(ongoing) 
ChAdOx1.5T4 
MVA.5T4 
≥18 
IM 
2.5x1010 vp 
23 (as of Feb 20) 
Clinicaltrials.gov: 
NCT03815942 
UK 
VAC067 
ChAdOx1 LS2 
18-45 
IM 
5x109 vp 
3 
Clinicaltrials.gov: 
NCT03203421 
2.5x1010 vp 
10 
UK 
MERS001 
ChAdOx1 MERS 
18-50 
IM 
5x109 vp 
6  
Clinicaltrials.gov: 
NCT03399578 
DOI: https://doi.org/10.4269/ajtmh.abstract2018 
Abstract#973, page 305. 
2.5x1010 vp 
9 
5x1010 vp 
9 
2.5x1010 vp  
(homologous prime-boost) 
2 
UK 
VAMBOX 
ChAdOx1 MenB.1 
18-50 
IM 
2.5x1010 vp 
3 
ISRCTN46336916 
5x1010 vp 
26 
UK 
CHIK001 
ChAdOx1 Chik 
18-50 
IM 
5x109 vp 
6 
Clinicaltrials.gov: 
NCT03590392 
DOI: https://doi.org/10.4269/ajtmh.abstract2019  
Abstract #59, page 19. 
2.5x1010 vp 
9 
5x1010 vp 
9 
UK 
ZIKA001 
ChAdOx1 Zika 
18-50 
IM 
5x109 vp 
6 
Clinicaltrials.gov: 
NCT04015648 
2.5x1010 vp 
9 (as of May 20) 
5x1010 vp 
- 
UK 
COV001 
ChAdOx1 nCoV-19 
18-55 
IM 
5 × 1010 vp 
544 
Folegatti, Ewer et al. Lancet 2020 (53) 

 
 
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Country 
Trial 
Vaccine 
Age 
Route 
Dose 
Number of 
Volunteers 
(Received ChAdOx1) 
Publication / Registration Number 
(ongoing) 
Clinicaltrials.gov: 
NCT04324606 
 
UK 
COV002 
(ongoing) 
ChAdOx1 nCoV-19 
18-55 
IM 
5 × 1010 vp 
4138 
Clinicaltrials.gov: 
NCT04400838 
 
 
56-69 
5 × 1010 vp 
149 
≥70 
5 × 1010 vp 
186 
Brazil 
COV003 
(ongoing) 
ChAdOx1 nCoV-19 
18-55 
IM 
5 × 1010 vp 
2019 (as of Aug 
2020) 
ISRCTN89951424 
 
 
South 
Africa 
COV005 
(ongoing) 
ChAdOx1 nCoV-19 
18-65 
IM 
5 × 1010 vp 
698 (as of Aug 
2020) 
Clinicaltrials.gov:  
NCT04444674 
 

 
 
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RVF001 Clinical Trial Protocol Version 3.0, 27th Apr 2021                                                                 
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3.9 
Rationale  
RVFV is an emerging zoonotic mosquito-borne viral disease with serious implications for 
livestock agriculture and trade, leading to significant economic losses and social impact. 
Furthermore, the virus is considered a global threat and it has been listed as a select agent 
with significant potential for international spread and use in bioterrorism. Previous RVF 
outbreaks in Somalia (2006-2007), Kenya (2006-2007), Tanzania (2007), and Sudan (2007-
2008) showed extensions to districts, which were not involved before. These outbreaks also 
demonstrated the changing epidemiology of the disease from being originally associated with 
livestock, to a seemingly highly virulent form infecting humans and causing considerably high-
fatality rates (54). More recently, RVFV has been associated with miscarriages in pregnant 
women (55). 
The widely used live attenuated RVFV vaccines in livestock in Africa are considered to be 
highly effective, but major safety concerns preclude their general use in humans. There are 
no licensed vaccines currently available for human use.  
Chimpanzee adenovirus vaccine vectors have been safely administered to over thousands of 
people using a wide range of infectious disease targets including malaria (56), HIV (57), 
tuberculosis, influenza (58), hepatitis C (59), RSV (60) and, most recently, Ebola (61). ChAdOx1 
viral vectored vaccines have shown to be both safe and immunogenic in previous clinical trials 
in the UK and a single-dose immunisation with ChAdOx1 RVF vaccine has shown to elicit high 
levels of neutralising antibody in target animal species (sheep, goats and cattle). These 
neutralising antibody titres are comparable to those elicited by the most immunogenic 
licensed livestock vaccine (i.e. Smithburn vaccine) and are within the range observed in 
naturally exposed humans living in RVFV-endemic settings in East Africa (20)(Warimwe, 
unpublished observations). These data have underpinned the co-development of ChAdOx1 
RVF for use in both livestock and humans.  
 
3.10   Vaccine Development Strategy 
A phase I clinical trial at a disease-endemic area (the MRC/Uganda Virus Research Unit, 
Entebbe) is planned following the ChAdOx1 RVF trial in Oxford. The optimal dose of ChAdOx1 
RVF will be determined following the Oxford and Ugandan trials and, provided there are no 
safety concerns, phase II studies will be conducted in Uganda and Kenya.   
 
 
 
 

 
 
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4.  
OBJECTIVES AND ENDPOINTS 
The number of volunteers has been chosen to generate adequate safety and immunogenicity 
data to meet these objectives, whilst minimising the number of volunteers exposed to a new 
vaccination regimen.  
 
4.1 
Primary Objective 
To assess the safety and tolerability of ChAdOx1 RVF in healthy adult volunteers.  
 
4.1.1 Primary Outcome Measures 
The specific endpoints for safety and reactogenicity will be actively and passively collected 
data on adverse events.  
The following parameters will be assessed for all study groups 
 Occurrence of solicited local reactogenicity signs and symptoms for 7 days following 
the vaccination 
 Occurrence of solicited systemic reactogenicity signs and symptoms for 7 days 
following the vaccination 
 Occurrence of unsolicited adverse events for 28 days following the vaccination 
 Change from baseline for safety laboratory measures  
 Occurrence of serious adverse events during the whole study duration 
Volunteers will undergo clinical follow up for a further 90 days following completion of the 
vaccination regimen. SAEs will be collected throughout the study. The duration of follow up 
reflects the desire to obtain  safety data with the first use of ChAdOx1 RVF in humans. 
 
4.2 
Secondary Objective 
To assess the cellular and humoral immunogenicity of ChAdOx1 RVF in healthy adult 
volunteers. 
 
4.2.1 Secondary Outcome Measures 
Measures of immunogenicity to the ChAdOx1 RVF vaccine may include:  
 ELISA to quantify antibodies to GnGc  proteins 
 RVFV neutralising antibody titres  
 Ex vivo ELISpot and flow cytometry responses to GnGc  
Other exploratory immunology may be carried out in collaboration with other specialist 
laboratories, including laboratories outside of Europe. This would involve transfer of 
serum/plasma and/or peripheral blood 

 
 
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 mononuclear cells (PBMC), but samples would be anonymised. Volunteers will be asked for 
their consent for this before enrolment.   
 
 
 

 
 
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5.  
STUDY OVERVIEW 
This is a first-in-human, open-label, dose escalation, phase I clinical trial to assess the safety 
and immunogenicity of the candidate ChAdOx1 RVF vaccine in healthy volunteers aged 18-
50. The vaccine will be administered intramuscularly.  
Volunteers will be recruited and vaccinated at the CCVTM, Oxford. There will be 3 study 
groups and a total of 15 volunteers will be enrolled (table 2). The sequence of enrolment is 
described in section 7.4.2.2. Volunteers will be initially recruited into Group 1 and 
subsequently into Groups 2 and 3 following interim clinical safety reviews (see section 7.4.2). 
Volunteers will be allocated to a study group by selecting eligible volunteers for enrolment 
following screening.  
 
5.1  
Rationale for Selected Doses 
Doses to be administered in this trial have been selected on the basis of clinical experience 
with the ChAdOx1 adenovirus vector expressing different inserts and similar adenovirus 
vectored vaccines (eg. ChAd63).  
A first-in-human dose escalation study using the ChAdOx1 vector encoding an influenza 
antigen (FLU004), safely administered ChAdOx1 NP+M1 at doses ranging from 5 x 108 to 5 x 
1010 vp. Subsequent review of the data identified an optimal dose of 2.5 x 1010 vp balancing 
immunogenicity and reactogenicity. This dose has subsequently been given to over 175 
volunteers in numerous larger phase 1 studies at the Jenner Institute (FLU005, TB034 
VANCE01, ADVANCE and VAC067) and ChAdOx1 vectored vaccines have thus far 
demonstrated to be very well tolerated. The vast majority of AEs have been mild-moderate 
and there have been no SARs until this date in these studies.  
Other ChAdOx1 vectored vaccines have been given at doses up to 5x1010vp (MERS001, 
VAMBOX, CHIK001 and nCoV-19) whilst a different simian adenovirus vector (ChAd63) has 
been safely administered at doses up to 2 x 1011 vp with an optimal dose of 5 x 1010 vp, 
balancing immunogenicity and reactogenicity. 
As this is a first-in-human assessment of the RVFV GnGc antigenic insert, the first dose of 
ChAdOx1 RVF proposed in this study (5 x 109 vp) is therefore 10 fold less than the expected 
tolerable dose of ChAdOx1 RVF (5x 1010 vp). Doses will be gradually increased aiming to 
provide an optimal dose of ChAdOx1 RVF considering the tolerability, reactogenicity and 
immunogenicity profiles. 
 
 
 

 
 
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5.2  
Study Groups 
Table 2. Study Groups 
Group 
Single Dose 
ChAdOx1 RVF 
Route 
Group 1 (n=3) 
5 x 109 vp 
IM 
Group 2 (n=6) 
2.5 x 1010 vp 
IM 
Group 3 (n=6) 
5 x 1010 vp 
IM 
 
 
5.2.1 Duration of study  
The total duration of the study will be 12 weeks from the day of enrolment for all volunteers.  
 
5.2.2 Definition of Start and End of Trial 
The start of the trial is defined as the date of the first vaccination of the first volunteer. The 
end of the trial is the date of the last visit of the last volunteer. 
 
5.3 
Potential Risks for volunteers 
The potential risk to participants is considered as low. The potential risks are those associated 
with phlebotomy and vaccination. In general, recombinant adenoviral vectors are safe. Similar 
vaccines encoding different antigens have been given to several thousand volunteers 
(including children) with a good safety profile.  
Phlebotomy:  
The maximum volume of blood drawn over the study period (approximately 300mL) should 
not compromise these otherwise healthy volunteers. There may be minor bruising, local 
tenderness or pre-syncopal symptoms associated with venepuncture, which will not be 
documented as AEs if they occur.  
Vaccination: 
ChAdOx1 RVF has not been used in humans before and therefore will be initially administered 
at the lower dose of 5 x 109 vp before progressing to the higher doses of 2.5 x 1010 and 5 x 
1010 vp in Groups 2 and 3.  Expected risks from vaccination include local effects such as pain, 
redness, warmth, swelling, tenderness or itching. Systemic reactions that could potentially 
occur following immunisation with a recombinant adenovirus vaccine include a flu-like illness 
with feverishness, fatigue, malaise, arthralgia, myalgia and headache.  
As with any vaccine, Guillain-Barré syndrome or immune-mediated reactions that can lead to 
organ damage may occur, but this should be extremely rare. Serious allergic reactions 
including anaphylaxis could also occur and for this reason volunteers will be vaccinated in a 

 
 
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clinical area where Advanced Life Support trained physicians, equipment and drugs are 
immediately available for the management of any serious adverse reactions (SAR). 
 
Thrombosis with Thrombocytopenia:  
In April 2021, MHRA and JCVI conducted a review of extremely rare reports of cerebral venous 
sinus thrombosis (and thrombosis of other major veins) with concurrent thrombocytopenia 
occurring after vaccination with ChAdOx1 nCoV-19 in the national COVID-19 vaccination 
programme. The potential mechanism of these events, and whether they are related to the 
ChAdOx1 viral vector or to the SARS-CoV-2 spike protein, is yet to be determined. Estimates 
of incidence of thrombosis with thrombocytopenia following ChAdOx1 nCoV-19 vaccination 
vary and may change further as more cases are gathered and case definitions are finalised; 
current UK estimates are of cases occurring after  less than 1 in 100,000 prime vaccinations. 
On the basis of their ongoing scientific review the UK Medicines Healthcare Regulatory 
Agency have concluded: “the evidence of a link with vaccination and COVID-19 is stronger, 
but more work is still needed”(62). The European Medicines Agency concluded that unusual 
blood clots with low blood platelets should be listed as very rare side effects of this vaccine. 
Both agencies concluded that there wasn’t enough evidence at present to say what the risk 
factors (e.g. age, gender, or other medical conditions) might be for having one of these rare 
clotting problems. Although the MHRA have received a higher number of reports from 
younger adults than older individuals. Cases of thrombosis with thrombocytopenia have also 
been reported after COVID-19 Vaccine Janssen, an adenovirus serotype 26 vectored spike-
protein based COVID-19 vaccine. The EMA has also conducted a review of these cases and 
concluded there is a likely causal relationship with the Janssen vaccine(63). 
Thrombosis with thrombocytopenia syndrome has not previously been reported following 
the use of live oral adenovirus serotype 4 and serotype 7 adenovirus vaccines in the United 
States, where these vaccines have been approved for vaccination of military personel(64-66). 
Over 1.3 million doses have been administered between 2011 to 2018 with no reports of 
thrombosis following vaccination to the US CDC/FDA Vaccine Adverse Event Reporting System 
(VAERS) post-marketing passive vaccine safety monitoring database(66).  
Both the MHRA and EMA have confirmed that the evidence to date does not suggest that the 
COVID-19 Vaccine AstraZeneca causes venous thromboembolism without a low platelet 
count(62, 67). 
All volunteers will be provided with this information via the study information booklet and 
will be kept updated should further information become available. They will also be 
specifically counselled on symptoms that could be warning signs of serious clotting events, as 
per public health advice being given to people receiving ChAdOx1 nCoV-19. 
 
 
 

 
 
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Potential interaction with other adenoviral vectored vaccines: 
The ChAdOx1 vector used in the ChAdOx1 RVF experimental vaccine is the same as that used 
in the Oxford AstraZeneca and similar to the one used in the Janssen (Johnson and Johnson) 
COVID-19 vaccines (Adenovirus 26). There is a theoretical risk that receiving the experimental 
ChAdOX1 RVF vaccine may reduce the benefit of subsequent administrations of certain 
vaccines such as the Janssen (Johnson & Johnson) or the AstraZeneca COVID-19 vaccines. This 
may be more likely to happen if the vaccines are given at short intervals. However, the 
immune response to the AstraZeneca COVID-19 vaccine was not affected in a study of 
individuals who received a previous ChAdOx1-vectored vaccine for a non-spike transgene at 
least one year earlier(68, 69).  
Other studies suggest that an interval of three months between administrations of two 
adenoviral vectored vaccines reduces the risk of this interference(70-74). For this reason, we 
will enrol participants who have been vaccinated with an mRNA Covid vaccine or will have 
their NHS Covid vaccine offer at least three months after the ChAdOx1 RVF vaccine. No such 
theoretical interference will be expected with mRNA or protein COVID-19 vaccines (such as 
Moderna, Pfizer, Novavax) and these can be given at least 2 weeks before or after the 
ChAdOx1 RVF.   
5.4 
Known Potential Benefits 
Volunteers will not benefit directly from participation in this study. However, it is hoped that 
the information gained from this study will contribute to the development of a safe and 
effective RVFV vaccine regimen. The only benefits for participants would be information 
about their general health status. 
 
 

 
 
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6. 
RECRUITMENT AND WITHDRAWAL OF TRIAL VOLUNTEERS 
6.1 
Volunteers 
Volunteers may be recruited by use of an advertisement +/- registration form formally 
approved by the ethics committee(s) and distributed or posted in the following places: 
 In public places, including buses and trains, with the agreement of the 
owner/proprietor. 
 In newspapers or other literature for circulation. 
 On radio via announcements. 
 On a website or social media site operated by our group or with the agreement of 
the owner or operator (including on-line recruitment through our web-site).  
 By e-mail distribution to a group or list only with the express agreement of the 
network administrator or with equivalent authorisation. 
 By email distribution to individuals who have already expressed an interest in taking 
part in any clinical trial at the Oxford Vaccine Centre. 
 On stalls or stands at exhibitions or fairs. 
 Via presentations (e.g. presentations at lectures or invited seminars). 
 Direct mail-out: This will involve obtaining names and addresses of adults via the 
most recent Electoral Roll. The contact details of individuals who have indicated that 
they do not wish to receive postal mail-shots would be removed prior to the 
investigators being given this information. The company providing this service is 
registered under the relevant data protection legislation. Investigators would not be 
given dates of birth or ages of individuals but the list supplied would only contain 
names of those aged between 18-50 years (as per the inclusion criteria). 
 Oxford Vaccine Centre databases: We may contact individuals from databases of 
groups within the CCVTM (including the Oxford Vaccine Centre database) of previous 
trial participants who have expressed an interest in receiving information about all 
future studies for which they may be eligible. 
 
6.2 
Informed consent 
All volunteers will sign and date the informed consent form before any study specific 
procedures are performed. The information sheet will be made available to the volunteer at 
least 24 hours prior to the screening visit. At the screening visit, the volunteer will be fully 
informed of all aspects of the trial, the potential risks and their obligations. The following 
general principles will be emphasised: 
 Participation in the study is entirely voluntary 
 Refusal to participate involves no penalty or loss of medical benefits 
 The volunteer may withdraw from the study at any time 
 The volunteer is free to ask questions at any time to allow him or her to understand 
the purpose of the study and the procedures involved 

 
 
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 The study involves research of an investigational vaccine 
 There is no direct benefit from participating 
 The volunteer’s GP will be contacted to corroborate their medical history. 
Volunteers will only be enrolled in the study if written or verbal information 
regarding the volunteer’s medical history is obtained from the GP. This can either be 
via the study team accessing patient’s electronic care summaries from local systems 
or by contacting the GP. 
 The volunteer’s blood samples taken as part of the study will be stored indefinitely 
and samples may be sent outside of the UK and Europe to laboratories in 
collaboration with the University of Oxford. These will be anonymised. 
The aims of the study and all tests to be carried out will be explained. The volunteer will be 
given the opportunity to ask about details of the trial, and will then have time to consider 
whether or not to participate. If they do decide to participate, they will sign and date one 
consent form from which copies are made , one for them to take away and keep, and one to 
be stored in the case report form (CRF) – this is a paper or electronic document used to collect 
data relating to a particular volunteer. These forms will also be signed and dated by the 
Investigator. 
Whilst the COVID-19 pandemic continues to affect the UK volunteers will be provided with an 
information sheet detailing the precautions being taken. They will be asked to agree to abide 
by the most recent UK government guidance on self-isolation, testing and social distancing. 
 
6.3 
Inclusion and exclusion criteria 
This study will be conducted in healthy adults, who meet the following inclusion and exclusion 
criteria: 
 
6.3.1 Inclusion Criteria 
The volunteer must satisfy all the following criteria to be eligible for the study: 
1. 
Healthy adults aged 18 to 50 years  
2. 
Able and willing (in the Investigator’s opinion) to comply with all study requirements 
3. 
Willing to allow the investigators to discuss the volunteer’s medical history with their  
General Practitioner or access this medical history electronically 
4. 
For females only, willingness to practice continuous effective contraception (see 
below) for at least 3 months from the final vaccination procedure and a negative 
pregnancy test on the day(s) of screening and vaccination 
5. 
Agreement to refrain from blood donation during the course of the study 
6. 
Able to provide written informed consent 
 
 

 
 
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6.3.2 Exclusion Criteria 
The volunteer may not enter the study if any of the following apply: 
1. 
Participation in another research study involving receipt of an investigational 
product in the 30 days preceding enrolment, or planned use during the study period  
2. 
Prior receipt of an investigational vaccine likely to impact on interpretation of the 
trial data. 
3. 
Prior receipt of any vaccines administered ≤30 days before enrolment and/or 
planned receipt of a vaccine ≤30 days after enrolment EXCEPT for protein, RNA (or 
other non-adenovirus based) COVID-19 vaccinations which may be given within 14 
days of the trial vaccine. 
4. 
Receipt of a recombinant simian adenoviral vaccine prior to enrolment 
5. 
Planned receipt of another adenoviral vectored vaccine (e.g. Oxford/Astrazeneca or 
Janssen COVID-19 vaccines) within 90 days after the vaccination with the ChAdOx1 
RVF 
6. 
Administration of immunoglobulins and/or any blood products within the three 
months preceding the planned administration of the vaccine candidate 
7. 
Any confirmed or suspected immunosuppressive or immunodeficient state, including 
HIV infection; asplenia; recurrent, severe infections and chronic (more than 14 days) 
immunosuppressant medication within the past 6 months (inhaled and topical 
steroids are allowed) 
8. 
COVID-19 infection diagnosed in the community in the 28 days prior to enrolment 
9. 
Any main covid-19 symptom within 28 days of enrolment:  
a. Fever (subjective or ≥37.8) 
b. New continuous cough 
c. Loss of sense of smell 
d. Loss of sense of taste  
10. 
Clinical suspicion of acute COVID-19 in the 28 days prior to enrolment 
11. 
History of allergic disease or reactions likely to be exacerbated by any component of 
the vaccine 
12. 
Any history of hereditary angioedema, acquired angioedema, or idiopathic 
angioedema. 
13. 
Any history of anaphylaxis in relation to vaccination 
14. 
Pregnancy, lactation or willingness/intention to become pregnant during the study 
15. 
History of cancer (except basal cell carcinoma of the skin and cervical carcinoma in 
situ) 
16. 
History of serious psychiatric condition likely to affect participation in the study 
17. 
Bleeding disorder (eg. factor deficiency, coagulopathy or platelet disorder), or prior 
history of significant bleeding or bruising following IM injections or venepuncture 
18. 
Any other serious chronic illness requiring hospital specialist supervision 
19. 
Suspected or known current alcohol abuse as defined by an alcohol intake of greater 
than 42 units every week 

 
 
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20. 
Suspected or known injecting drug abuse in the 5 years preceding enrolment 
21. 
Seropositive for hepatitis B surface antigen (HBsAg) 
22. 
Seropositive for hepatitis C virus (antibodies to HCV)  
23. 
Any clinically significant abnormal finding on screening biochemistry or haematology 
blood tests or urinalysis 
24. 
Any other significant disease, disorder or finding which may significantly increase the 
risk to the volunteer because of participation in the study, affect the ability of the 
volunteer to participate in the study or impair interpretation of the study data 
25. 
Inability of the study team to contact the volunteer’s GP (or access summary care 
record, if available) to confirm medical history and safety to participate 
26. 
Prior natural exposure to RVFV as determined by seropositivity for RVFV antigens by 
ELISA and neutralizing antibody assay (serology will be requested at the discretion of 
the investigator) 
27. 
History of confirmed major thrombotic event (including cerebral venous sinus 
thrombosis, deep vein thrombosis, pulmonary embolism), history of 
antiphospholipid syndrome, or history of heparin induced thrombocytopenia 
 
6.3.3 Effective contraception for female volunteers of childbearing potential 
Female volunteers are required to use an effective form of contraception during the course 
of the study, for at least 3 months after their final vaccination procedure. As this is a Phase I, 
`first-in-human, study there is no information about the effect of this vaccine on a foetus. 
Male subjects with female partners of child-bearing potential are not required to use barrier 
methods for the purposes of contraception whilst taking part in this study as the risk of 
excretion of the vaccine is negligible. 
Acceptable forms of contraception for female volunteers include: 
 Established use of oral, injected or implanted hormonal methods of contraception. 
 Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
 Barrier methods of contraception (condom or occlusive cap with spermicide) 
 Male sterilisation, if the vasectomised partner is the sole partner for the subject. 
 True abstinence: when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation 
methods), declaration of abstinence for the duration of exposure to IMP, and 
withdrawal are not acceptable methods of contraception 
 
Under this protocol, a woman is considered of childbearing potential (WOCBP), 
i.e. fertile, following menarche and until becoming post-menopausal unless permanently 
sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and 

 
 
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bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months 
without an alternative medical cause. 
 
6.3.4 Prevention of ‘Over Volunteering’ 
Volunteers will be excluded from the study if they are concurrently involved in another trial. 
In order to check this, volunteers will be asked to provide their National Insurance or Passport 
number (if they are not entitled to a NI number) and will be registered on a national database 
of participants in clinical trials (www.tops.org.uk). 
 
6.3.5 Criteria for postponement of vaccination 
The following events constitute contraindications to administration of the vaccine at that 
point in time; if any one of these events occurs at the time scheduled for vaccination, the 
subject may instead be vaccinated at a later date following resolution and within the window 
of screening procedures (defined in section 7.4.1), or withdrawn at the discretion of the 
Investigator.  
 Acute disease at the time of vaccination. Acute disease is defined as the presence of 
a moderate or severe illness with or without fever.  
 Temperature of >37.5°C (99.5°F) at the time of vaccination. 
 
6.3.6 Withdrawal of Volunteers 
In accordance with the principles of the current revision of the Declaration of Helsinki and 
any other applicable regulations, a volunteer has the right to withdraw from the study at any 
time and for any reason, and is not obliged to give his or her reasons for doing so. The 
Investigator may withdraw the volunteer at any time in the interests of the volunteer’s health 
and well-being. In addition the volunteer may withdraw/be withdrawn for any of the 
following reasons: 
 Administrative decision by the Investigator. 
 Ineligibility (either arising during the study or retrospectively, having been overlooked 
at screening). 
 Significant protocol deviation. 
 Volunteer non-compliance with study requirements. 
 An AE, which requires discontinuation of the study involvement or results in inability 
to continue to comply with study procedures. 
The reason for withdrawal will be recorded in the CRF. If withdrawal is due to an AE, 
appropriate follow-up visits or medical care will be arranged, with the agreement of the 
volunteer, until the AE has resolved, stabilised or a non-trial related causality has been 
assigned. Any volunteer who is withdrawn from the study may be replaced, if that is possible 

 
 
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within the specified time frame. The Local Safety Monitor (LSM) may recommend withdrawal 
of volunteers.  
Any volunteer who fails to attend for two or more follow-up visits during the study will be 
deemed to have withdrawn from the study. 
If a volunteer withdraws from the study, blood samples collected before their withdrawal 
from the trial will be used/ stored unless the volunteer specifically requests otherwise.  
In all cases of subject withdrawal, excepting those of complete consent withdrawal, long-term 
safety data collection, including some procedures such as safety bloods, will continue as 
appropriate if subjects have received one or more vaccine doses.  
 
 
6.4 
Compliance with Dosing Regime 
All doses in this vaccine study will be administered by the Investigator and recorded in the 
CRF. The study medication will be at no time in the possession of the volunteer and 
compliance will, therefore, not be an issue. 
 
6.5 
Pregnancy 
Should a volunteer become pregnant during the trial, she will be followed up as other 
volunteers and in addition will be followed until pregnancy outcome. We will not routinely 
perform venepuncture in a pregnant volunteer. 
 
 

 
 
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7. 
CLINICAL PROCEDURES 
This section describes the clinical procedures for evaluating study participants and follow-up 
after administration of study vaccine.  
 
7.1 
Study procedures 
All volunteers will have the same schedule of clinic attendances and procedures as indicated 
in the schedules of attendance (Table 5). All subjects will receive the ChAdOx1 RVF vaccine, 
and undergo follow-up for a total of 12 weeks. The total volume of blood donated during the 
study will be 300mL. Additional visits or procedures may be performed at the discretion of 
the investigators, e.g., further medical history and physical examination, urine microscopy in 
the event of positive urinalysis or additional blood tests if clinically relevant.  
 
7.2 Observations 
Pulse, blood pressure and temperature will be measured at the time-points indicated in the 
schedule of procedures and may also be measured as part of a physical examination if 
indicated at other time-points. 
 
7.3 Blood Tests and Urinalysis 
Blood will be drawn for the following laboratory tests and processed: 
1. At Oxford University Hospitals’ NHS Trust using NHS standard procedures: 
 Haematology; Full Blood Count  
 Biochemistry; Sodium, Potassium, Urea, Creatinine, Albumin, Liver Function Tests 
(ALT, ALP, Bilirubin) 
 Diagnostic serology; HBsAg, HCV antibodies, HIV antibodies (specific consent will be 
gained prior to testing blood for these blood-borne viruses) 
 Immunology; Human Leukocyte Antigen (HLA) typing 
Additional safety blood tests may be performed if clinically relevant at the discretion of the 
medically qualified investigators. These generally include, but are not limited to AST, GGT and 
a coagulation screen. 
 
2. At University of Oxford research laboratories: 
 Exploratory Immunology; Immunogenicity will be assessed by a variety of 
immunological assays. These may include antibodies to Gn and Gc proteins by ELISA 
and virus neutralising assays, ex vivo ELISpot assays for interferon gamma and flow 
cytometry assays, functional antibody assays and B cell analyses. Other exploratory 
immunological assays including cytokine analysis and other antibody assays, DNA 

 
 
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analysis of genetic polymorphisms potentially relevant to vaccine immunogenicity and 
gene expression studies amongst others may be performed at the discretion of the 
Investigators. 
 
3. Urinalysis; Urine will be tested for protein, blood and glucose at screening. For female 
volunteers only, urine will be tested for beta-human chorionic gonadotrophin (β-HCG) 
at screening and immediately prior to each vaccination. 
 
Collaboration with other specialist laboratories in the UK, Europe and outside of Europe for 
further exploratory immunological tests may occur. This would involve the transfer of serum 
or plasma and/or PBMC to these laboratories, but these would remain anonymised. 
Volunteers will be asked for their consent for this before enrollment. Immunological assays 
will be conducted according to local SOPs.  
Subjects will be informed that there may be leftover samples of their blood (after all testing 
for this study is completed), and that such samples may be stored indefinitely in the Oxford 
Vaccine Center Biobank for possible future research (exploratory immunology), including 
human DNA and RNA analyses to search for correlates of vaccine immunogenicity and 
efficacy. Subjects will be able to decide if they will permit such future use of any leftover 
samples. If a subject elects not to permit this, all of that subject’s leftover samples will be 
discarded after the required period of storage to meet Good Clinical Practice (GCP) and 
regulatory requirements. Urine samples will be destroyed after analysis and will not be stored 
for future research use.  
 
7.4 
Study visits 
The study visits and procedures will be undertaken by one of the clinical trials team. The 
procedures to be included in each visit are documented in the schedule of attendances (Table 
5). Each visit is assigned a time-point and a window period, within which the visit will be 
conducted. 
 
7.4.1 Screening visit 
All potential volunteers will have a screening visit, which may take place up to 90 days prior 
to vaccination. Informed consent will be taken before screening, as described in section 6.2. 
If consent is obtained, the screening procedures indicated in the schedule of attendances will 
be undertaken. To avoid unnecessary additional venepuncture, if the appropriate blood test 
results for screening are available for the same volunteer from a screening visit for another 
Jenner Institute Clinical Trials group vaccine study, these results may be used for assessing 
eligibility (provided the results date is within the 3 months preceding enrolment in RVF001). 

 
 
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The subject’s general practitioner will be contacted with the written permission of the subject 
after satisfactory screening as notification that the subject has volunteered for the study and 
to ascertain any significant medical history. During the screening the volunteers will be asked 
to provide their National Insurance or passport number so that this can be entered on to a 
national database which helps prevent volunteers from participating in more than one clinical 
trial simultaneously or over-volunteering for clinical trials (www.tops.org.uk). 
Abnormal clinical findings from the urinalysis or blood tests at screening will be assessed by 
the lead clinician according to the relevant SOP. Abnormal blood tests following screening will 
be assessed according to site-specific laboratory adverse event grading tables which are filed 
in the trial master file (TMF) or the Investigator Site File (ISF). Any abnormal test result 
deemed clinically significant may be repeated to ensure it is not a single occurrence. If an 
abnormal finding is deemed to be clinically significant, the volunteer will be informed and 
appropriate medical care arranged with the permission of the volunteer.  
The eligibility of the volunteer will be reviewed by the study clinician at the end of the 
screening visit and again when all results from the screening visit have been considered. 
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. If eligible, a day 0 visit will be scheduled 
for the volunteer to receive the vaccine. 
 
7.4.2 Day 0: Enrolment and Vaccination Visit 
Volunteers will not be considered enrolled in the study until they have received a vaccine. 
Before vaccination, the eligibility of the volunteer will be reviewed including re-checking 
informed consent and willingness to be vaccinated. Pulse, blood pressure and temperature 
will be observed and if necessary, a medical history and physical examination may be 
undertaken to determine need to postpone vaccination depending on criteria listed in section 
6.3.5. Vaccinations will be administered as described below. 
 
7.4.2.1 Vaccinations  
Before each vaccination, the on-going eligibility of the volunteer will be reviewed. All vaccines 
will be administered intramuscularly according to SOP VC002 Vaccination as described below 
in section 8.4 and the vaccine dilution SOP when required. The injection site will be covered 
with a sterile dressing and the volunteer will stay in the CCVTM for observation, in case of 
immediate adverse events. Observations will be taken 30 minutes after vaccination (+/- 5 
minutes) and the sterile dressing removed and injection site inspected. Observations will also 
be taken at 60 minutes (+/- 10 minutes) before the volunteer leaves. An oral thermometer, 
tape measure and diary card (paper or electronic) will be given to each volunteer, with 
instructions on use, along with the emergency 24 hour telephone number to contact the on-
call study physician if needed. 
Diary cards will collect information on the timing and severity of the following solicited AEs: 

 
 
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Table 3. Solicited AEs as collected on post vaccination diary cards 
 
Local solicited AEs 
Systemic solicited AEs 
Pain 
Fever 
Redness 
Feverishness 
Warmth 
Joint pains 
 Itch 
Muscle pains 
 
Fatigue 
 
Headache 
 
Nausea  
 
Malaise 
 
Volunteers will be instructed on how to self-assess the severity of these AEs. There will also 
be space on the diary card to self-document unsolicited AEs, and whether medication was 
taken to relieve the symptoms. 
 
7.4.2.2 Sequence of Enrolment and Vaccination of Volunteers 
For safety reasons, the first volunteer in Group 1 will be vaccinated ahead of any other 
volunteers and the profile of adverse events will be reviewed after 48 hours (±24h) post 
vaccination. Provided there are no safety concerns, as assessed by the CI and the Local Safety 
Monitor (LSM), another 2 volunteers will be vaccinated at the same dose after at least 48 
hours has elapsed following the first volunteer being vaccinated and at least 1 hour apart 
from each other. An independent safety review will be conducted by the LSM after 
vaccination of all 3 volunteers in group 1. This review will include an assessment of the profile 
of adverse events and the results of safety blood tests at day 7 post vaccination. The CI and 
the LSM will be asked to provide the decision on whether to proceed with vaccinations of the 
first volunteer to receive the next incremental dose in group 2. If there are no safety concerns, 
the first volunteer in group 2 may be vaccinated.  
Enrolment of the first volunteer in Group 2 will only proceed if the CI and LSM assess the data 
from the first three vaccinees in Group 1 as indicating that it is safe to do so. The first subject 
in Group 2 will be vaccinated alone, and a 48 hour gap allowed before vaccinating further 
subjects in this group. Provided there are no safety concerns, as assessed by the CI and the 
LSM, another 2 volunteers will be vaccinated at the same dose after at least 48 hours has 
elapsed following the first volunteer being vaccinated and at least 1 hour apart from each 
other and will be reviewed in a further 48h (±24h). Provided there are no safety concerns as 
assessed by the CI and LSM, the remaining participants in the group may be vaccinated. An 

 
 
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independent safety review will be conducted by the LSM after vaccination of all 6 volunteers. 
This review will include an assessment of the profile of adverse events and the results of 
safety blood tests at day 7 post vaccination. The CI and the LSM will be asked to provide the 
decision on whether to proceed with vaccinations of the  first volunteer to receive the next 
incremental dose in group 3. If there are no safety concerns, the first volunteer in group 3 
may be vaccinated.  
Enrolment of the first volunteer in Group 3 will only proceed if the CI and LSM assess the data 
from all 6 vaccinees in Group 2 as indicating that it is safe to do so. The first subject in Group 
3 will be vaccinated alone, and a 48 hour gap allowed before vaccinating further subjects in 
this group. Provided there are no safety concerns, as assessed by the CI and the LSM, another 
2 volunteers will be vaccinated at the same dose after at least 48 hours has elapsed following 
the first volunteer being vaccinated and at least 1 hour apart from each other and will be 
reviewed in a further 48h (±24h). Provided there are no safety concerns as assessed by the CI 
and LSM, the remaining participants in the group may be vaccinated. 
The enrolment sequence is summarised below (table 4): 
Table 4. Sequence of enrolment  
Sequence 
Volunteer groups 
Minimum Interval 
before next step 
Local Safety Monitor 
Interim Safety Review 
Step 1 
Group 1 first volunteer 
48 hours 
Y 
Step 2 
Group 1 second volunteer 
1 hour 
N 
Step 3 
Group 1 third volunteer 
7 days 
Y 
Step 4 
Group 2 first volunteer 
48 hours 
Y 
Step 5 
Group 2 second volunteer 
1 hour 
N 
Step 6 
Group 2 third volunteer 
48 hours 
Y 
Step 7 
Group 2 remaining volunteers 
7 days 
Y 
Step 8 
Group 3 first volunteer 
48 hours 
Y 
Step 9 
Group 3 second volunteer 
1 hour 
N 
Step 10 
Group 3 third volunteer 
48 hours 
Y 
Step 11 
Group 3 remaining volunteers 
n/a 
n/a 
 
7.4.3 Subsequent visits:  days 2, 7, 14, 28, 56 and 84  
Follow-up visits will take place 48 hours (±24h), 7 days (± 2 days), 14 days (± 3 days), 28 days 
(± 3 days), 56 days (± 7 days) and 84 days (± 7 days) . Volunteers will be assessed for local and 
systemic adverse events, interim history, physical examination, review of diary cards (paper 
or electronic) and blood tests at these time points as detailed in the schedule of attendances. 
Blood will also be taken for exploratory immunology purposes. Photographs of the injection 
site may be taken with the volunteer’s consent and at the investigator’s discretion. 
If volunteers experience adverse events (laboratory or clinical), which the investigator 
(physician), CI and/or LSM determine necessary for further close observation, the volunteer 
may be admitted to an NHS hospital for observation and further medical management under 
the care of the Consultant on call. 

 
 
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At the end of the study, GP’s will be notified about the status of their patient’s enrolment in 
the trial. 
 
7.4.4 COVID-19 Study Considerations 
The study will be carried out in line with the latest Public Health England (PHE) advice. Local 
SOPs for the use of appropriate personal protective equipment (PPE) and social distancing 
will be followed by clinical staff. 
Participants must consent to inform the trial team of covid-19 infection during the study as 
part of the informed consent process, in order to be enrolled in the study. Participants will be 
reminded to follow the up to date local public health guidance regarding COVID-19 during the 
trial. Inkeeping with PHE guidance on vaccine associated fever during the pandemic (75), 
participants experiencing fever within the first 48 hours of vaccination, with no other primary 
symptom of covid-19 (cough, anosmia, ageusia) will not be required to self-isolate unless 
there is otherwise clinical suspicion of COVID-19. 
Participants will be able to discuss symptoms with a medically qualified oncall study clinician 
via mobile phone at all times during the study. Participants describing potential COVID-19 
symptoms may be recommend to seek follow up and testing for COVID-19 through healthcare 
pathways available to them. 

 
 
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Table 5. Schedule of attendances 
 
S = screening visit; (X) = if considered necessary ^ = Vital signs includes pulse, blood pressure and temperature; 
$ = Biochemistry will include Sodium, Potassium, Urea, Creatinine, Albumin and Liver function tests. £ = 
Exploratory immunology includes antibodies to RVFV, ex vivo interferon-gamma ELISpot responses to RVFV 
** Timeline is approximate only. Exact timings of visits relate to the day on enrolment, ie, each visit must occur 
at indicated number of days after enrolment ± time window. 
% Cumulative blood volume for Oxford volunteers if blood taken as per schedule, and excluding any repeat 
safety blood test that may be necessary. 
 
 
Attendance Number 
1S 
2 
3 
4 
5 
6 
7 
8 
Timeline** 
(days) 
≤ 
90 
0 
2 
7 
14 
28 
56 
84 
Time window (days) 
 
 
±1 
±2 
±3 
±3 
±7 
±7 
Informed Consent 
X 
 
 
 
 
 
 
 
Review contraindications, inclusion and 
exclusion criteria 
X 
X 
 
 
 
 
 
 
Vaccination 
 
X 
 
 
 
 
 
 
Vital signs^ 
X 
X 
X 
X 
X 
X 
X 
X 
Ascertainment of adverse events 
 
X 
X 
X 
X 
X 
X 
X 
Diary cards provided 
 
X 
 
 
 
 
 
 
Diary cards collected 
 
 
 
 
 
X 
 
 
Medical History, Physical Examination 
X 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Biochemistry$, Haematology (mL) 
5 
5 
5 
5 
 
5 
 
 
Exploratory immunology£ (mL) 
 
50 
 
10 
50 
50 
50 
50 
Urinalysis  
X 
 
 
 
 
 
 
 
Urinary HCG (women only) 
X 
X 
 
 
 
 
 
 
HLA typing (mL) 
 
4 
 
 
 
 
 
 
HBsAg, HCV Ab, HIV serology (mL) 
5 
 
 
 
 
 
 
 
Blood volume per visit 
10 
59 
5 
15 
50 
55 
50 
50 
Cumulative blood volume% 
10 
69 
74 
89 
139 194 
244 
294 

 
 
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8. 
INVESTIGATIONAL PRODUCTS 
The following vaccinations will be given in this study:  
1. 
ChAdOx1 RVF  5 x 109vp 
2. 
ChAdOx1 RVF  2.5 x 1010vp 
3. 
ChAdOx1 RVF  5 x 1010vp 
 
8.1. 
 Manufacturing and Presentation 
8.1.1 Description of ChAdOx1 RVF   
ChAdOx1 RVF vaccine consists of the replication-deficient simian adenovirus vector ChAdOx1, 
encoding the RVFV envelope glycoproteins (Gn and Gc) under the control of the human CMV 
major immediate early promoter. 
 
8.1.2 ChAdOx1 RVF formulation and packaging 
ChAdOx1 RVF is manufactured by Advent S.r.l., Pomezia, Italy, in formulation buffer at a 
nominal concentration of >1.0 x 1011 vp/mL . The drug product is filled into 3 mL glass vials 
(supplied sterile by Nuova Ompi) with a 13 mm grey chlorobutyl rubber freeze-dry injection 
stopper (supplied sterile by West Pharma) and a 13 mm aluminium Flip Off seal (supplied 
sterile by West Pharma). The vials are supplied sterile.  The containers and closures are tested 
for compliance with defined specifications. The vials are made from Ph Eur Type 1 glass. 
 
8.2 
 Supply 
ChAdOx1 RVF has been formulated and vialed under Good Manufacturing Practice conditions 
at ADVENT S.R.L., Italy. At the Clinical Biomanufacturing Facility (CBF), University of Oxford, 
the vaccine will be certified and labelled for the trial by a Qualified Person (QP) before transfer 
to the clinical site. 
 
8.3  
Storage 
The vaccine is stored at nominal -80oC in a locked freezer, at the clinical site. All movements 
of the study vaccines will be documented in accordance with existing standard operating 
procedure (SOP). Vaccine accountability, storage, shipment and handling will be in 
accordance with relevant SOPs and forms. 
 
8.4  
Administration of Investigational Medicinal Products 
On vaccination day, ChAdOx1 RVF will be allowed to thaw to room temperature and will be 
administered within 1 hour of removal from the freezer. The vaccine will be administered 
intramuscularly into the deltoid of the non-dominant arm (preferably). All volunteers will be 
observed in the unit for 1 hour (±10 minutes) after vaccination.  During administration of the 

 
 
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investigational products, Advanced Life Support drugs and resuscitation equipment will be 
immediately available for the management of anaphylaxis.  Vaccination will be performed 
and the IMPs handled according to the relevant SOPs. 
 
8.5 Minimising environmental contamination with genetically modified organisms 
(GMO) 
The study will be performed in accordance with UK Genetically Modified Organisms 
(Contained Use) Regulations (2014). In order to minimise dissemination of the recombinant 
vectored vaccine virus into the environment, inoculation sites will be covered with a dressing 
after immunisation. This should absorb any virus that may leak out through the needle track. 
The dressing will be removed from the injection site after 30 minutes (+15/- 5 minutes) and 
will be disposed as GMO waste by autoclaving. 

 
 
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9. 
ASSESSMENT OF SAFETY 
Safety will be assessed by the frequency, incidence and nature of adverse events and serious 
adverse events arising during the study. 
 
9.1 Definitions 
9.1.1 Adverse Event (AE) 
An AE is any untoward medical occurrence in a volunteer, which may occur during or after 
administration of an Investigational Medicinal Product (IMP) and does not necessarily have a 
causal relationship with the intervention. An AE can therefore be any unfavourable and 
unintended sign (including an abnormal laboratory finding), symptom or disease temporally 
associated with the study intervention, whether or not considered related to the study 
intervention. 
 
9.1.2 Adverse Reaction (AR) 
An AR is any untoward or unintended response to an IMP. This means that a causal 
relationship between the IMP and an AE is at least a reasonable possibility, i.e., the 
relationship cannot be ruled out. All cases judged by the reporting medical Investigator as 
having a reasonable suspected causal relationship to an IMP (i.e. possibly, probably or 
definitely related to an IMP) will qualify as adverse reactions. 
 
9.1.3 Unexpected Adverse Reaction  
An adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g., IB for an unapproved IMP). 
 
9.1.4 Serious Adverse Event (SAE) 
An SAE is an AE that results in any of the following outcomes, whether or not considered 
related to the study intervention. 
 Death  
 Life-threatening event (i.e., the volunteer was, in the view of the Investigator, at 
immediate risk of death from the event that occurred). This does not include an AE 
that, if it occurred in a more severe form, might have caused death. 
 Persistent or significant disability or incapacity (i.e., substantial disruption of one’s 
ability to carry out normal life functions). 
 Hospitalisation, regardless of length of stay, even if it is a precautionary measure for 
continued 
observation. 
Hospitalisation 
(including 
inpatient 
or 
outpatient 
hospitalisation for an elective procedure) for a pre-existing condition that has not 
worsened unexpectedly does not constitute a serious AE. 
 An important medical event (that may not cause death, be life threatening, or require 
hospitalisation) that may, based upon appropriate medical judgment, jeopardise the 

 
 
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volunteer and/or require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples of such medical events include allergic reaction 
requiring intensive treatment in an emergency room or clinic, blood dyscrasias, or 
convulsions that do not result in inpatient hospitalisation. 
 Congenital anomaly or birth defect. 
 
Hospitalisations for elective procedures that are planned prior to enrolment into the study 
will not be reported as SAEs. 
 
9.1.5 Serious Adverse Reaction (SAR) 
An adverse event (expected or unexpected) that is both serious and, in the opinion of the 
reporting Investigator or Sponsors, believed to be possibly, probably or definitely due to an 
IMP or any other study treatments, based on the information provided. 
 
9.1.6 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A serious adverse reaction, the nature and severity of which is not consistent with the 
information about the medicinal product in question set out in the IB or Summary of Product 
Characteristics (SmPC). 
 
9.2 
Foreseeable Adverse Reactions:  
The foreseeable ARs following vaccination with ChAdOx1 RVF include injection site pain, 
erythema, warmth, swelling, pruritus, myalgia, arthralgia, headache, fatigue, fever, 
feverishness, malaise and nausea.   
 
9.3 
Expected Serious Adverse Events 
No serious adverse events are expected in this study. 
 
9.4 
Causality Assessment 
For every AE, an assessment of the relationship of the event to the administration of the 
vaccine will be undertaken by the CI-delegated clinician. An intervention-related AE refers to 
an AE for which there is a possible, probable or definite relationship to administration of a 
vaccine. An interpretation of the causal relationship of the intervention to the AE in question 
will be made, based on the type of event; the relationship of the event to the time of vaccine 
administration; and the known biology of the vaccine therapy (Table 6). 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 vaccination will be considered 
and investigated. Causality assessment will take place during planned safety reviews, interim 

 
 
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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. 
 
Table 6. Guidelines for assessing the relationship of vaccine administration to an AE. 
0 
No 
Relationship 
No temporal relationship to study product and 
Alternate aetiology (clinical state, environmental or other 
interventions); and 
Does not follow known pattern of response to study product 
1 
Unlikely 
Unlikely temporal relationship to study product and 
Alternate aetiology likely (clinical state, environmental or other 
interventions) and 
Does not follow known typical or plausible pattern of response to 
study product. 
2 
Possible 
 
Reasonable temporal relationship to study product; or 
Event not readily produced by clinical state, environmental or other 
interventions; or 
Similar pattern of response to that seen with other vaccines 
3 
Probable 
 
Reasonable temporal relationship to study product; and 
Event not readily produced by clinical state, environment, or other 
interventions or  
Known pattern of response seen with other vaccines 
4 
Definite 
 
Reasonable temporal relationship to study product; and 
Event not readily produced by clinical state, environment, or other 
interventions; and  
Known pattern of response seen with other vaccines 
 
9.5 
Reporting Procedures for All Adverse Events (see SOP VC027) 
All local and systemic AEs occurring in the 28 days following each vaccination observed by the 
Investigator or reported by the volunteer, whether or not attributed to study medication, will 
be recorded (excluding those expected consequences from venepuncture, described in 
section 5.3). Recording and reporting of all AEs will take place as detailed in SOP VC027. All 
AEs that result in a volunteer’s withdrawal from the study will be followed up until a 
satisfactory resolution occurs, or until a non-study related causality is assigned (if the 
volunteer consents to this). Serious adverse events (SAEs) will be collected throughout the 
entire trial period. 
 
 

 
 
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9.5.1 Reporting Procedures for Serious AEs (see SOP OVC005 Safety Reporting) 
In order to comply with current regulations on serious adverse event reporting to regulatory 
authorities, the event will be documented accurately and notification deadlines respected. 
SAEs will be reported on the SAE forms to members of the study team immediately the 
Investigators become aware of their occurrence, as described in SOP OVC005. Copies of all 
reports will be forwarded for review to the Chief Investigator (as the Sponsor’s 
representative) within 24 hours of the Investigator being aware of the suspected SAE. The 
local safety monitor (LSM) will be notified of SAEs that are deemed possibly, probably or 
definitely related to study interventions; the LSM will be notified immediately (within 24 
hours) of the Investigators’ being aware of their occurrence. SAEs will not normally be 
reported immediately to the ethical committee(s) unless there is a clinically important 
increase in occurrence rate, an unexpected outcome, or a new event that is likely to affect 
safety of trial volunteers, at the discretion of the Chief Investigator and/or LSM. In addition 
to the expedited reporting above, the Chief Investigator (on behalf) of the Sponsor shall 
include all SAEs in the annual Development Safety Update Report (DSUR) report. 
Hospitalisations for elective procedures that are planned prior to enrolment into the study 
will not be reported as SAEs. 
 
9.5.2 Reporting Procedures for SUSARS 
The Chief Investigator will report all SUSARs to the MHRA and ethical committee(s) within 
required timelines (15 days for all SUSARs, unless life threatening in which case 7 days, with 
a final report within a further 8 days (total 15). The Chief Investigator will also inform all 
Investigators concerned of relevant information about SUSARs that could adversely affect the 
safety of participants. All SUSARs and deaths occurring during the study will be reported to 
the Sponsor. For all deaths, available autopsy reports and relevant medical reports will be 
made available for reporting to the relevant authorities. 
 
9.5.3 Development Safety Update Report 
A Development Safety Update Report (DSUR) will be submitted by the CI to the competent 
authority and ethical committee on the anniversary of the first approval date from the 
regulatory authority for each IMP. 
 
9.6 
Assessment of severity 
The severity of clinical and laboratory adverse events will be assessed according to the scales 
in Tables 6-8, also described in the SOP VC027. 
 
 
 

 
 
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Table 7. Severity grading criteria for local adverse events. 
 
*erythema or swelling ≤3mm is an expected consequence of skin puncture and will therefore 
not be considered an adverse event. 
 
Table 8. Severity grading criteria for physical observations 
 
Grade 1 
(mild) 
Grade 2 
(moderate) 
Grade 3 
(severe) 
Fever (oral) 
37.6°C - 38.0°C 
38.1°C – 39.0°C 
>39.0°C 
Tachycardia (bpm)* 
101 - 115 
116 – 130 
>130 
Bradycardia (bpm)** 
50 – 54 
40 – 49 
<40 
Systolic hypertension (mmHg) 
141 - 159 
160 – 179 
≥180 
Systolic hypotension (mmHg)*** 
85 - 89 
80 – 84 
<80 
Diastolic hypertension (mmHg) 
91 - 99 
100 – 109 
≥110 
*Taken after ≥10 minutes at rest 
**Use clinical judgement when characterising bradycardia among some healthy subject 
populations, for example, conditioned athletes. 
***Only if symptomatic (e.g. dizzy/ light-headed) 
 
 
 
 
 
 
Adverse Event 
Grade 
Intensity 
Erythema at injection site* 
1 
>3 - ≤50 mm 
2 
>50 - ≤100 mm 
3 
>100 mm 
Swelling at injection site 
1 
>3 - ≤20 mm 
2 
>20 - ≤50 mm 
3 
>50 mm 
Ulceration/necrosis of skin at injection site 
1 
- 
2 
- 
3 
Any 

 
 
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Table 9. Severity grading criteria for local and systemic AEs. 
GRADE 0 
None: Symptom not experienced 
GRADE 1 
Mild: Short-lived or mild symptoms; medication may be required. No 
limitation to usual activity 
GRADE 2 
Moderate: Mild to moderate limitation in usual activity. Medication may 
be required. 
GRADE 3 
Severe: Considerable limitation in activity. Medication or medical attention 
required.  
 
9.7 
Procedures to be followed in the event of abnormal findings 
Laboratory parameters for inclusion/exclusion in the trial will be considered on an individual 
basis, with investigator discretion for interpretation of results and the need for repeated 
tests. Laboratory adverse events will be assessed using the tables as detailed in SOP VC027. 
Abnormal clinical findings from medical history, examination or blood tests will be assessed 
as to their clinical significance throughout the trial. 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.  
 
9.8 Local Safety Monitor 
A Local Safety Monitor (LSM) will be appointed to provide real-time safety oversight. The LSM 
will review SAEs deemed possibly, probably or definitely related to study interventions. The 
LSM will be notified within 24 hours of the Investigators’ being aware of their occurrence. The 
LSM has the power to place the study on hold if deemed necessary following a study 
intervention-related SAE. At the time of writing the LSM will be  Dr Brian Angus, a Clinical 
Tutor in Medicine, Honorary Consultant Physician and Director, Centre for Tropical Medicine 
at the University of Oxford.. All correspondence between Investigator and LSM will be 
conveyed by the Investigator to the trial Sponsor. 
The LSM may be contacted for advice and independent review by the Investigator or trial 
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. 
 

 
 
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9.8.1 Interim Safety Reviews 
Interim safety reviews with the LSM are schedule during the enrolment of the first volunteers 
in each group and prior to dose escalations, as outlined in section 7.4.2.2.  
The safety profile of the IMP will be assessed on an on-going basis by the Investigators with 
communication to the LSM as necessary. The Chief Investigator and relevant Investigators (as 
per the trial delegation log) will also review safety issues and SAEs as they arise.  
 
9.9 
Safety Stopping/Holding Rules 
Safety holding rules have been developed considering the fact that this is a first-in-human 
dose escalation study.  
‘Solicited adverse events’ are those listed as foreseeable adverse events in section 9.2 of the 
protocol, occurring within the first 7 days after vaccination (day of vaccination and six 
subsequent days). ‘Unsolicited adverse events’ are adverse events other than the foreseeable 
AEs occurring within the first 7 days, or any AEs occurring after the first 7 days after 
vaccination. 
 
9.9.1 Group holding rules 
The group holding rules are described below: 
 Solicited local adverse events: 
o If 2 or more participants experience ANY grade 3 solicited local adverse event 
beginning within 2 days of vaccination (day of vaccination and one subsequent 
day). 
 
 Solicited systemic adverse events:  
o If 2 or more participants experience ANY grade 3 solicited  systemic adverse 
event beginning within 2 days of vaccination (day of vaccination and one 
subsequent day).  
 
 Unsolicited adverse events: 
o If 2 or more participants experience ANY grade 3  unsolicited adverse event 
(including laboratory adverse events) that is considered possibly, probably or 
definitely related to vaccination.  
 
 A serious adverse event considered possibly, probably or definitely related to 
vaccination occurs 
 
 Death that is considered related to vaccination occurs 
 
 A life-threatening reaction occurs 

 
 
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If a holding rule has been met and following an internal safety review it is deemed appropriate 
to restart dosing, a request to restart dosing with pertinent data must be submitted to the 
regulatory authority as a request for a substantial amendment. The internal safety review will 
consider:  
 The relationship of the AE or SAE to the vaccine. 
 The relationship of the AE or SAE to the vaccine dose, 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) are discussed. 
 New, relevant safety information from ongoing research programs on the various 
components of the vaccine. 
The local ethics committee and vaccine manufacturers will also be notified if a holding rule is 
activated or released.  
As per section 6.3.5, if a volunteer has an acute illness (moderate or severe illness with or 
without fever) or a fever (oral temperature greater than 37.5°C) at the scheduled time of 
administration of investigational product, the volunteer will not receive the vaccine at that 
time. The vaccine may be administered to that volunteer at a later date within the time 
window specified in the protocol (see Table 5) or they may be withdrawn from the study at 
the discretion of the Investigator.  
All vaccinated volunteers will be followed for safety until the end of their planned 
participation in the study or until resolution or stabilisation (if determined to be chronic 
sequelae) of their AEs, providing they consent to this. 
 
In addition to these pre-defined criteria, the study can be put on hold upon advice of the Local 
Safety Monitor, Chief Investigator, Study Sponsor, Regulatory Authority or Ethical 
Committee(s) , for any single event or combination of multiple events which, in their 
professional opinion, jeopardise the safety of the volunteers or the reliability of the data. 
 
 
 

 
 
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10.  
STATISTICS  
This is a descriptive safety study, where volunteers will be vaccinated with a single dose of 
ChAdOx1 RVF. Fifteen volunteers will be vaccinated in total. This sample size should allow an 
estimation to be made of the frequency and magnitude of outcome measures, rather than 
aiming to obtain statistical significance for differences between groups. Safety data will be 
presented according to frequency, severity and duration of adverse events.  
The primary analysis for immunogenicity will be to assess the difference in magnitude of RVFV 
specific T-cell and antibody responses between the groups. We will assess vaccine 
immunogenicity by comparing the change in these immunological parameters from baseline 
to different time points. 
 
Sample Size Selection 
This is a descriptive phase I first in human trial that will balance the safety of volunteers with 
the aims to assess the vaccine’s safety profile and immunogenicity after selected doses of the 
vaccines. The primary dose comparison will be between Groups 1, 2 and 3, which will have 3-
6 subjects each. RVFV specific immunogenicity will be the key immunological readout 
assessed by a variety of immunological assays.  
 
 
 

 
 
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11.  
DATA MANAGEMENT 
11.1 Data Handling 
The Chief Investigator will be responsible for all data that accrues from the study. The data 
will be entered into the volunteers’ CRFs in a paper and/or electronic format (using 
OpenClinica™ database). Electronic data will be stored on secure servers which are 
outsourced by OpenClinica™. Data will be entered in a web browser on PCs in the CCVTM 
building and then transferred to the OpenClinica Database by encrypted (Https) transfer. 
OpenClinica™ meets FDA part 11B standards. This includes safety data, laboratory data (both 
clinical and immunological) and outcome data.  
Adverse event data will also be entered onto electronic or paper diaries by the volunteer  
 
11.2 Record Keeping 
The Investigators will maintain appropriate medical and research records for this trial, in 
compliance with GCP and regulatory and institutional requirements for the protection of 
confidentiality of volunteers. The Chief Investigator, co-Investigators and clinical research 
nurses will have access to records. The Investigators will permit authorised representatives 
of the Sponsor(s), as well as ethical and regulatory agencies to examine (and when required 
by applicable law, to copy) clinical records for the purposes of quality assurance reviews, 
audits and evaluation of the study safety and progress. 
With the volunteers’ consent, we will keep their contact details after participation in the study 
is complete, so we may inform them of opportunities to participate in future vaccine related 
research. This will be entirely optional and participation in this study will not be affected by 
their decision to allow or not allow storage of their contact details beyond participation in 
this trial. Details will be stored electronically on a secure server and only authorised 
individuals at the CCVTM will have access to it. We will not, under any circumstances, share 
their contact details with any third party institutions without their permission. Volunteers will 
be informed that being contacted does not oblige them to agree to take part in future 
research and they can ask us to have their contact details removed from our database at any 
time. 
 
11.3 Source Data and Case Report Forms (CRFs) 
All protocol-required information will be collected in CRFs designed by the Investigators. All 
source documents will be filed in the CRF. Source documents are original documents, data, 
and records from which the volunteer’s CRF data are obtained. For this study, these will 
include, but are not limited to, volunteer consent form, blood results, GP response letters, 
laboratory records, diaries, and correspondence. In the majority of cases, CRF entries will be 
considered source data as the CRF is the site of the original recording (i.e. there is no other 
written or electronic record of data). In this study this will include, but is not limited to medical 

 
 
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history, medication records, vital signs, physical examination records, urine assessments, 
blood results, adverse event data and details of vaccinations. All source data and volunteer 
CRFs will be stored securely.  
 
11.4 Data Protection  
The study protocol, documentation, data and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorised third party, without prior written approval of the sponsor. 
 
11.5 Data Quality 
Data collection tools will undergo appropriate validation to ensure that data is collected 
accurately and completely. Datasets provided for analysis will be subject to quality control 
processes to ensure analysed data is a true reflection of the source data. 
Trial data will be managed in compliance with local data management SOPs (including the 
overarching SOP OVC007 Data and Database Management). If additional, study specific 
information is required, an approved Data Management Plan will be implemented. 
The trial will comply with the General Data Protection Regulation (GDPR) and Data Protection 
Act 2018, which requires data to be de-identified as soon as it is practical to do so. 
 
11.6 Archiving 
Study data may be stored electronically on a secure server, and paper notes will be kept in a 
key-locked filing cabinet at the CCVTM – Churchill Hospital, University of Oxford. All essential 
documents will be retained for a minimum of 5 years after the study has finished. The need 
to store study data for longer in relation to licensing of the vaccine will be subject to ongoing 
review. For effective vaccines that may be licensed, we may store research data securely at 
the University of Oxford for at least 15 years after the end of the study, subject to adjustments 
in clinical trials regulations.  Participants’ bank details will be stored for 7 years in line with 
University of Oxford financial policy.  
General archiving procedures will be conducted in compliance to SOP OVC020 Archiving. 
 
 
 

 
 
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12. 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES 
 
12.1 Investigator procedures 
Approved site-specific standard operating procedures (SOPs) will be used at all clinical and 
laboratory sites. 
 
12.2 Monitoring 
Monitoring will be performed according to the principles of GCP by Clinical Trials Research 
Governance (CTRG). Following written SOPs, the monitors will verify that the clinical trial is 
conducted and data are generated, documented and reported in compliance with the 
protocol, GCP and the applicable regulatory requirements. The Investigator sites will provide 
direct access to all trial related source data/documents and reports for the purpose of 
monitoring and auditing by the Sponsor and inspection by local and regulatory authorities. 
 
12.3 Protocol deviation  
Any deviations from the protocol will be documented in a protocol deviation form and filed 
in the trial master file. Each deviation will be assessed as to its impact on volunteer safety and 
study conduct. Significant deviations will be listed in the end of study report. 
 
12.4 Audit & inspection  
The QA manager conducts systems based internal audits to check that trials are being 
conducted according to local procedures and in compliance with GCP and applicable 
regulations.  
The Sponsor, trial sites, and ethical committee(s) may carry out audit to ensure compliance 
with the protocol, GCP and appropriate regulations.  
GCP inspections may also be undertaken by the MHRA to ensure compliance with protocol 
and the Medicines for Human Use (Clinical Trials) Regulations 2004, as amended. The Sponsor 
will assist in any inspections and will support the response to the MHRA as part of the 
inspection procedure. 
 
 
 
 
 

 
 
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13. 
SERIOUS BREACHES 
The Medicines for Human Use (Clinical Trials) Regulations contain a requirement for the 
notification of "serious breaches" to the MHRA within 7 days of the Sponsor becoming aware 
of the breach.  
A serious breach is defined as “A breach of GCP or the trial protocol which is likely to effect 
to a significant degree  
(a) the safety or physical or mental integrity of the subjects of the trial; or 
(b) the scientific value of the trial”. 
In the event that a serious breach is suspected the Sponsor will be informed within one 
working day. 
 
 
  
 
 

 
 
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14.  
ETHICS AND REGULATORY CONSIDERATIONS 
14.1 Declaration of Helsinki 
The Investigators will ensure that this study is conducted according to the principles of the 
current revision of the Declaration of Helsinki. 
 
14.2 Guidelines for Good Clinical Practice 
The Investigators will ensure that this study is conducted in full conformity with the Good 
Clinical Practice (GCP). 
 
14.3 Approvals 
The protocol, informed consent form, participant information sheet and any proposed 
advertising material will be submitted to an appropriate Research Ethics Committee (REC), 
HRA (where required), regulatory authorities (MHRA in the UK), and host institution(s) for 
written approval. 
The Investigator will submit and, where necessary, obtain approval from the above parties 
for all substantial amendments to the original approved documents. 
No substantial amendments to this protocol will be made without consultation with, and 
agreement of, the Sponsor. Any substantial amendments to the trial that appear necessary 
during the course of the trial must be discussed by the Investigator and Sponsor concurrently. 
If agreement is reached concerning the need for an amendment, it will be produced in writing 
by the Chief Investigator and will be made a formal part of the protocol following ethical and 
regulatory approval. 
The Investigator is responsible for ensuring that changes to an approved trial, during the 
period for which regulatory and ethical committee(s) approval has already been given, are 
not initiated without regulatory and ethical committee(s)’ review and approval except to 
eliminate apparent immediate hazards to the subject. 
 
14.4 Volunteer Confidentiality 
All data will be anonymised: volunteer data will be identified by a unique study number in the 
CRF and database. A separate confidential file containing identifiable information will be 
stored in a secured location in accordance with the relevant data protection legislation. Only 
the Sponsor representative, Investigators, the clinical monitor, the REC and the MHRA will 
have access to the records. Photographs taken of vaccination sites (if required, with the 
volunteer’s written, informed consent) will not include the volunteer’s face and will be 
identified by the date, trial code and subject’s unique identifier. Once developed, 
photographs will be stored as confidential records, as above. This material may be shown to 
other professional staff, used for educational purposes, or included in a scientific publication. 

 
 
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15.  
FINANCING AND INSURANCE 
15.1  Financing  
The study is funded by the UK Biotechnology and Biological Sciences Research Council (BBSRC) 
and the Medical Research Council (MRC)/Department of Health, through the UK Vaccines 
Network. 
 
15.2  Insurance 
The University has a specialist insurance policy in place, which would operate in the event of 
any participant suffering harm as a result of their involvement in the research (Newline 
Underwriting Management Ltd, at Lloyd’s of London).  
 
15.3  Compensation 
Volunteers will be compensated for their time and for the inconvenience caused by 
procedures. They will be compensated £25 for attending the screening visit. For all other trial 
visits as outlined in Table 5, compensation will be calculated according to the following: 
 Travel expenses: 
o £15 per visit. Where travel expenses are greater than £15 per visit because the 
volunteer lives outside the city of the trial site, the volunteer will be given 
further reimbursement to meet the cost of travel necessary for study visits. 
 
 Inconvenience of blood tests: 
o £10 per blood donation 
 
 Time required for visit:  
o £20 per hour 
 
The total amount compensated will be approximately £370 depending on the exact number 
of visits and whether any repeat or additional visits are necessary.  
 
16. 
CONTRACTUAL ARRANGEMENTS  
  
An appropriate service level agreement will be put in place between the Sponsor and 
Oxford University Hospitals NHS Foundation Trust to cover arrangements for processing of 
blood samples.  
 
 

 
 
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17. 
PUBLICATION POLICY 
The Investigators will be involved in reviewing drafts of the manuscripts, abstracts, press 
releases and any other publications arising from the study. Data from the study may also be 
used as part of a thesis for a PhD or MD. 
18. 
DEVELOPMENT OF A NEW PRODUCT/PROCESS OR THE GENERATION OF 
INTELLECTUAL PROPERTY  
Ownership of IP generated by employees of the University vests in the University.  The 
protection and exploitation of any new IP is managed by the University’s technology transfer 
office, Oxford University Innovations. 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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19. 
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Appendix A: Oxford Laboratory Adverse Event Severity Grading  
Severity grading criteria for clinically significant laboratory abnormalities; adapted from FDA guidelines (1) 
using Oxford University Hospitals NHS Foundation Trust laboratory reference ranges.  
(Ox) Routine Haematology
Lab Range
Grade 0
Grade 1
Grade 2
Grade 3
Haemoglobin
Male
130 - 170
126 - 170
115 - 125
100 - 114
<100
Female
120 - 150
114 - 150
105 - 113
90 - 104
<90
White Blood Cells Elevated
11.50 - 15.00
15.01 - 20.00
>20
Low
2.50 - 3.50
1.50 - 2.49
<1.50
Platelets
x109/l
150 - 400
136 - 400
125 - 135
100 - 124
<100
Neutrophils
x109/l
2.0 - 7.0
1.5 - 7.0
1.00 - 1.49
0.50 - 0.99
<0.50
Lymphocytes
x109/l
1.0 - 4.0
1.0 - 4.0
0.75 - 0.99
0.50 - 0.74
<0.50
Eosinophils
x109/l
0.0 - 0.5
0.0 - 0.64
0.65 - 1.50
1.51 - 5.00
>5.00
Routine Biochemistry
Lab Range
Grade 0
Grade 1
Grade 2
Grade 3
Sodium
Elevated
147 - 148
149 - 150
>150
Low
132 - 134
130 - 131
<130
Potassium
Elevated
5.1 - 5.2
5.3 - 5.4
>5.4
Low
3.2 - 3.3
3.0 - 3.1
<3.0
Urea
mmol/l
2.5 - 7.4
2.5 - 8.1
8.2 - 8.9
9.0 - 11.0
>11.0
1.1-1.5*ULN
>1.5-3.0*ULN
>3.0*ULN
Creatinine
µmol/l
49 - 104
49 - 113
114 -156
157 - 312
>312
1.3-1.5*ULN
>1.5-2.0*ULN
>2.0*ULN
Bilirubin
Normal LFT
µmol/l
0 - 21
0 - 26
27 - 31
32-42
>42
1.1-1.25*ULN
>1.25-1.5*ULN
>1.5-1.75*ULN
Bilirubin
Abormal LFT
µmol/l
0 - 21 
0 - 22
23 - 26
27 - 31
>31
When accompanied by any increase in LFT
1.25 - 2.5*ULN
>2.5 - 5.0*ULN
>5.0*ULN
ALT
IU/l
10 - 45
10 - 55
56 - 112
113 - 225
>225
1.1 - 2.0*ULN
>2.0 - 3.0*ULN
>3.0*ULN
Alk Phosphatase
IU/l
30 - 130
30 - 142
143 - 260
261 - 390
>390
Albumin
g/l
32 - 50
32 - 50
28 - 31
25 - 27 
<25
Coagulation Studies
1.10*ULN
>1.10 - 1.20*ULN
>1.2*ULN
Prothrombin time
s
9.0 - 12.0
9.0 - 13.1
13.2
13.3 - 14.4
>14.4
(APTT)
1.10 - 1.20*ULN
>1.20 - 1.40*ULN
>1.4*ULN
Activated Partial Thromboblasin Time 
s
20.0 - 30.0
20.0 - 32.9
33.0 - 36.0
36.1 - 42.0
>42.0
Fibrinogen
g/l
1.5 - 4.0
1.5 - 4.0
1.25 - 1.49
1.0 - 1.24
<1.0
Other
AST
1.25 - 2.5*ULN
>2.5 - 5.0*ULN
>5.0*ULN
Aspartate transferase  
IU/l
15 - 42
15 - 51
52 - 105
106 -210
>210
GGT
1.25 - 2.5*ULN
>2.5 - 5.0*ULN
>5.0*ULN
Gamma-glytamyl transpeptidase 
IU/l
15 - 40
15 - 50
51 - 100
101 - 200
>200
VC027 Appendix (OUH - v3.0 27 Jul 2016)
g/l
x109/l
mmol/l
135 - 145
135 - 146
mmol/l
3.5 - 5.0
3.4 - 5.0
4.00 - 11.00
3.51 - 11.49
Adverse Event Data Collection and Analysis - Version: 1.4. Index: VC027.