A Phase I/II Randomized, Two Parts, Dose-Finding Study To Evaluate The Safety, Tolerability and Immunogenicity Of An Inactivated, Adjuvanted SARS-CoV-2 Virus Vaccine Candidate (VLA2001), Against Covid-19 In Healthy Subjects
Phase: PHASE1
Conditions: SARS-CoV-2 Virus Infection
Sponsor: Valneva Austria GmbH

VLA2001
Clinical Study Protocol VLA2001-201 Version 7.0
31-Aug-21
Valneva Austria GmbH
CONFIDENTIAL
page 1 / 109
Clinical Study Protocol 
DRUG SUBSTANCE(S)
VLA2001 
VERSION NO.
7.0 
STUDY CODE
VLA2001-201 
DATE
31 August 2021
A PHASE I/II RANDOMIZED, TWO PARTS, DOSE-FINDING STUDY TO EVALUATE 
THE SAFETY, TOLERABILITY AND IMMUNOGENICITY OF AN INACTIVATED, 
ADJUVANTED SARS-COV-2 VIRUS VACCINE CANDIDATE (VLA2001), AGAINST 
COVID-19 IN HEALTHY SUBJECTS
Protocol amended to include booster vaccination with VLA2001
Phase I/II study 
PROTOCOL NUMBER:
VLA2001-201
Sponsor
Valneva Austria GmbH
 
 
 
Campus Vienna Biocenter 3 
A-1030 Vienna, Austria
NOTE: The information contained in this document is the intelligence property of Valneva Austria 
GmbH. The privileged and confidential information is intended only for the use of the individual 
or entity to whom it has been sent or to whom it has been given by a member of Valneva's staff. 
If the reader of this document is not the intended recipient, you are hereby notified that any 
dissemination, distribution or copying of this item is strictly prohibited. If you have received this 
item in error, please notify us by telephone, and immediately return the original and all enclosures 
to us at Valneva Austria GmbH, Campus Vienna Biocenter 3, 1030 Vienna, Austria.

VLA2001
Clinical Study Protocol VLA2001-201 Version 7.0
31-Aug-21
Valneva Austria GmbH
CONFIDENTIAL
page 2 / 109
1. PROTOCOL SIGNATURE PAGE
A PHASE I/II RANDOMIZED, TWO PARTS, DOSE-FINDING STUDY TO EVALUATE 
THE SAFETY, TOLERABILITY AND IMMUNOGENICITY OF AN INACTIVATED, 
ADJUVANTED SARS-COV-2 VIRUS VACCINE CANDIDATE (VLA2001), AGAINST 
COVID-19 IN HEALTHY SUBJECTS 
Protocol Number:
VLA2001-201
With their signature, Investigators and the Sponsor agree to conduct this study in 
accordance with the Protocol, International Conference on Harmonization (ICH), Good 
Clinical Practice (GCP) guidelines and with the applicable local regulatory requirements. 
Moreover, the site will keep all information obtained from the participation in this study 
confidential unless otherwise agreed in writing.
Principal Investigator
Print Name
Signature
Date
Signature
Date
Bénédicte Querton 
Clinical Operations 
Valneva Austria GmbH
Signature
Date
Signature
Date 
Juan-Carlos Jaramillo, MD 
Sponsor’s Responsible Medical Officer 
Valneva Austria GmbH
Signature
Date

VLA2001
Clinical Study Protocol VLA2001-201 Version 7.0
31-Aug-21
Valneva Austria GmbH
CONFIDENTIAL
page 3 / 109
2. STUDY PERSONNEL
Clinical Operations 
 
 
 
 
Sponsor’s Medical / Safety Officer 
 
 
 
 
 
Study Medical Monitor 
 
 
 
 
 
2.1 Study Organization
The contact details
of
the organisation/individuals involved in the study (e.g.; 
Investigator(s), Sponsor’s representative(s), laboratories, oversight committees [including 
ethics committees {ECs}, as applicable]) will be maintained by the Sponsor and provided 
to the Investigator.

VLA2001
Clinical Study Protocol VLA2001-201 Version 7.0
31-Aug-21
Valneva Austria GmbH
CONFIDENTIAL
page 4 / 109
3. SERIOUS ADVERSE EVENT REPORTING
The Investigator will comply with applicable laws/requirements for reporting serious 
adverse events (SAEs). For information on the definition and assessment of adverse 
events (AEs), refer to Section 15.1 and 15.2, respectively. 
All Adverse Events of Special Interest (AESIs) will be treated as important medical 
event and will therefore be treated as SAEs. For information on the definition of adverse 
events of special interest (AESIs), refer to Section 15.10.
All SAEs should be reported on the SAE Report Form in the eCRF within 24 hours 
of the Investigator becoming aware of the event. Under certain circumstances the 
initial notification could be done by phone, but nevertheless a written SAE Report 
Form has to be submitted within 24 hours to:
Pharm-Olam International
Fax:
 
Email:
Safety Hotline:

VLA2001
Clinical Study Protocol VLA2001-201 Version 7.0
31-Aug-21
Valneva Austria GmbH
CONFIDENTIAL
page 5 / 109
4. PREGNANCY REPORTING
The Investigator will comply with applicable laws/requirements for reporting pregnancies. 
For information on the definition and assessment of pregnancies, refer to Section 15.11.2. 
All Pregnancies* should be reported on the Pregnancy Report Form to Pharm-Olam 
International by fax or email within 24 hours of the Investigator becoming aware of 
the event.
Safety Desk
Fax:
 
Email:
 
Safety Hotline:
* A pregnancy is not considered an SAE. If a seriousness criterion applies in addition to the 
pregnancy (e.g. hospitalisation, congenital anomaly/birth defect) the pregnancy qualifies as an 
SAE. In such case a Pregnancy Report Form and an SAE Report Form have to be filled out.

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 6 / 109 
 
5. CLINICAL STUDY SYNOPSIS 
INVESTIGATIONAL PRODUCT, DOSAGE AND MODE OF ADMINISTRATION 
Title 
A PHASE I/II  RANDOMIZED, TWO PARTS, DOSE-
FINDING STUDY TO EVALUATE THE SAFETY, 
TOLERABILITY AND IMMUNOGENICITY OF AN 
INACTIVATED, ADJUVANTED SARS-COV-2 VIRUS 
VACCINE CANDIDATE (VLA2001), AGAINST COVID-
19 IN HEALTHY SUBJECTS  
 
Name of Investigational Medicinal 
Product (IMP) 
Inactivated, adjuvanted SARS-CoV-2 vaccine 
VLA2001 
 
Name(s) of Active Ingredient(s) 
Inactivated, adjuvanted SARS-CoV-2 vaccine based on 
strain hCoV-19/Italy/INMI1-isl/2020 (VLA2001) Adjuvant: 
a combination of aluminium hydroxide and CpG 1018  
VLA2001 is a highly-purified, whole virus, SARS-CoV-2 vaccine produced on Vero cells and 
inactivated with β-propiolactone. Vaccine is adjuvanted with the licensed adjuvant cytosine 
phospho-guanine (CpG) 1018 (produced by Dynavax, contained in HEPLISAV-B®) in 
combination with aluminium hydroxide.  
VLA2001 has been developed using the same manufacturing platform as that used for the 
commercial vaccine IXIARO®, a purified, inactivated, whole virus, aluminium hydroxide-
adjuvanted Japanese encephalitis vaccine that has been approved by regulatory authorities 
worldwide (including the Food and Drug Administration [FDA], European Medicines Agency 
[EMA] and Therapeutic Goods Administration).  
An acceptable safety profile was demonstrated for IXIARO in seven randomised, controlled 
studies with a total safety database of 3,945 healthy adults. The most common adverse reactions 
in adults across all studies were headache, myalgia, injection site pain, and injection site 
tenderness. No specific safety signals (including hypersensitivity reactions and neurologic 
disorders) were identified for IXIARO through clinical studies and post-marketing 
pharmacovigilance (IXIARO clinical review memorandum, 2018). 
This is a first-in-human phase I/II study that will evaluate three dose levels of VLA2001 (Low 
dose, medium dose, high dose) for safety, tolerability and immunogenicity in a two-dose primary 
schedule (Day 1; Day 22) in a healthy young adult population aged 18 to 55 years. 
Booster Phase: 
Study participants who have completed the primary immunization schedule (two vaccinations), 
will be invited to participate in a Booster Phase to investigate the immunogenicity and safety of 
a booster dose with VLA2001 administered at approximately 8-9 months after completing the 
primary immunization schedule. 
 
 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 7 / 109 
 
CLINICAL CONDITION(S)/INDICATION(S) 
Active immunisation for the prevention of COVID-19 (disease caused by SARS-CoV-2) 
STUDY PHASE 
Phase I/II 
PLANNED STUDY PERIOD 
Initiation 
Q4 / 2020 
Duration 
The overall study duration (First Subject In–Last Subject Out [LSO]) is 
estimated to be approximately 16 months. Individual participation is 
approximately 15 months from enrolment to study completion unless the 
study is prematurely discontinued. 
Completion 
Part A (Visit 4, Day 36): LSO Feb 2021 
Part B (Visit 6, Day 208 (Month 7)): LSO planned Aug 2021 
Booster Phase: 
Part C (Visit 7-10, Month 9-15: LSO planned Mar 2022) 
Individual study parts will be analysed sequentially. 
STUDY OBJECTIVES 
Primary: 
1) The primary objective of this study is to evaluate the tolerability, safety and immunogenicity 
of the inactivated, adjuvanted SARS-CoV-2 vaccine candidate VLA2001 up to 14 days after 
completion of a two-dose primary immunization schedule in healthy adults aged 18 to 55 
years.  
 
Secondary: 
1) To determine the optimal dose level of the inactivated, adjuvanted SARS-CoV-2 vaccine 
candidate VLA2001 in healthy adults aged 18 to 55 years.  
2) To evaluate tolerability, safety and immunogenicity of the inactivated, adjuvanted SARS-
CoV-2 vaccine candidate VLA2001 up to 6 months after the last vaccination in healthy adults 
aged 18 to 55 years. 
3) To evaluate tolerability, safety and immunogenicity of a booster dose with vaccine candidate 
VLA2001 in healthy adults aged 18 to 55 years. 
 
Exploratory: 
 
To evaluate cellular immune response after vaccination with the inactivated, adjuvanted 
SARS-CoV-2 vaccine candidate VLA2001 after completion of a two-dose primary 
immunization schedule and after a booster vaccination.  

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 8 / 109 
 
STUDY DESIGN 
The study is a randomised, dose-escalation, multicentre study with three dose groups (low, 
medium and high dose groups); 50 Participants have been recruited to each dose group. The 
study will be conducted in three parts: Part A (Day 1 to Day 36) and Part B (Day 37 to Day 208). 
Following an evaluation of initial data (i.e. data up to Day 36) from the study, a Booster Phase 
(Part C) has been added to the study. 
The study will start with an open-label, staggered recruitment for the first 15 Participants and 
subsequently in the blinded part of the study for all remaining 135 Participants. Randomization 
will be done in 1:1:1 fashion for the 3 dose levels. 
Figure: Study Design 
 
For safety reasons, the first 15 Participants will be included into the study in an open-label, not 
randomized manner following a staggered dose escalation of VLA2001. Dose escalation will be 
done at a single site to ensure permanent oversight of safety data by one principal investigator 
during the recruitment of the 15 sentinel Participants.  
Dose escalation starts with the first vaccination of the first sentinel participant in the low dose 
treatment group. After vaccination, the first Participant of a dosing group will be observed for the 
development of any acute reaction at the study site for 3 hours after the vaccination procedure. 
Prior to discharge from the study site, vital signs will be measured and the Participant will be 
instructed to use the e-Diary. The study site will contact the Participant per phone approximately 
24 hours after vaccination to assess the safety status of the Participant. The provided information 
must be compared with the entries in the Participant´s e-Diary. The minimum time before the 
next Participants are vaccinated is therefore 24 hours. The next 4 Participants of the same dosing 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 9 / 109 
 
group will be vaccinated at least with a one-hour interval between each Participant. These 4 
Participants will be observed for 60 minutes at the study site to monitor for the development of 
any acute reaction. Before discharge, vital signs will be measured and Participants will be 
instructed to use their e-Diaries. Safety telephone calls will be performed by the study site 
approximately 48 hours after vaccination. After confirmation by the investigator that no stopping 
criteria (see Section 10.6) has been met, the procedure will be repeated with the first Participant 
of the next dose level. The minimum time before vaccination of a new dose level will be 48 hours.
 
A Data Safety and Monitoring Board (DSMB) will review the accrued safety data at Day 4 of all 
15 sentinel Participants. After favourable DSMB review randomization of the remaining 135 
Participants across all sites will be initiated.  
The remaining 135 Participants will be enrolled, screened and randomised to the three dose 
groups in the blinded part of the study. Participants will be observed for 30 minutes post 
vaccination on Day 1. An unscheduled safety telephone call will be performed in case a Grade 3 
AE or SAE will be reported by the Participant via e-Diary. All participants will be followed by e-
Diary for 7 days post vaccination, starting on the day of vaccination. Participants will return to the 
study site on Day 8 (Visit 2). After (approximately) 20 participants per dose group have been 
randomised and followed up 7 days post first vaccination, and periodically up to Day 36 for all 
randomised Participants, the DSMB will review the accrued safety data. All Participants will 
receive their second vaccination on Day 22 (Visit 3) and will be followed up on Day 36 (Visit 4), 
14 days after the second vaccination. The DSMB will review safety data up to Day 36.  
In Part B, participants will be followed up on Day 106 (Visit 5) and Day 208/Month 7 (Visit 6), 
6 months after the second vaccination. DSMB safety data review will occur ad-hoc in line with 
the DSMB Charter. 
Booster Phase: 
At Visit 6 (Month 7), all participants who previously had received two study vaccinations will be 
asked for their consent to take part in the Booster Phase (Part C). Independently of the dose 
received during the primary immunization, participants will receive a booster dose (high dose) of 
VLA2001.  
The Booster vaccination will also be offered to participants who have either had a confirmed 
COVID-19 disease or who have received a national COVID-19 vaccination. 
The Booster vaccination will be administered at Visit 7. Visit 7 is expected to be performed in 
September 2021. This timing will translate to the booster dose being given to the participants at 
approximately 8 to 9 Months after completion of the primary immunization schedule. 
Participants will be asked to return to the study site for two follow-up visits, 2 weeks after the 
booster vaccination (visit 8) and one month after the booster vaccination (Visit 9).  
6 months after the Booster vaccination, participants will be followed-up through a safety phone 
call. This telephone call is also the end of the study for the participants that consented to the 
booster part of the study.  
Additional safety data review by the DSMB will occur when necessary (ad-hoc) as defined in the 
DSMB Charter. A final review of the generated safety data will be performed by the DSMB once 
all participants have completed the clinical study. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 10 / 109 
 
STUDY ENDPOINTS 
Safety endpoints  
Primary: Frequency and severity of solicited AEs (local and systemic reactions) within 7 days 
after any vaccination of the primary vaccination series. 
Secondary  
 
Frequency and severity of any unsolicited AE until Day 36. 
 
Frequency and severity of any vaccine-related AE until Day 36. 
 
Frequency and severity of any AE until Day 208. 
 
Frequency and severity of any vaccine-related AE until Day 208. 
 
Frequency and severity of any SAE until Day 36. 
 
Frequency and severity of any AESI until Day 36. 
 
Frequency and severity of any SAE until Day 208. 
 
Frequency and severity of an AESI until Day 208. 
Booster Phase: 
 
Frequency and severity of solicited AEs (local and systemic reactions) within 7 days after the 
booster vaccination 
 
Frequency and severity of any unsolicited AE up to Visit 9 
 
Frequency and severity of any vaccine-related AE up to Visit 9 
 
Frequency and severity of any SAE up to Visit 10 
 
Frequency and severity of any AESI up to Visit 10 
 
Immunogenicity 
Primary: Geometric mean titre (GMT) for neutralizing antibodies against SARS-CoV-2 
determined by wild-type virus neutralizing assay at Day 36. 
Secondary 
 
Immune response as measured by neutralizing antibody titres against SARS-CoV-2 on 
Day 8, Day 22, Day 106 and Day 208. 
 
Proportion of Participants with seroconversion in terms of neutralizing antibodies on Day 8, 
Day 22, Day 36, Day 106 and Day 208. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 11 / 109 
 
 
Fold increase of SARS-CoV-2 neutralizing antibody titres on Day 8, Day 22, Day 36, Day 106 
and Day 208 compared with baseline. 
 
GMTs for IgG antibodies against SARS-CoV-2, determined by ELISA, at Day 1, Day 8, Day 
22, Day 36, Day 106 and Day 208. 
 
Proportion of Participants with seroconversion in terms of IgG antibodies against SARS-CoV-
2 as determined by ELISA on Day 8, Day 22, Day 36, Day 106 and Day 208. 
Booster Phase: 
 
Geometric mean fold rise (GMFR) from pre-booster time point (Visit 7) to 2 weeks after 
booster dose (Visit 8) with regards to neutralizing antibodies.  
 
Geometric mean fold rise (GMFR) from pre-booster time point (Visit 7) to 4 weeks after 
booster dose (Visit 9) with regards to neutralizing antibodies.  
 
Proportion of Participants with 4-fold increase from pre-booster dose (Visit 7) to 2 weeks after 
booster dose (Visit 8) with regards to neutralizing antibodies.  
 
Proportion of Participants with 4-fold increase from pre-booster dose (Visit 7) to 4 weeks after 
booster dose (Visit 9) with regards to neutralizing antibodies.  
 
Geometric mean titres (GMT) measured as neutralizing antibody titres against SARS-CoV-2 
at Visit 7, Visit 8 and Visit 9. 
 
Geometric mean fold rise (GMFR) from pre-booster dose (Visit 7) to 4 weeks after booster 
dose (Visit 9) with regards to S-protein binding antibodies (ELISA).  
 
Geometric mean fold rise (GMFR) from pre-booster dose (Visit 7) to 2 weeks after booster 
dose (Visit 8) with regards to S-protein binding antibodies (ELISA).  
 
Proportion of Participants with 4-fold increase from pre-booster dose (Visit 7) to 4 weeks after 
booster dose (Visit 9) in regards to S-protein binding antibodies (measured by ELISA).  
 
Proportion of Participants with 4-fold increase from pre-booster dose (Visit 7) to 2 weeks after 
booster dose (Visit 8) in regards to S-protein binding antibodies (measured by ELISA).  
 
 
 
GMT measured as IgG antibodies against SARS-CoV-2 as determined by ELISA, at Visit 7, 
Visit 8 and Visit 9. 
 
Exploratory 
 
Cellular immune response on Day 1, Day 36 , Day 208 and Visit 7 and Visit 8.  
 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 12 / 109 
 
CRITERIA FOR INCLUSION / EXCLUSION 
Approximately 150 male and female adults who satisfy the inclusion and exclusion criteria listed 
below will be invited to participate in the study. 
Inclusion criteria 
Participants who meet ALL of the following criteria are eligible for the study: 
1. Participant is 18 to 55 yearsi of age on the Day of screening (Visit 0). 
2. Participant who has a smart phone and is willing and able to install and use the e-Diary. 
3. Participant has an understanding of the study and its procedures, agrees to its provisions, 
and voluntarily gives written informed consent prior to any study-related procedures. 
4. Participant is generally healthyii as determined by the Investigator’s clinical judgement 
based on medical history, physical examination and screening laboratory tests. 
5. Participant has a Body Mass Index (BMI) of 18.0-30.0 kg/m2, inclusive, at screening (Visit 
0). 
6. If Participant is of childbearing potential: 
a) Participant has practiced an adequate method of contraception (see below) during 
the 30 days before screening (Visit 0). 
b) Participant has a negative serum or urine pregnancy test at screening (Visit 0) or 
Visit 1, respectively.  
c) Participant agrees to employ adequate birth control measures up to Day 106 (Visit 
5). This includes one of the following measures: 
 
Hormonal contraceptives (e.g. implants, birth control pills, patches). 
 
Intrauterine hormone-release systems and intrauterine device. 
 
Barrier type of birth control measure (e.g. diaphragms, cervical caps). 
 
Vasectomy in the male sex partner ≥ 3 months prior to first vaccination. 
 
Same sex relationships. 
Exclusion criteria 
Participants who meet ANY of the following criteria are NOT eligible for this study: 
1. Clinically significant infection or other acute illness, including fever ≥ 38°C within 48 hours 
prior to the planned study vaccination. 
2. History of laboratory-confirmed SARS-CoV-2 infection. 
                                                 
i From the day a person turns 18 years until the last day before the person turns 56 years of age. 
ii Participants are considered generally healthy if they have (1) no active disease (acute illness, exacerbation of 
a chronic condition or a chronic – progressive illness) which requires treatment and/or follow-up, and (2) no 
disease that is identified as an exclusion criterion or (3) if they are healthy and have a preexisting stable disease, 
defined as disease not requiring significant change in therapy or hospitalization for worsening disease during the 
6 weeks before screening. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 13 / 109 
 
3. Participant had close contact to persons with confirmed SARS-CoV-2 infection within 30 
days prior to screening (Visit 0). 
4. Participant has participated in a clinical study involving an investigational SARS-CoV-2 
vaccine or has received or plans to receive a licensed SARS-CoV-2 vaccine during the 
duration of the study. 
5. Participant has an acute or recent infection not due to SARS-CoV-2 (and who is not 
symptom-free in the week prior to the Screening Visit (Visit 0). 
6. Participant has a history of SARS-CoV-1 or MERS infection (self-reported) 
7. Participant tests positive for human immunodeficiency virus (HIV), hepatitis B surface 
antigen (HBsAg) or hepatitis C virus (HCV). 
8. Participant has received any vaccine within 30 days prior Visit 1 other than the study 
intervention, with the exception of the seasonal influenza vaccination. Participants will be 
encouraged to receive this vaccination at least 7 days after their study vaccine.  
9. Participant has abnormal findings in any required study investigations (including medical 
history, physical examination, and clinical laboratory) considered clinically relevant by the 
Investigator.  
10. Participants with either medical history of or present acute or progressive, unstable or 
uncontrolled clinical conditions (e.g. cardiovascular, respiratory, neurologic, psychiatric, 
or rheumatologic conditions) that pose a risk for participation or completion of the study, 
based on Investigator’s clinical judgement. Examples include Participants with poorly 
controlled or unstable underlying disease, ongoing suspected or active inflammation, 
poor compliance with pharmacologic treatment, or presence of high-risk comorbidities 
(e.g. significant cardiopulmonary disease). 
11. Participants with underlying diseases with a high risk of developing severe COVID-19 
symptoms if infected, including those with any of the following risk factors:  
 
Hypertension.  
 
Diabetes mellitus.  
 
Chronic liver disease. 
 
Chronic pulmonary disease. 
 
Asthma. 
 
Current vaping or smoking. 
 
History of chronic smoking within the prior year. 
12. Participant has a history of malignancy in the past 5 years other than squamous cell or 
basal cell skin cancer. If there has been surgical excision or treatment more than 5 years 
ago that is considered to have achieved a cure, the Participant may be enrolled. A history 
of hematologic malignancy is a permanent exclusion. Participants with a history of skin 
cancer must not be vaccinated at the previous tumour site. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 14 / 109 
 
13. Participant has a known or suspected defect of the immune system, such as Participants 
with congenital or acquired immune deficiency, including infection with HIV, status post 
organ transplantation or other autoimmune diseases. 
14. Participant received immuno-suppressive therapy within 4 weeks prior to Visit 1 or receipt 
of immunosuppressive therapy is expected during the study. Immuno-suppressive 
therapy is defined as administration of chronic (longer than 2 weeks) prednisone or 
equivalent ≥ 0.05 mg/kg/day within 4 weeks prior to Visit 1 (topical and inhaled steroids 
are allowed), radiation therapy or immunosuppressive cytotoxic drugs/ monoclonal 
antibodies in the previous 3 years. 
15. Participant has a history of any vaccine related contraindicating event (e.g., anaphylaxis, 
allergy to components of the candidate vaccine, other known contraindications). 
16. Participant presents with clinical conditions representing a contraindication to 
intramuscular vaccination and blood draws. 
17. Participant is pregnant (positive serum or urine pregnancy test at screening or Visit 1, 
respectively), has plans to become pregnant up to Day 106 of the study or lactating at 
the time of enrolment.  
18. Participant has donated blood, blood fractions or plasma within 4 weeks prior to Visit 1 or 
received blood-derived products (e.g. plasma) within 12 weeks prior to Visit 1 in this study 
or plans to donate blood or use blood products during the study.  
19. Participant with clinically significant bleeding disorder (e.g. factor deficiency, 
coagulopathy or platelet disorder) or prior history of significant bleeding or bruising 
following IM injections or venipuncture. 
20. Participant has a rash, dermatological condition or tattoos that would, in the opinion of 
the Investigator, interfere with injection site reaction rating. 
21. Participant has a known or suspected problem with alcohol or drug abuse as determined 
by the Investigator. 
22. Participant has any condition that, in the opinion of the Investigator, may compromise the 
Participant’s well-being, might interfere with evaluation of study endpoints, or would limit 
the Participant’s ability to complete the study.  
23. Participant is committed to an institution (by virtue of an order issued either by the judicial 
or the administrative authorities). 
24. Participant has participated in another clinical study involving an investigational medicinal 
product (IMP) or device within 4 weeks prior to Visit 0 (screening) or is scheduled to 
participate in another clinical study involving an IMP, or device during the course of this 
study. 
25. Participant is a member of the team conducting the study or in a dependent relationship 
with one of the study team members. Dependent relationships include close relatives 
(i.e., children, partner/spouse, siblings, parents) as well as employees of the Investigator 
or site personnel conducting the study. 
 
Additional criteria to be re-confirmed before enrolment into the Booster Phase: 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 15 / 109 
 
Inclusion criteria  
Participants who meet ALL of the following criteria are eligible for the Booster phase: 
B1. Participant has received complete VLA2001 primary immunization (two vaccinations 
according to the protocol) 
B2. Participant has a smart phone and is willing and able to install and use the e-Diary. 
B3. Participant has an understanding of the study and its procedures, agrees to its provisions, 
and voluntarily gives written informed consent prior to any study-related procedures. 
B4. Participant is generally healthyiii as determined by the Investigator’s clinical judgement 
B5. If a participant is of childbearing potential: 
a. Participant has a negative urine pregnancy test at visit 7 prior to booster 
vaccination.  
b. Participant agrees to employ adequate birth control measures up to 3 months 
after the Booster vaccination. This includes one of the following measures: 
i. Hormonal contraceptives (e.g. implants, birth control pills, patches). 
ii. Intrauterine hormone-release systems and intrauterine device. 
iii. Barrier type of birth control measure (e.g. diaphragms, cervical caps). 
iv. Vasectomy in the male sex partner ≥ 3 months prior to first vaccination. 
v.  Same sex relationships. 
 
Exclusion criteria 
Participant who meet ANY of the following criteria are NOT eligible for the Booster Phase: 
B1. Clinically significant infection or other acute illness, including fever ≥ 38°C within 48 hours 
prior to the planned Booster vaccination. 
B2. Participant has an acute or recent infection not due to SARS-CoV-2 and is not symptom-
free in the week prior to the Booster vaccination (Visit 7). 
B3. Participant has received any vaccine within 30 days prior Visit 7, with the exception of the 
seasonal influenza vaccination. Participants will be encouraged to receive this 
vaccination at least 7 days after their Booster vaccine.  
B4. Participant has abnormal findings in any required study investigations (including medical 
history, physical examination, and clinical laboratory) that is considered clinically relevant 
by the Investigator.  
                                                 
iii Participants are considered generally healthy if they have (1) no active disease (acute illness, exacerbation of 
a chronic condition or a chronic – progressive illness) which requires treatment and/or follow-up, and (2) no 
disease that is identified as an exclusion criterion or (3) if they are healthy and have a preexisting stable disease, 
defined as disease not requiring significant change in therapy or hospitalization for worsening disease during the 
6 weeks before screening/ before Day 208. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 16 / 109 
 
B5. Participant has received immuno-suppressive therapy within 4 weeks prior to Visit 7 or is 
expected to receive immunosuppressive therapy during the study. Immuno-suppressive 
therapy is defined as administration of chronic (longer than 2 weeks) prednisone or 
equivalent ≥ 0.05 mg/kg/day within 4 weeks prior to Visit 7 (topical and inhaled steroids 
are allowed), radiation therapy or immunosuppressive cytotoxic drugs or monoclonal 
antibodies in the previous 3 years. 
B6. Participant has clinical conditions representing a contraindication to intramuscular 
vaccination and blood draws. 
B7. Participant is pregnant (positive urine pregnancy test at Visit 7, respectively), has plans 
to become pregnant at time of the enrolment to the Booster Phase (Visit 7). 
B8. Participant has a rash, dermatological condition that would, in the opinion of the 
Investigator, interfere with injection site reaction rating. 
B9. Participant has a known or suspected problem with alcohol or drug abuse as determined 
by the Investigator. 
B10. 
Participant has any condition that, in the opinion of the Investigator, may compromise 
the Participant’s well-being, might interfere with evaluation of study endpoints, or would 
limit the Participant’s ability to complete the study.  
B11. 
Participant is committed to an institution (by virtue of an order issued either by the 
judicial or the administrative authorities). 
B12. 
Participant has participated in another clinical study involving an investigational 
medicinal product (IMP) or device within 4 weeks prior to Visit 7 or is scheduled to 
participate in another clinical study involving an IMP, or device during the course of this 
study. 
Delaying Administration of Study vaccination  
Vaccination will be delayed if: 
1. Participant has current febrile illness (body temperature equal or greater 38.0°C) or other 
acute illness within 48 hours prior vaccination.  
2. An illness which in the judgement of the investigator may interfere with tolerability (7 days 
post booster) and safety assessment 
3. Participant has received antipyretics within 6 hours prior to the scheduled time of 
vaccination. 
4. Receipt of any vaccine within 30 days prior to study intervention, with the exception of 
the seasonal influenza vaccine. Participants will be encouraged to receive this 
vaccination at least 7 days before or after their study vaccine. 
In addition, for a rescheduled vaccination all inclusion and none of the exclusion criteria must be 
met; in case not all of these criteria are met, the Participant will be excluded from further 
vaccination.  
The rescheduled visit should be within the specified time window for the vaccination visit. In case 
the time window for a rescheduled first vaccination cannot be met, the Participant might be invited 
for a re-screening. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 17 / 109 
 
STATISTICAL ANALYSIS 
Sample size justification 
No formal sample size calculation has been performed. A total of 150 Participants is considered 
sufficient to obtain initial safety data for VLA2001, especially since inactivated vaccines are a 
well-established, safe vaccine technology. Fifty Participants per group will allow for 95% 
confidence that an AE with a true underlying incidence of about 2% would be observed in the 
present study.  
For the Booster Phase of this study, no formal sample size calculation has been performed and 
no minimal or maximal number of participants is defined. Based on operational considerations 
the total number of participants is expected to be up to approximately 80. 
Statistical methods 
Primary safety analysis: The number and percentage of Participants with solicited local and 
systemic AEs within 7 days after each and after any vaccination of the primary vaccination series 
(Day 1; Day 22) will be presented. Differences between treatment groups will be assessed for 
significance using Fisher’s exact test. 
Primary immunogenicity analysis: This will be a comparison of GMTs for SARS-CoV-2 
neutralizing antibodies at 14 days after the second dose (i.e. Day 36). Geometric mean titres 
(GMTs) and GMT ratios will be estimated by applying an analysis of variance (ANOVA) including 
the factor treatment group and study site. Tukey’s HSD test will be applied for pair wise 
comparisons. 
Secondary safety analysis: The number and percentage of participants with unsolicited AEs, 
related AEs, AESIs and SAEs will be presented for each study arm, overall, by system organ 
class/preferred term and by severity. Differences between study groups will be assessed for 
significance using Fisher’s exact (Fisher-Freeman-Halton) test, whereby a significant overall test 
will be amended by pair-wise tests, and 95% confidence interval (CI) will be presented for all AE 
rates. 
Secondary immunogenicity analysis: This will include the comparison of the GMTs as well as 
comparison of geometric mean fold increase (GMFI) between study groups on other study days. 
ANOVA models will be applied as described for the primary immunogenicity endpoint. 
Seroconversion rates for various study days as well as rates of Participants reaching certain fold-
increase will be compared between the study groups using Fisher’s exact (Fisher-Freeman-
Halton) test, whereby a significant overall test will be amended by pair-wise tests, and 95% CIs 
will be calculated. 
Data Analysis 
The following data analyses will be performed:  

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 18 / 109 
 
 
Part A includes safety and immunogenicity data after all participants have completed Visit 4 
(Day 36).  
 
Part B includes safety and immunogenicity data after all Participants have completed Visit 6 
(Day 208). 
 
An additional data analysis will be performed during part B after all Participants have 
completed Visit 5 (Day 106) 
 Part C includes Visits 7 to 10. An analysis of Part C will be done when all participants have 
completed visit 9.  
 Final analysis will be done when all participants have completed the last visit (Visit 10) 
 
Interim/Final Report 
An interim report will be compiled based on the Visit 5 data (Day 106) and a second interim report 
will be compiled based on the full Part B and partial Part C (Visit 7, Visit 8 and Visit 9) data. 
A final study report will be published after completion of Part C (including Visit 10). 
SAFETY ASSESSMENTS 
1. Unsolicited adverse events
Unsolicited events, which include clinically relevant laboratory parameter changes and 
symptoms noted during symptom-driven physical examinations, need to be documented in the 
respective AE section of the electronic Case Report Form (eCRF) during the applicable study 
visit (Visits 1 to 9 or unscheduled visit(s) before Visit 9, if applicable), regardless of their source. 
Serious adverse events and Adverse Events of Special interest (AESIs) will continue to be 
documented until the end of the study. The Investigator will follow-up each AE until it is resolved 
or until the medical condition of the Participant is stable. Serious adverse events ongoing at the 
time of Visit 9 will be followed until resolution, achievement of stable clinical conditions, or until 
the overall end of the study at the latest. Serious adverse events that are fatal, life-threatening 
or suspected to be related to study treatment will continue to be reported until 6 months after the 
last vaccination of the respective Participant (i.e. Visit 9). The following information will be 
documented for each AE: severity, causality, outcome, seriousness, medically-attended, action 
taken to treat AE, start and stop dates. 
2. Solicited adverse events 
Solicited AEs will be reported in the e-Diary by the Participant for 7 consecutive days after each 
vaccination including booster dose, starting on the day of vaccination. They will be graded by the 
investigator according to the FDA’s Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials. 
a) Injection site reactions 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 19 / 109 
 
Solicited injection site reactions include injection site pain, itching, tenderness, redness and 
swelling/induration. Participants will be provided with a measuring tool to measure the size of 
any measurable injection site reaction.  
b) Systemic reactions 
Solicited 
systemic 
reactions 
include 
fever/body 
temperature, 
fatigue, 
headache, 
nausea/vomiting, muscle pain. 
c) Fever and body temperature 
Participants will be provided with a digital thermometer to individually measure their body 
temperature orally once every evening from vaccination until Day 7 after each vaccination. In 
case fever (oral body temperature ≥ 38.0°C) occurs, participants should measure their body 
temperature every 4 to 8 hours until fever resolves (oral body temperature < 38.0°C). The time 
at which the first body temperature of < 38.0°C is recorded is considered to be the end of the 
fever episode. All fever measurements should be recorded by the participant in the Participant’s 
diary including the first value that shows a return to normal body temperature.   
3. Adverse events of special interest 
Participants will be carefully monitored for development of adverse events of special interest 
(AESI). All AESIs will be treated as medically significant and will therefore be treated as SAEs 
and an SAE report form will be completed for AESIs, in particular, and the information will be 
provided to the DSMB. The DSMB will do the following: perform a thorough review of each case, 
advise whether additional clinical work-up is required, conduct a final adjudication of all AESI and 
assess whether cases were new in onset and whether there is any relationship to administration 
of the study vaccine. 
Electronic diary 
Participants will be instructed and trained to use the electronic diary (e-Diary) to collect solicited 
AEs within 7 days after each vaccination including the Booster dose. The following information 
will be collected: 
 
Oral body temperature. 
 
Solicited injection site reactions. 
 
Solicited systemic reactions. 
 
Symptoms Relating to SARS-CoV-2. 
 
Other AEs. 
 
Any new medication or changes in medication taken after vaccination. 
Study staff will be prompted to perform a phone call visit if a) no diary data are being reported by 
the Participant, b) a grade 3 solicited event has been reported, c) indication for serious adverse 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 20 / 109 
 
event is observed. Study participants will be prompted to contact the study site in case of 
symptoms relating to COVID-19 (see section 15.2.5). 
 
CASE DEFINITIONS 
A case of COVID-19 is defined as follows:  
Virologically (SARS-CoV-2 positive) confirmed SARS-CoV-2 infection with one or more of the 
following symptoms listed below:  
 
Fever or chills  
 
Persistence of Cough as defined by NHS, as a lot of coughing for more than 1 hour, or three or more 
coughing episodes in 24 hours. If the participant usually has a cough, it may be worse than usual. 
 
Shortness of breath or difficulty breathing  
 
Fatigue  
 
Muscle or body aches  
 
Headache  
 
A loss or change of smell and taste 
 
Sore throat  
 
Congestion  
 
Nausea or vomiting (more than one episode and/or persisting) 
 
Diarrhoea 
With the exception of fever, shortness of breath, or difficulty breathing, the symptom must be 
present for 2 or more consecutive days.  
Cases are defined by laboratory confirmation of SARS-CoV-2 and signs/symptoms/examinations 
that occur within 14 calendar days of the initial symptom(s). 
Procedures in the Event of COVID-19 like Signs and Symptoms 
As a risk mitigation strategy, all enrolled participants will be intensively monitored during the 
conduct of the study to rapidly diagnose COVID-19 and referred for treatment according to 
local site procedures, if applicable. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 21 / 109 
 
Participant who report at least one of the above-mentioned symptoms during the study, must 
contact the study team. In case of confirmed COVID-19 symptoms Participants will be tested 
on site by a validated test.  
In case of a negative test result, Participants will be invited for a second confirmatory test on 
site after 2 days. In the event the result is still negative, the Participant will continue with 
scheduled visits. 
If either or both tests are positive, the participant will be performing a COVID-19 illness visit at 
site. Where supported, home or mobile visits may be substituted for this site visit. As part of these 
visits, samples (a saliva sample and blood samples) will be taken for antigen and antibody 
assessment as well as recording of COVID-19-related clinical and laboratory information. During 
the Booster Phase, saliva samples will not be collected in line with the schedule of assessment 
(section 22.3) 
Participant should continue for 14 days after symptoms onset or until resolution of the COVID-
19 episode, whichever comes last, with the home-collection self-swab kit every 2 days. 
Resolution of COVID-19 is defined as having 2 consecutive SARS-CoV-2 negative swabs 
and 2 consecutive days with no COVID-19 related signs and symptoms.  
All confirmed COVID-19 episodes will be communicated to the respective participant and to other 
authorities according to local regulations. In addition, participants will be educated about current 
applicable public health guidance for confirmed COVID-19 cases. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 22 / 109 
 
6. TABLE OF CONTENTS 
1. PROTOCOL SIGNATURE PAGE ............................................................................... 2 
2. STUDY PERSONNEL ................................................................................................. 3 
2.1 Study Organization ................................................................................................................ 3 
3. SERIOUS ADVERSE EVENT REPORTING ............................................................... 4 
4. PREGNANCY REPORTING ....................................................................................... 5 
5. CLINICAL STUDY SYNOPSIS ................................................................................... 6 
6. TABLE OF CONTENTS ............................................................................................ 22 
7. LIST OF ABBREVIATIONS ...................................................................................... 27 
8. INTRODUCTION ....................................................................................................... 29 
8.1 Clinical Condition/Indication ................................................................................................ 29 
8.1.1 Transmission, Disease and Diagnosis ........................................................................................ 29 
8.1.2 Prospects for Vaccine Development ........................................................................................... 30 
8.2 Valneva’s Candidate Vaccine .............................................................................................. 31 
8.3 Findings From Nonclinical and Clinical Studies .................................................................. 32 
8.3.1 Non-clinical Summary ................................................................................................................. 32 
8.3.2 Clinical Summary ........................................................................................................................ 32 
8.4 Study Rationale ................................................................................................................... 32 
8.4.1 Possible Benefits for Participant ................................................................................................. 33 
8.4.2 Possible Benefits for Society ....................................................................................................... 34 
8.4.3 Possible Risks/Inconveniences for the Participant ...................................................................... 34 
9. STUDY PURPOSE AND OBJECTIVES ................................................................... 36 
9.1 Study Purpose ..................................................................................................................... 36 
9.2 Primary Objective ................................................................................................................ 36 
9.3 Secondary Objectives.......................................................................................................... 36 
9.4 Exploratory Objective .......................................................................................................... 36 
10. STUDY DESIGN ..................................................................................................... 37 
10.1 Overall Study Design ......................................................................................................... 37 
10.1.1 Part A ........................................................................................................................................ 37 
10.1.2 Part B ........................................................................................................................................ 38 
10.1.3 Part C (Booster phase) ............................................................................................................. 38 
10.2 Study Duration ................................................................................................................... 38 
10.3 Study Endpoints ................................................................................................................ 39 
10.3.1 Safety Endpoint ......................................................................................................................... 39 
10.3.1.1 Primary Endpoint ............................................................................................................... 39 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 23 / 109 
 
10.3.1.2 Secondary Endpoints ........................................................................................................ 39 
10.3.2 Immunogenicity Endpoints ........................................................................................................ 40 
10.3.2.1 Primary Endpoint ............................................................................................................... 40 
10.3.2.2 Secondary Endpoints ........................................................................................................ 40 
10.3.2.3 Exploratory Endpoint ......................................................................................................... 41 
10.4 Justification for Study Design and Dosage ....................................................................... 41 
10.4.1 Selection of Study Population ................................................................................................... 42 
10.5 Randomisation and Blinding .............................................................................................. 42 
10.5.1 Blinding Process ....................................................................................................................... 43 
10.5.2 Unblinding ................................................................................................................................. 43 
10.6 Study stopping criteria ....................................................................................................... 43 
10.6.1 During staggered dose escalation period: ................................................................................. 44 
10.6.2 During entire study period: ........................................................................................................ 44 
11. PARTICIPANT SELECTION, WITHDRAWAL AND DISCONTINUATION .............. 46 
11.1 Inclusion Criteria ................................................................................................................ 46 
11.2 Exclusion Criteria ............................................................................................................... 48 
11.3 Delay Criteria ..................................................................................................................... 51 
11.4 Pregnancy Testing and Birth Control ................................................................................ 52 
11.5 Participant Withdrawal or Discontinuation ......................................................................... 53 
11.6 Lost to Follow-up ............................................................................................................... 55 
11.7 Re-screening of Participants ............................................................................................. 55 
12. INVESTIGATIONAL MEDICINAL PRODUCT......................................................... 56 
12.1 Description of VLA2001 ..................................................................................................... 56 
12.2 IMP Labelling & Packaging ............................................................................................... 57 
12.3 IMP Storage ....................................................................................................................... 57 
12.3.1 VLA2001 Storage ...................................................................................................................... 57 
12.3.2 Dispensing and Accountability of Investigational Medicinal Product ......................................... 58 
13. STUDY PROCEDURES .......................................................................................... 59 
13.1 Informed Consent and Enrolment ..................................................................................... 59 
13.2 Participant Identification Code ........................................................................................... 59 
13.3 Investigational Treatment .................................................................................................. 59 
13.3.1 Description of Treatment ........................................................................................................... 59 
13.3.2 Vaccine Preparation and Administration ................................................................................... 59 
13.3.3 Post- Vaccination Observation .................................................................................................. 61 
13.4 Screening and Study Visits ............................................................................................... 61 
13.4.1 Unscheduled Visit ..................................................................................................................... 62 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 24 / 109 
 
13.4.2 Early Termination Visit .............................................................................................................. 63 
13.5 Procedures for Monitoring Participant Compliance ........................................................... 64 
14. ASSESSMENT OF IMMUNOGENICITY ................................................................. 64 
14.1 Additional Testing Procedures .......................................................................................... 65 
15. ASSESSMENT OF SAFETY ................................................................................... 66 
15.1 Definitions .......................................................................................................................... 66 
15.1.1 Adverse Events ......................................................................................................................... 66 
15.1.2 Serious Adverse Event .............................................................................................................. 66 
15.1.3 Adverse Events of Special Interest ........................................................................................... 67 
15.1.4 Medically-Attended Adverse Event ........................................................................................... 67 
15.1.5 Pre-existing Diseases ............................................................................................................... 67 
15.1.6 Untoward Medical Occurrences Not Considered Adverse Events ............................................ 67 
15.2 Collection, Documentation and Assessment of Adverse Events ...................................... 67 
15.2.1 Unsolicited Adverse Events ...................................................................................................... 67 
15.2.1.1 Severity ............................................................................................................................. 68 
15.2.1.2 Causality ........................................................................................................................... 69 
15.2.2 Assessment and Outcome of Adverse Events .......................................................................... 70 
15.2.3 Solicited Adverse Events .......................................................................................................... 70 
15.2.3.1 Injection Site Reaction – Measurement and Evaluation .................................................... 71 
15.2.3.2 Systemic Reactions – Measurement and Evaluation ........................................................ 71 
15.2.3.3 Fever and Body Temperature ........................................................................................... 72 
15.2.4 Assessment of Symptoms Relating to SARS-CoV-2 ................................................................. 72 
15.2.5 Procedures in the Event of COVID-19 like Signs and Symptoms ............................................. 73 
15.3 Electronic Diary ................................................................................................................. 74 
15.4 Medical, Medication, and Non-Drug Therapy History ....................................................... 75 
15.4.1 Medical history .......................................................................................................................... 75 
15.4.2 Concomitant Medications and Non-Drug Therapies.................................................................. 75 
15.5 Vital Signs .......................................................................................................................... 77 
15.6 Physical Examinations....................................................................................................... 78 
15.7 Clinical Laboratory Parameters ......................................................................................... 78 
15.8 Saliva Samples .................................................................................................................. 80 
15.9 Case Definitions ................................................................................................................ 80 
15.10 Adverse Events of Special Interest ................................................................................. 82 
15.11 Adverse Event Reporting Procedures ............................................................................. 82 
15.11.1 Serious Adverse Event ............................................................................................................ 82 
15.11.2 Pregnancy ............................................................................................................................... 83 
15.11.3 Data Safety Monitoring Board ................................................................................................. 84 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 25 / 109 
 
15.11.4 Sponsor ................................................................................................................................... 85 
15.11.5 Investigator ............................................................................................................................. 85 
16. STATISTICS ........................................................................................................... 86 
16.1 Sample Size and Power Calculations ............................................................................... 86 
16.2 Datasets and Analysis Cohorts ......................................................................................... 86 
16.3 Handling of Missing, Unused, and Spurious Data ............................................................. 87 
16.4 Methods of Analysis .......................................................................................................... 87 
16.4.1 Primary Safety Endpoint ........................................................................................................... 88 
16.4.2 Primary Immunogenicity Endpoint ............................................................................................. 88 
16.4.3 Secondary Endpoints ................................................................................................................ 88 
16.4.3.1 Secondary Safety Endpoints ............................................................................................. 88 
16.4.3.2 Secondary Immunogenicity Endpoints .............................................................................. 88 
16.4.4 Exploratory Endpoints ............................................................................................................... 89 
16.5 Planned Data Analysis of the Study .................................................................................. 89 
16.6 Clinical Study Report ......................................................................................................... 89 
17. ETHICS AND REGULATORY ASPECTS ............................................................... 90 
17.1 Compliance Statement ...................................................................................................... 90 
17.2 Ethics Committee and Regulatory Authorities ................................................................... 90 
17.3 Participant Information and Informed Consent .................................................................. 90 
18. QUALITY CONTROL AND QUALITY ASSURANCE ............................................. 91 
18.1 Source Data and Records ................................................................................................. 91 
18.2 Investigator’s Responsibility .............................................................................................. 91 
18.3 Training .............................................................................................................................. 91 
18.4 Monitoring .......................................................................................................................... 92 
18.5 Audit and Inspection .......................................................................................................... 92 
18.6 Non-Compliance with the Protocol/Deviations from the Protocol ..................................... 92 
18.7 Confidentiality of Participant’s Data ................................................................................... 92 
19. DATA HANDLING AND RECORD KEEPING ......................................................... 92 
19.1 Information of Investigators ............................................................................................... 92 
19.2 Electronic Case Report Forms .......................................................................................... 93 
19.2.1 Data Recorded Directly on Case Report Forms ........................................................................ 93 
19.2.2 Electronic Case Report Form Entries ........................................................................................ 93 
19.2.3 Changes to Electronic Case Report Form Data ........................................................................ 93 
19.2.4 Electronic Case Report Form Entry Validation .......................................................................... 93 
19.2.5 Data Collection .......................................................................................................................... 94 
19.3 Coding of Adverse Events, Drugs and Diseases .............................................................. 94 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 26 / 109 
 
19.4 Investigator File ................................................................................................................. 94 
19.4.1 Maintenance ............................................................................................................................. 94 
19.4.2 Archiving and destruction .......................................................................................................... 94 
19.4.3 Provision of Additional Information ............................................................................................ 94 
20. PUBLICATION POLICY ......................................................................................... 95 
21. LIABILITIES AND INSURANCE ............................................................................. 95 
22. SUPPLEMENTS ..................................................................................................... 96 
22.1 Study Flow Chart ............................................................................................................... 96 
22.2 Schedule of Study Procedures and Assessments ............................................................ 97 
22.3 Toxicity Grading Scale for Abnormal Laboratory Assessments ...................................... 101 
22.4 Adverse Events of Special Interest ................................................................................. 103 
23. REFERENCES ...................................................................................................... 105 
 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 27 / 109 
 
7. LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ANOVA 
Analysis of variance 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
CFR 
Case fatality ratio 
CI 
Confidence interval 
CpG 
Cytosine phospho-guanine 
COVID-19 
Coronavirus-induced disease 2019 
CRA 
Clinical research associate 
CRO 
Contract research organisation 
CRP 
C-reactive protein 
CSR 
Clinical study report 
DSMB 
Data and safety monitoring board 
EC 
Ethics committee 
eCRF 
Electronic case report form 
ELISA 
Enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
ET 
Early termination (visit) 
ESR 
Erythrocyte sedimentation rate 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMFI 
Geometric mean fold increase 
GMT 
Geometric mean titre 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation  
IMP 
Investigational medicinal product 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 28 / 109 
 
Abbreviation 
Definition 
ITT 
Intent-to-treat (population) 
IXRS 
Interactive Voice/Web Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
NHS 
National Health Service 
NHP 
Non Human Primate 
PP 
Per-protocol population 
PBMC 
Peripheral blood Mononuclear Cell 
PPAS 
Per-Protocol Analysis Set 
PRNT 
Plaque reduction neutralization test 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus-2 
SOP 
Standard operating procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
Th 
T helper cell 
UK 
United Kingdom 
WBC 
White blood cell 
 
 
 
 
 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 29 / 109 
 
8. INTRODUCTION 
8.1 Clinical Condition/Indication  
8.1.1 Transmission, Disease and Diagnosis 
Since December 2019, coronavirus-induced disease 2019 (COVID-19) has spread around 
the world, with over 24 million confirmed cases as of the 27 Aug 2020 
(https://coronavirus.jhu.edu/, accessed 28 Aug 2020). SARS-CoV-2 was initially isolated and 
the genome was published internationally by Chinese scientists on January 10, 2019. SARS-
CoV-2 is the seventh member of the family of coronaviruses to infect humans. Novel 
coronaviruses from Wuhan, together with two bat-derived SARS-like strains, form a distinct 
clade in lineage B of the subgenus Sarbecovirus. SARS-CoV-2 is a group 2b coronavirus 
(as are MERS-CoV and SARS-CoV), with a whole genome similarity of up to 80% to SARS-
CoV (Yang and Leibowitz, 2015). SARS-CoV-2 is an enveloped, non-segmented, positive 
sense RNA virus. Structurally, SARS-CoV-2 has four main structural proteins, which are 
conserved across coronaviruses; namely the spike glycoprotein, small envelope 
glycoprotein, membrane glycoprotein, and nucleocapsid protein, along with several 
accessory proteins. The spike protein facilitates binding of envelope viruses to host cells by 
attraction with angiotensin-converting enzyme 2 (ACE2) expressed in lower respiratory tract 
cells. (Astuti and Ysrafil, 2020). 
Human infection is characterized by an incubation period of 2 to 7 days (typically 5 days 
across many studies), up to a maximum of 14 days. Symptoms of COVID-19 are non-specific 
and the disease presentation can range from no symptoms (asymptomatic) to severe 
pneumonia and death. Common symptoms include fever, cough, dyspnoea, myalgia, 
fatigue, sputum, haemoptysis and diarrhoea. Lymphocytopenia and pneumonia are also 
common (Chaolin et al, 2020; Guan et al, 2020). In a study of 41 patients, complications 
included acute respiratory distress syndrome (29%), acute heart injury (12%), and secondary 
infections (10%); 32% of patients required treatment in the intensive care unit (Chaolin et al, 
2020). In an analysis of 1099 confirmed cases, 25.2% of patients had at least one underlying 
disease (such as hypertension, chronic obstructive pulmonary disease). On admission, 50% 
of the patients presented ground-glass shadow on a chest computed tomography scan 
(Guan et al, 2020). Recent studies indicate that patients ≥ 60 years of age are at higher risk 
than children (Li et al, 2020a; Wang et al, 2020). Up to 5% of patients with COVID-19 
developed acute respiratory distress syndrome (Wang et al, 2019) (Li et al, 2020a) (Guan et 
al, 2019). According to the World Health Organisation (WHO), 10% to 15% of patients aged 
≤ 50 years’ experience moderate to severe infection. Recovery time is about 2 weeks for 
persons with mild disease and 3 to 6 weeks for persons with severe or critical disease, based 
on Chinese Centers of Disease Control and Protection data and the current U.S. experience 
in California and Washington.  

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 30 / 109 
 
Analysis of the first 55,924 laboratory confirmed COVID-19 cases in China showed that 
mortality increases with age, with the highest mortality among people over 80 years of age 
(case fatality ratio [CFR] 21.9%). The CFR was higher among males than females (4.7% vs. 
2.8%). The CFR was much higher in patients with comorbidities (CFR 7.6% to 13.2%) than 
those without (CFR 1.4%). (WHO, 2020) Similar results were found in a study analysing 
17,425,445 adults in the UK between 01 February and 25 April 2020. In total 5683 deaths 
were attributed to COVID-19 (Williamson et al, 2020).  
It is not known if SARS-CoV-2 will remain as worldwide pandemic. It is also not known if 
immunity is acquired after symptomatic or asymptomatic SARS-CoV-2 infection and how 
long it might last.  
No antiviral treatment is currently available for human and animal coronavirus. General 
strategies for clinical management include bed rest and supportive treatment, including 
antiviral therapy (Arabi et al, 2018), antibiotic application, immunomodulating therapy (Arabi 
et al, 2020), organ function support, respiratory support, bronchoalveolar lavage, blood 
purification and extracorporeal membrane oxygenation (ECMO; Wang et al, 2020; Zumla et 
al, 2020). 
For detailed information on the disease and epidemiology please refer to the Investigator’s 
Brochure. 
8.1.2 Prospects for Vaccine Development 
More than 140 SARS-CoV-2 vaccine candidates are currently under preclinical 
development; an additional 24 are in clinical development. Vaccine candidates include 
inactivated whole virus vaccine compositions, protein subunit, viral vector, virus-like-particle 
approaches to RNA and DNA vaccine candidates (WHO, 2020). 
Two Chinese companies, Sinovac and Sinopharm, launched phase III studies of their 
inactivated virus vaccine candidates in Brazil and the United Arab Emirates. Sinovac’s 
vaccine candidate, a whole virus grown in Vero cells which is inactivated by ß-propiolactone 
and adjuvanted with aluminium hydroxide, was tested in phase I/II studies in 743 healthy 
volunteers. The incidence rate of adverse reactions (15.0% among all participants) was lower 
compared with results of other candidate vaccines using other platforms (other platforms 
mostly >60%, some even 100%). No vaccine-related serious adverse events had been 
observed (Xia et al. 2020). 
 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 31 / 109 
 
The epidemic nature of SARS-CoV-19 has to date resulted in more than 46 million infected 
people and over 1,2 million deaths and is a serious threat to global health 
(https://coronavirus.jhu.edu, accessed on 2 November 2020). Research is focused on the 
urgent demand to identify an effective treatment and to develop effective prophylaxis. The 
goal is to reduce the overall vaccine development process from an average of 10–15 years 
to 1-2 years. To enable this rapid development, several vaccine approaches need to be 
tested in parallel in clinical studies, using standardized protocols for vaccine evaluation. 
Furthermore, development of manufacturing processes to enable rapid production of large 
quantities of high-quality clinical grade and GMP materials is of great importance. (WHO, 
2020). Taken together, this provides strong justification for the development of a vaccine. 
8.2 Valneva’s Candidate Vaccine 
VLA2001 is a highly-purified, whole virus, SARS-CoV-2 vaccine produced on Vero cells and 
inactivated with β-propiolactone.  
VLA2001 viral strain is derived from a Chinese tourist from Hubei diagnosed in a hospital in 
Rome (Stefanelli et al, 2020).  
VLA2001 is adjuvanted with the licensed adjuvant cytosine phospho-guanine (CpG) 1018 
(produced by Dynavax, contained in HEPLISAV-B®) in combination with aluminium 
hydroxide.  
VLA2001 has been developed using the same manufacturing platform as that used for the 
commercial vaccine IXIARO®, a purified, inactivated, whole virus, aluminium hydroxide-
adjuvanted Japanese encephalitis vaccine that has been approved by regulatory authorities 
worldwide (including the Food and Drug Administration [FDA], European Medicines Agency 
[EMA] and Therapeutic Goods Administration). It is similar in composition to VLA2001, with 
a good safety profile consistent with findings from pre-licensure clinical studies. As of April 
2017, 2,532,480 Participants worldwide have been vaccinated with IXIARO (IXIARO clinical 
review memorandum, 2018). 
VLA2001 has demonstrated excellent purity and overall a biological, chemical and physical 
profile comparable to that of IXIARO®. 
A detailed description of the vaccine and the mechanism of action can be found in the 
Investigator’s Brochure. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 32 / 109 
 
8.3 Findings from Nonclinical and Clinical Studies 
8.3.1 Non-clinical Summary 
VLA2001 was immunogenic in mice and non-human primates. In mice, an increase in 
immunogenicity (dose sparing effect) was observed when CpG 1018 was used together with 
Aluminium Hydroxide in preclinical studies with VLA2001. A strong Th1 response may be 
important to minimize potential risks for vaccine mediated enhanced respiratory disease 
(VAED) or antibody disease enhancement (ADE) upon infection. A strong Th2 response has 
been implicated with VAED or ADE for other viruses. The presence of CpG 1018 skewed 
the immune response in mice after immunization with VLA2001 towards a pronounced Th1 
response which mitigates this at the moment theoretical concern. 
Cynomolgus macaques immunized with VLA2001 were protected from a combined 
intranasal and tracheal challenge with SARS-CoV-2. SARS-CoV-2 genomic RNA could 
transiently be detected in immunized macaques on day 2 post infection at a very low level in 
nasoparyngeal and tracheal swabs, but not at all in BAL. Subgenomic SARS-CoV-2 RNA 
was not detectable at all, neither in nasopharyngeal and tracheal swabs, nor in BAL. For 
further details please refer to the Investigator’s Brochure. 
8.3.2 Clinical Summary 
VLA2001-201 is the first clinical study that is currently ongoing.  
For further information on the expected clinical profile of VLA2001, please refer to the 
Investigator’s Brochure. 
8.4 Study Rationale 
This phase I/II clinical study will be the first study using the SARS-CoV-2 vaccine candidate 
VLA2001 in humans. Valneva´s vaccine virus is produced using an established antigen 
production process. The whole virus is produced on Vero cells and then the antigen 
undergoes inactivation with β-propiolactone to ensure that surface protein conformation 
remains intact. Therefore, Valneva anticipates that its candidate vaccine will induce 
protective antibody responses with specificity to a variety of antigenic virus targets. The 
vaccine is adjuvanted with CpG 1018 plus aluminium hydroxide. This combination has shown 
encouraging results from another vaccine candidate (in combination with S-Trimer antigen 
from SARS-CoV-2, Liang et al. 2020). In non-human primates challenged with SARS-CoV-
2, there was an absence of measurable viral load in lung tissue as well as other clinical 
measures, and in rodents a Th1-polarized T cell response was observed. For both adjuvants 
an extensive safety databases exists as they are contained in already licensed vaccines.  

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 33 / 109 
 
VLA2001 was immunogenic in mice and an increase in immunogenicity (dose sparing effect) 
was observed when CpG 1018 was used together with alum. The presence of CpG 1018 
skewed the immune response towards a pronounced Th1 response. A strong Th1 response 
is important to minimize potential risks for enhanced respiratory disease (ERD) or antibody 
disease enhancement (ADE) upon infection. One potential cause for ERD or ADE is a strong 
Th2 response. In addition, neutralizing antibodies could be measured at the highest 
immunization dose (3.0 AU) in the presence of CpG 1018, the measured neutralizing titre 
was in a similar range as the neutralizing titre determined for the plasma pool derived from 
convalescent donors. 
Due to extensive experience with other inactivated whole-virus vaccine candidates, the 
established production process and the use of adjuvants already included in other licensed 
vaccine Valneva considers the risk for safety concerns to be limited. 
8.5 Rationale and Justification for the Booster Phase. 
Following the successful completion of the Part A primary analysis (Day 36), the high dose 
was found to be the optimal dose as defined in the primary objective of the study. Based on 
the assessed comparable safety and superior immunogenicity results at Day 36, the high 
dose has been selected for further clinical development. Valneva has decided to extend the 
VAL2001-201 study, by investigating the effects of a Booster dose at 8-9 months after 
completion of the primary immunization schedule with VLA2001. The booster dose will be 
offered to all participants who do not meet an exclusion criteria regardless of their initial 
response to the primary immunization schedule in the different dose groups. Hence, the 
effect of a booster dose will be studied in a population with different levels of pre-existing 
antibody levels against SARS-CoV-2. 
8.5.1 Possible Benefits for Participant 
This is a first-in-human study, therefore the clinical benefits of VLA2001 have not yet be 
established. The overall benefit and risk balance for individual participants in the study 
cannot be ascertained. 
An initial analysis of the data up to Day 36 from this study has shown that VLA2001 is 
generally safe and well tolerated across all dose groups tested, with no safety concerns 
identified by an independent Data Safety Monitoring Board. There were no statistically 
significant differences between dose groups and no differences between first and second 
vaccinations in terms of reactogenicity. The majority of Adverse Events (AEs) were mild or 
moderate and only two subjects reported severe solicited AEs (headache and fatigue). The 
majority of solicited AEs resolved quickly. VLA2001 was fund to be highly immunogenic with 
more than 90% of all study participants developing significant levels of antibodies to the 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 34 / 109 
 
SARS-CoV-2 virus spike protein across all dose groups tested.  In the high dose group which 
is the selected as the optimum dose, the GMT of neutralizing antibodies antibody titers 
measured 2 weeks after completion of the 2-dose schedule was at or above levels for a 
panel of convalescent sera. 
8.5.2 Possible Benefits for Society  
SARS-CoV-2 has a high infection rate and has the potential to cause serious illness, 
especially in older populations and those people who are immunocompromised. A vaccine 
for SARS-CoV-2 will help reduce the severe and unprecedented disruption the pandemic 
has caused to people’s lives worldwide. It will reduce the burden of healthcare services that 
had to find extra resources to care for critically ill COVID-19 patients and will also reduce the 
risk to frontline workers of contracting the virus. The pandemic has had a huge economic 
impact globally, forcing many businesses to close and people to isolate or shield indoors to 
prevent the spread of the virus. Many people have lost their jobs as a result. Businesses 
have been burdened by the extra cost of disinfectant, plastic shields, social distancing (fewer 
customers) and personal protective equipment. An effective vaccine will help ameliorate 
these global impacts. 
8.5.3 Possible Risks/Inconveniences for the Participant 
In general, risks associated with vaccination with an inactivated virus vaccine are considered 
low and several inactivated whole virus vaccines, such as Japanese encephalitis vaccine 
IXIARO, have been shown to have an excellent safety profile (Ishikawa et al, 2014; Amicizia 
et al, 2013). 
VLA2001 has been developed using the same Vero cell platform as that used for IXIARO. 
An acceptable safety profile was demonstrated for IXIARO in seven randomised, controlled 
studies with a total safety database of 3,945 healthy adults. The most common adverse 
reactions in adults across all studies were headache, myalgia, injection site pain, and 
injection site tenderness. No specific safety signals (including hypersensitivity reactions and 
neurologic disorders) were identified for IXIARO through clinical studies and post-marketing 
pharmacovigilance (IXIARO clinical review memorandum, 2018).  
Five clinical studies have been performed using hepatitis B virus vaccine HEPLISAV-B with 
CpG 1018 as the adjuvant; 9597 individuals aged 18–70 years received at least one dose of 
treatment. Reported AEs included injection site pain, injection site redness, injection site 
swelling, fatigue, headache, malaise and fever. No causal relationship was found between 
myocardial infarctions/deaths and HEPLISAV-B/CpG 1018. Five Participants had potentially 
immune-mediated AEs; granulomatosis, polyangiitis, lichen planus, Guillain-Barré 
Syndrome and Graves’ disease. No causal relationship was found between autoimmune 
AEs and HEPLISAV-B/CpG 1018 (HEPLISAV-B SmPC). 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 35 / 109 
 
The possibility of Participants experiencing headache, myalgia, injection site pain, and 
injection site tenderness and potentially immune-mediated AEs cannot be ruled out. 
The likelihood of a Participant to experience a vaccine-associated enhanced disease (VAED) 
following administration of VLA2001 is considered low but cannot be excluded. 
Vaccine-induced enhancement of disease has also been described for SARS-CoV and 
MERS-CoV in animal models, but proof of human SARS-CoV or MERS-CoV vaccine 
associated enhanced disease does not exist as these candidate vaccines were never tested 
for efficacy nor used in outbreak situations. For SARS and MERS, the mechanism of 
enhanced disease observed in mice has been associated with a Th2-mediated eosinophilic 
infiltration in the lung, which is reminiscent of ERD effects observed after RSV infection of 
mice immunized with RSV. While vaccine-associated enhanced disease was observed in 
nonclinical studies with experimental SARS and MERS vaccines, it is not a given that the 
same risk applies to COVID-19 vaccines. To the sponsor’s knowledge, antibody-related 
COVID-19 disease enhancement has not been observed in nonclinical models yet. In 
addition, vaccine mediated disease enhancement was not observed in phase I/II studies of 
other whole virus inactivated SARS-CoV-2 vaccine candidates (Xia et al 2020).  
Participants in the present study will be informed of the theoretical risk of disease 
enhancement in the informed consent form (ICF) and as a risk mitigation strategy, all enrolled 
Participants will intensively monitored during the conduct of the study to rapidly diagnose 
COVID-19 and refer for treatment, if applicable. 
The blood draws performed during the study carry the possible risks of pain, hematoma, and 
in very rare cases an infection at the venepuncture site. 
After vaccination Participants will remain at the study site for close observation by study team 
to monitor development of any acute reactions. The first 5 Participants of the three dosing 
groups (sentinel testing group) will remain under observation for at least 60 minutes after 
vaccination to monitor development of acute reactions. If at Day 4 safety review (DSMB) of 
these initial Participants no acute reactions have been observed, the observation time at the 
study site for the remaining 135 Participants in the study may be reduced to at least 30 
minutes.  
Necessary emergency equipment and medications must be available at the study site to 
treat severe allergic reactions. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 36 / 109 
 
9. STUDY PURPOSE AND OBJECTIVES 
9.1 Study Purpose 
The purpose of this study is to evaluate the tolerability, safety and immunogenicity of 
VLA2001 and to optimise the dose for phase II and III studies. Immunogenicity will be 
investigated in a larger study sample after safety has been demonstrated in this combined 
phase I/II study.  
This study is being extended to investigate the tolerability, safety and immunogenicity of a 
booster vaccination with VLA2001. 
9.2 Primary Objective 
 
The primary objective of this study is to evaluate the tolerability, safety and 
immunogenicity of the inactivated, adjuvanted SARS-CoV-2 vaccine candidate VLA2001 
up to 14 days after completion of a two-dose primary immunization schedule in healthy 
adults aged 18 to 55 years.  
9.3 Secondary Objectives 
1) To determine the optimal dose level of inactivated, adjuvanted SARS-CoV-2 vaccine 
candidate VLA2001 in healthy adults aged 18 to 55 years.  
2) To evaluate tolerability, safety and immunogenicity of the inactivated, adjuvanted SARS-
CoV-2 vaccine candidate VLA2001 up to 6 months after the last vaccination in healthy 
adults aged 18 to 55 years. 
3) To evaluate tolerability, safety and immunogenicity of a booster dose with vaccine 
candidates VLA2001 in healthy adults aged 18 to 55 years. 
9.4 Exploratory Objective 
 
To evaluate cellular immune response after vaccination with the inactivated, adjuvanted 
SARS-CoV-2 vaccine candidates VLA2001 after completion of a two-dose primary 
immunization schedule and after a booster vaccination. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 37 / 109 
 
10. STUDY DESIGN 
10.1 Overall Study Design  
This is a first-in-human phase I/II study that will evaluate three dose levels of VLA2001 (low, 
medium, high) for safety, tolerability and immunogenicity in a two-dose schedule in a healthy 
young adult population aged 18 to 55 years. 
The study will be a randomised, double-blind, dose-escalation, multicentre study with three 
dose groups and 50 Participants recruited to each dose group. The study is conducted in 
three parts. Part A (Day 1 to Day 36), Part B (Day 37 to Day 208) followed by the Booster 
Phase: Part C (Visits 7 to 10). 
Following an evaluation of Part A data (i.e. data up to Day 36) from the present study, further 
clinical studies will be initiated. 
The study design for Study VLA2001-201 is illustrated in Section 22.1. 
Assessments, including immunogenicity and solicited and unsolicited AEs, SAEs or AESIs 
will be performed at the time points specified in sections 22.2 and 22.3 (specific for Booster 
Phase) up to Visit 10 (6 months post booster). In addition, samples will be taken for later 
investigation of cellular immune responses and mucosal immune responses. 
10.1.1 Part A 
For safety reasons, the first 15 participants will be included into the study in an open-label, 
not randomized manner following a staggered dose escalation of VLA2001. Dose escalation 
will be done at a single site to ensure permanent oversight on safety data by one principal 
investigator during the recruitment of the 15 sentinel Participants.  
Dose escalation starts with the first vaccination of the first sentinel Participant in the low dose 
treatment group. After vaccination, the first Participant of a dosing group will be observed for 
the development of any acute reaction at the study site for 3 hours after the vaccination 
procedure. Prior to discharge from the study site, vital signs will be measured and the 
Participant will be instructed to use the e-Diary. The study site will contact the Participant per 
phone approximately 24 hours after vaccination to assess the safety status of the Participant. 
The provided information must be compared with the entries in the Participant´s e-Diary. The 
minimum time before the next Participants are vaccinated is therefore 24 hours. The next 4 
Participants of the same dosing group will be vaccinated at least with a one-hour interval 
between each Participant. These 4 Participants will be observed for 60 minutes at the study 
site to monitor for the development of acute reaction. Before discharge, vital signs will be 
measured and Participants will be instructed to use their e-Diaries. Safety telephone calls 
will be performed by the study site after approximately 48 hours after vaccination. After 
confirmation by the investigator that no stopping criteria (see Section 10.6) has been met, 
the procedure will be repeated with the first Participant of the next dose level. The minimum 
time before vaccination of a new dose level will be 48 hours. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 38 / 109 
 
A Data Safety and Monitoring Board (DSMB) will review the accrued safety data at Day 4 of 
all 15 sentinel Participants. After favourable DSMB review randomization of the remaining 
135 Participants across all sites will be initiated.  
The remaining 135 Participants will be enrolled, screened and randomised in a 1:1:1 fashion 
to the three dose groups in the blinded part of the study. Participants will be observed for 30 
minutes post vaccination on Day 1. An unscheduled safety telephone call will be performed 
in case a Grade 3 AE or SAE will be reported by the Participant via e-Diary. All Participants 
will be followed by e-Diary for 7 days post vaccination, starting on the day of vaccination. 
Participants will return to the study site on Day 8 (Visit 2). After (approximately) 20 
Participants per dose group have been randomised and followed up 7 days post first 
vaccination, and periodically up to Day 36 for all randomised Participants, the DSMB will 
review the accrued safety data. All Participants will receive their second vaccination on Day 
22 (Visit 3) and will be followed up on Day 36 (Visit 4), 14 days after the second vaccination. 
The DSMB will review safety and immunogenicity data up to Day 36.  
10.1.2 Part B 
All Participants will be further followed up on Day 106 (Visit 5) and Day 208 (Visit 6), 6 months 
after the second vaccination.  
10.1.3 Part C (Booster Phase) 
During their Day 208/ Month 7 (Visit 6) study visit, all eligible participants will be invited to 
take part in the Booster Phase (Part C) to investigate tolerability, safety and immunogenicity 
of a booster dose of VLA2001 (high dose).  
Due to planning considerations, all consenting participants will receive the Booster 
vaccination between mid to end September 2021 (Visit 7), this corresponds to about 8-9 
months after completing the primary vaccination series. 
Participants will be asked to return to the study site for a follow-up visit approximately two 
weeks after the booster vaccination then 1 month after the booster vaccination. Participants 
will be followed-up for safety during a phone call approximately 6 months after the booster 
vaccination.  
A scheduled DSMB review will be performed once all vaccinated Participants have 
completed their Visit 7. Additional safety data review will occur when necessary (ad-hoc) as 
defined in the DSMB Charter. A final review of generated safety data will be performed by 
the DSMB once all participants have completed this clinical study. 
 
10.2 Study Duration 
The overall study duration (First Participant In [FSI] –Last Participant Out [LSO]) is estimated 
to be approximately 16 months. Individual Participant participation is approximately 15 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 39 / 109 
 
months from enrolment (i.e. Informed Consent signed) to study completion unless the study 
is prematurely discontinued.  
Part A of the study will be completed when the last Participant has completed Day 36 
(14 days after the second vaccination). Part B of the study will be completed when the last 
Participant has completed Day 208 (6 months after the second vaccination). The Booster 
Phase (Part C) will be completed when the last participant has completed the safety follow-
up call 6 months (Visit 10) after the Booster vaccination.  
10.3 Study Endpoints 
10.3.1 Safety Endpoint 
10.3.1.1 Primary Endpoint 
 
Frequency and severity of solicited AEs (local and systemic reactions) within 7 days after 
any vaccination of the primary vaccination series.  
10.3.1.2 Secondary Endpoints 
The following secondary tolerability and safety endpoints will be determined: 
 
Frequency and severity of any unsolicited AE until Day 36. 
 
Frequency and severity of any vaccine-related AE until Day 36. 
 
Frequency and severity of any AE until Day 208. 
 
Frequency and severity of any vaccine-related AE until Day 208. 
 
Frequency and severity of any SAE until Day 36. 
 
Frequency and severity of any AESI until Day 36. 
 
Frequency and severity of any SAE until Day 208. 
 
Frequency and severity of an AESI until Day 208. 
Booster Phase: 
 
Frequency and severity of solicited AEs (local and systemic reactions) within 7 days after 
the booster vaccination 
 
Frequency and severity of any unsolicited AE up to Visit 9 
 
Frequency and severity of any vaccine-related AE up to Visit 9 
 
Frequency and severity of any SAE up to Visit 10 
 
Frequency and severity of any AESI up to Visit 10 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 40 / 109 
 
 
10.3.2 Immunogenicity Endpoints 
10.3.2.1 Primary Endpoint 
 Geometric mean titre (GMT) for neutralizing antibodies against SARS-CoV-2 determined 
by wild-type virus neutralizing assay at Day 36. 
10.3.2.2 Secondary Endpoints 
The following secondary immunogenicity endpoints will be evaluated: 
 
Immune response as measured by neutralizing antibody titres against SARS-CoV-2 on 
Day 8, Day 22, Day 106 and Day 208  
 
Proportion of Participants with seroconversion on Day 8, Day 22, Day 36, Day 106 and 
Day 208, in Participants negative for SARS-CoV-2 at Screening 
 
Fold increase of SARS-CoV-2 neutralizing antibody titres on Day 8, Day 22, Day 36, Day 
106 and Day 208 compared with baseline 
 
GMTs for IgG against SARS-CoV-2, determined by ELISA, at Day 1, 8, 22, 36, 106, and 
208. 
 
Proportion of Participants with seroconversion in terms of IgG antibodies against SARS-
CoV-2 as determined by ELISA on Day 8, Day 22, Day 36, Day 106 and Day 208. 
Booster Phase: 
 
Geometric mean fold rise (GMFR) from pre-booster time point (Visit 7) to 2 weeks after 
booster dose (Visit 8) with regards to neutralizing antibodies.  
 
Geometric mean fold rise (GMFR) from pre-booster time point (Visit 7) to 4 weeks after 
booster dose (Visit 9) with regards to neutralizing antibodies.  
 
Proportion of Participants with 4-fold increase from pre-booster dose (Visit 7) to 2 weeks 
after booster dose (Visit 8) with regards to neutralizing antibodies.  
 
Proportion of Participants with 4-fold increase from pre-booster dose (Visit 7) to 4 weeks 
after booster dose (Visit 9) with regards to neutralizing antibodies.  
 
Geometric mean titres (GMT) measured as neutralizing antibody titres against SARS-
CoV-2 at Visit 7, Visit 8 and Visit 9. 
 
Geometric mean fold rise (GMFR) from pre-booster dose (Visit 7) to 4 weeks after 
booster dose (Visit 9) with regards to S-protein binding antibodies (ELISA).  
 
Geometric mean fold rise (GMFR) from pre-booster dose (Visit 7) to 2 weeks after 
booster dose (Visit 8) with regards to S-protein binding antibodies (ELISA).  

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 41 / 109 
 
 
Proportion of Participants with 4-fold increase from pre-booster dose (Visit 7) to 4 weeks 
after booster dose (Visit 9) in regards to S-protein binding antibodies (measured by 
ELISA).  
 
Proportion of Participants with 4-fold increase from pre-booster dose (Visit 7) to 2 weeks 
after booster dose (Visit 8) in regards to S-protein binding antibodies (measured by 
ELISA).  
 
GMT measured as IgG antibodies against SARS-CoV-2, as determined by ELISA, at 
Visit 7, Visit 8 and Visit 9. 
 
10.3.2.3 Exploratory Endpoint 
 
Cellular immune response on Day 1, Day 36, Day 208 and Visit 7 and Visit 8.  
 
10.4 Justification for Study Design and Dosage  
This phase I/II study is designed as a blinded, randomised, multicentre study to evaluate the 
safety, 
tolerability 
and 
immunogenicity 
of 
three 
dose 
levels 
of 
VLA2001.  
This study is being extended to investigate the safety, tolerability and immunogenicity of a 
booster vaccination with VLA2001. 
VLA2001 is expected to have a safety profile comparable with that of other inactivated 
vaccines such as IXIARO. However, since this is a first-in-human study with VLA2001 the 
study will, as a safety precaution, begin with enrolment of 15 sentinel Participants (5 
Participants per dosing group). This open-label dose escalation will be done at a single site 
to ensure permanent oversight on safety data by one principal investigator during the 
recruitment of the 15 sentinel Participants. Dose escalation starts with the first vaccination 
of the first sentinel Participant in the low dose treatment group. If no safety concern is 
detected, four further Participants are vaccinated after 24 hours within the same treatment 
group. At least a one-hour interval must be followed between vaccinations of Participants. If 
no safety concern is identified within 48 hours after vaccination, vaccinations in the medium 
dose level are initiated. Again only one Participant will receive the first medium-dose 
vaccination, if no safety concerns are identified, another four Participants will be enrolled 
after 24 hours in the same treatment group. The same process will be followed for the high-
dose treatment group. Each of the 15 sentinel Participants will be observed on-site for at 
least 60 minutes following vaccination. 
A Data Safety and Monitoring Board (DSMB) will review the accrued safety data after the 
sentinel Participants of the high dose group have passed their 3-days post vaccination time 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 42 / 109 
 
point before randomization of further Participants across all sites will be initiated. The part of 
the study will be conducted double-blind in order to limit the introduction of a safety bias by 
the Participants and/or Investigator’s staff performing medical safety assessments. 
10.4.1 Selection of Study Population 
The study will randomize approximately 150 healthy adult Participants aged 18 to 55 years. 
The proposed study population has been selected to conduct this first-in-human study in 
adults of good health. A maximum age limit of 55 years has been chosen in this first-in-
human study in order to reduce the chance of observed adverse safety outcomes that might 
be due to medical conditions that are more likely to occur in older adults and were not 
identified prior to study entry. 
10.5 Randomisation and Blinding 
The first 15 Participants will be enrolled in the study in an open-label, not randomized dose-
escalating manner. The remaining 135 Participants will be randomised in a blinded manner 
in a 1:1:1 fashion to the three dose groups on Day 1 as described in Section 10.1.  
All participants who do not meet any exclusion criteria for a booster dose will be invited to 
receive a booster dose with VLA2001. 
Each Participant will have a unique Participant screening number obtained from the 
interactive voice response system/interactive web response system (IXRS) assigned at the 
screening visit. The Investigator will keep a record (i.e. the Participant screening log) of 
Participants who entered screening. 
The IMP will be prepared by study staff in accordance with the treatment allocation provided 
in the IXRS. An overview of persons who will be (un)blinded is provided below: 
Unblinded: 
 
Fifteen sentinel Participants. 
 
Members of the DSMB. 
 
Unblinded statistician(s) at CRO (Pharm-Olam) who will be responsible for following 
tasks: 
o Generation of the randomization code list 
o Attendance of unblinded sessions of DSMB meetings 
o Generating safety data tables/listings/figures for the DSMB meetings 
 
Blinded: 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 43 / 109 
 
 
The 135 Participants in the randomised part of the study. 
 
Investigators and other site staff  
 
Biostatisticians writing the Statistical Analysis Plan and developing the statistical 
analysis. 
 
Clinical research associates (CRAs) responsible for monitoring study data. 
 
All laboratory personnel at central laboratories for safety and immunogenicity laboratory 
assessments. 
 
All other Sponsor and contract research organisation (CRO) staff not otherwise specified 
above will be unblinded as part of the Part A statistical analysis. Laboratory personnel at 
the Sponsor’s testing labs remain blinded throughout the study for additional testing 
procedures. 
10.5.1 Blinding Process 
IMP will be provided to the study sites in a blinded manner, i.e. no visual differentiation will 
be possible, same volumes will have to be administered for all dose groups. Identification of 
and allocation of the syringe to a specific Participant is ensured by placing a tear-off label 
containing a kit number, Participant number, date of injection and operator onto the label. 
Booster 
phase:  
VAL2001 vaccine will be administered as open label.  
Further details are presented in the IMP Manual. 
10.5.2 Unblinding 
The randomisation assignment is not to be revealed except in emergency cases where 
unblinding is necessary for the clinical management of an AE/SAE. In such events, the 
Investigator must either inform the Sponsor before breaking the blind or immediately after 
unblinding.  
In case of emergency, the vaccine administered to the Participants can be revealed 
through the web-response system (IXRS). 
10.6 Study stopping criteria 
The DSMB can issue a recommendation to stop the study during ad-hoc DSMB meetings, 
or to discontinue a treatment group, e.g. in response to an excess rate of AEs with the same 
suspected underlying pathological mechanism. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 44 / 109 
 
Study vaccinations will be suspended, pending DSMB review and assessment, should any 
of the following criteria be met during the course of the study: 
10.6.1 During staggered dose escalation period: 
 
One or more Participants experience an SAE or AESI with no likelier alternative cause 
than the study vaccine (i.e. related).  
 
One or more Participants experience a severe systemic allergic reaction, e.g. 
generalized urticaria or anaphylaxis within 24 hours following vaccine administration, with 
no likelier alternative cause than the study vaccine. 
 
One or more Participants experience Grade 4 local reaction at the vaccination site, 
characterized by ulceration, necrosis or any Grade 4 local reaction that requires 
emergency medical care within seven days after study vaccine administration.  
 
One or more Participants in the same treatment group experience the same Grade 3 
solicited local AE 48 hours following vaccination.  
 
One or more Participants in the same treatment group experience the same severe 
(Grade 3 or Grade 4) solicited systemic AE within 48 hours following vaccination, with no 
likelier alternative cause than the study vaccine. 
10.6.2 During entire study period (including the Booster phase): 
 
One or more Participants experience an SAE or AESI with no likelier alternative cause 
than the study vaccine (i.e. possibly or probably related). 
 
Two or more Participants experience a Grade 3 systemic allergic reaction, e.g. 
generalized urticaria within 10 days after vaccine administration, or anaphylaxis within 
24 hours following vaccine administration, with no likelier alternative cause than the study 
vaccine. 
 
Three or more Participants in the same dose group experience the same Grade 3iv 
solicited injection site reaction that (1) occurs within 7 days following vaccination and (2) 
lasts longer than 3 days. 
                                                 
iv Note: for the purpose of this study, AEs graded as potentially life threatening (Grade 4) will be 
reported as SAEs (see Section 16.1.2) and will thus fall under the first criterion in Section 11.6. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 45 / 109 
 
 
Three or more Participants in the same dose group experience the same Grade 3 
solicited systemic reaction that (1) occurs within 7 days following vaccination, (2) lasts 
longer than 3 days, and (3) has no likelier alternative cause than the study vaccine. 
 
Three or more Participants in the same dose group experience the same Grade 3 
unsolicited AE, including Grade 3 laboratory abnormalities that are assessed to be 
clinically relevant by the Investigator, that (1) occurs within 36 days following first 
vaccination, and (2) has no likelier alternative cause than the study vaccine. 
Grade 3 and Grade 4 solicited and unsolicited AEs will be confirmed with the site prior to 
stopping the study due to a pre-defined stopping rule. If any of the above-mentioned criteria 
is met or the DSMB recommends halting the study or discontinue a dose group for other 
reasons (e.g. in response to an excess rate of AEs with the same suspected underlying 
pathological mechanism), the Sponsor will notify the appropriate regulatory authorities and 
EC according to local requirements. 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
the study intervention under clinical intervention are met. The sponsor has a legal 
responsibility to notify both the local regulatory authority and other agencies about the safety 
of a study intervention under clinical investigation. The sponsor will comply with country-
specific regulatory requirements relating safety reporting to the regulatory authority, 
IRBs/ECs, and investigators. Investigator safety reports must be prepared for SUSARs 
according to local regulatory requirements and sponsor policy and forwarded to investigators 
as necessary. An investigator who receives SUSARs or other specific safety information 
(e.g., summary or listing of SAEs) from the sponsor will review and then file it along the 
SRSD(s) for the study and will notify the IRB/EC, if appropriate according to local 
requirements. 
If a study stopping rule is met, the DSMB will review all pertinent safety data to provide a 
recommendation for the study to continue/discontinue based on cumulative safety data 
evaluation and any other relevant data available at the time of review. Vaccination of 
Participants already enrolled in the study and restart of recruitment may only proceed after 
positive DSMB recommendation, and relevant regulatory authorities and EC will be informed. 
The Sponsor or Investigator may also stop the study for any medical reason at any time. 
If the Sponsor or Investigator decides to terminate the study before it is completed, they will 
notify each other in writing, stating the medical reason(s) for early termination. In terminating 
the study, the Sponsor and the Investigator will ensure that adequate consideration is given 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 46 / 109 
 
to the protection of the Participants’ interests. The Sponsor or Investigator will notify the 
relevant regulatory authorities or EC in writing in accordance with local requirements. 
Documentation will be submitted for filing in the Central and Investigator File and the Trial 
Master File. 
11. PARTICIPANT SELECTION, WITHDRAWAL AND DISCONTINUATION 
Approximately 150 male and female adults who satisfy the inclusion and exclusion criteria 
listed below will be invited to participate in the study. 
11.1 Inclusion Criteria 
Participants who meet ALL of the following criteria are eligible for the study: 
1. Participant is 18 to 55 yearsv of age on the Day of screening (Visit 0). 
2. Participant who has a smart phone and is willing and able to install and use the e-
Diary. 
3. Participant has an understanding of the study and its procedures, agrees to its 
provisions, and voluntarily gives written informed consent prior to any study-related 
procedures. 
4. Participant is generally healthyvi as determined by the Investigator’s clinical 
judgement based on medical history, physical examination and screening laboratory 
tests. 
5. Participant has a Body Mass Index (BMI) of 18.0-30.0 kg/m2, inclusive, at screening 
(Visit 0). 
6. If Participant is of childbearing potential: 
a) Participant has practiced an adequate method of contraception (see below) 
during the 30 days before screening (Visit 0). 
b) Participant has a negative serum or urine pregnancy test at screening (Visit 
0) or Visit 1, respectively.  
c) Participant agrees to employ adequate birth control measures up to Day 106 
(Visit 5). This includes one of the following measures: 
 
Hormonal contraceptives (e.g. implants, birth control pills, patches). 
 
Intrauterine hormone-release systems and intrauterine device. 
 
Barrier type of birth control measure (e.g. diaphragms, cervical caps). 
                                                 
v From the day a person turns 18 years until the last day before the person turns 56 years of age. 
vi Participants are considered generally healthy if they have (1) no active disease (acute illness, exacerbation of 
a chronic condition or a chronic – progressive illness) which requires treatment and/or follow-up, and (2) no 
disease that is identified as an exclusion criterion or (3) if they are healthy and have a preexisting stable disease, 
defined as disease not requiring significant change in therapy or hospitalization for worsening disease during the 
6 weeks before enrollment.. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 47 / 109 
 
 
Vasectomy in the male sex partner ≥ 3 months prior to first 
vaccination. 
 
Same sex relationships. 
 
 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 48 / 109 
 
11.2 Exclusion Criteria 
Participants who meet ANY of the following criteria are NOT eligible for this study: 
1. Clinically significant infection or other acute illness, including fever ≥ 38 °C within 48 
hours prior to the planned study vaccination 
2.  History of laboratory-confirmed SARS-CoV infection 
3. Participant had close contact to persons with confirmed SARS-CoV-2 infection within 
30 days prior to screening (Visit 0). 
4. Participant has participated in a clinical study involving an investigational SARS-CoV-
2 vaccine or has received or plans to receive a licensed SARS-CoV-2 vaccine during 
the duration of the study. 
5. Participant has an acute or recent infection not due to SARS-CoV-2 (and who is not 
symptom-free in the week prior to the Screening Visit (Visit 0). 
6. Participant has a history of SARS-CoV1, MERS infection (self-reported) 
7. Participant tests positive for human immunodeficiency virus (HIV), hepatitis B surface 
antigen (HBsAg) or hepatitis C virus (HCV). 
8. Participant has received any vaccine within 30 days prior Visit 1 other than the study 
intervention, with the exception of the seasonal influenza vaccination. Participants 
will be encouraged to receive this vaccination at least 7 days after their study vaccine. 
9. Participant has abnormal findings in any required study investigations (including 
medical history, physical examination, and clinical laboratory) considered clinically 
relevant by the Investigator.  
10. Participants with either medical history of or present acute or progressive, unstable 
or uncontrolled clinical conditions (e.g. cardiovascular, respiratory, neurologic, 
psychiatric, or rheumatologic conditions) that pose a risk for participation or 
completion of the study, based on Investigator’s clinical judgement. Examples include 
individuals with poorly controlled or unstable underlying disease, ongoing suspected 
or active inflammation, poor compliance with pharmacologic treatment, or presence 
of high-risk comorbidities (e.g. significant cardiopulmonary disease). 
11. Participants with an underlying disease with a high risk of developing severe COVID-
19 symptoms including those with any of the following risk factors:  
 
Hypertension.  
 
Diabetes mellitus 
 
Chronic liver disease 
 
Chronic pulmonary disease. 
 
Asthma. 
 
Current vaping or smoking. 
 
History of chronic smoking within the prior year. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 49 / 109 
 
12. Participant has a history of malignancy in the past 5 years other than squamous cell 
or basal cell skin cancer. If there has been surgical excision or treatment more than 
5 years ago that is considered to have achieved a cure, the Participant may be 
enrolled. A history of hematologic malignancy is a permanent exclusion. Participants 
with a history of skin cancer must not be vaccinated at the previous tumour site. 
13. Participant has a known or suspected defect of the immune system, such as 
Participants with congenital or acquired immune deficiency, including infection with 
HIV, status post organ transplantation or other autoimmune diseases 
14. Participant received immuno-suppressive therapy within 4 weeks prior to Visit 1 or 
receipt of immunosuppressive therapy is expected during the study. Immuno-
suppressive therapy is defined as administration of chronic (longer than 2 weeks) 
prednisone or equivalent ≥ 0.05 mg/kg/day within 4 weeks prior to study entry (topical 
and inhaled steroids are allowed), radiation therapy or immunosuppressive cytotoxic 
drugs/ monoclonal antibodies in the previous 3 years. 
15. Participant has a history of any vaccine related contraindicating event (e.g., 
anaphylaxis, allergy to components of the candidate vaccine, other known 
contraindications). 
16. Participant presents with clinical conditions representing a contraindication to 
intramuscular vaccination and blood draws. 
17. Participant is pregnant (positive serum or urine pregnancy test at screening or Visit 
1, respectively), has plans to become pregnant up to Day 106 of the study or lactating 
at the time of enrolment.  
18. Participant has donated blood, blood fractions or plasma within 4 weeks or received 
blood-derived products (e.g. plasma) within 12 weeks prior to vaccination in this study 
or plans to donate blood or use blood products during the study.  
19. Participant has a history of coagulation dysfunction (e.g. coagulation factor 
deficiency, coagulation disease) 
20. Participant has a rash, dermatological condition or tattoos that would, in the opinion 
of the Investigator, interfere with injection site reaction rating. 
21. Participant has a known or suspected problem with alcohol or drug abuse as 
determined by the Investigator. 
22. Participant has any condition that, in the opinion of the Investigator, may compromise 
the Participant’s well-being, might interfere with evaluation of study endpoints, or 
would limit the Participant’s ability to complete the study.  
23. Participant is committed to an institution (by virtue of an order issued either by the 
judicial or the administrative authorities). 
24. Participant has participated in another clinical study involving an investigational 
medicinal product (IMP) or device within 4 weeks prior to study enrolment or is 
scheduled to participate in another clinical study involving an IMP, or device during 
the course of this study. 
25. Receipt or planning receipt of investigational products indicated for the treatment or 
prevention of SARS-CoV-02 or COVID-19. NOTE: For Participants who get COVID-

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 50 / 109 
 
19, receipt of licensed treatment options and/or participation in investigational studies 
is permitted. 
26. Participant is a member of the team conducting the study or in a dependent 
relationship with one of the study team members. Dependent relationships include 
close relatives (i.e., children, partner/spouse, siblings, parents) as well as employees 
of the Investigator or site personnel conducting the study. 
 
11.3 Booster Phase 
11.3.1 Inclusion Criteria for Booster Phase: 
Participants who meet ALL of the following criteria are eligible for the Booster phase: 
B1. Participant has received complete VLA2001 primary immunization (two vaccinations 
according to the protocol) 
B2. Participant who has a smart phone and is willing and able to install and use the e-
Diary. 
B3. Participant has an understanding of the study and its procedures, agrees to its 
provisions, and voluntarily gives written informed consent prior to any study-related 
procedures. 
B4. Participant is generally healthyvii as determined by the Investigator’s clinical 
judgement  
B5. If a participant is of childbearing potential: 
a. Participant has a negative urine pregnancy test at Visit 7 prior to booster 
vaccination.  
b. Participant agrees to employ adequate birth control measures up to 3 months 
after the Booster vaccination. 
This includes one of the following measures: 
i. Hormonal contraceptives (e.g. implants, birth control pills, patches). 
ii. Intrauterine hormone-release systems and intrauterine device. 
iii. Barrier type of birth control measure (e.g. diaphragms, cervical caps). 
iv. Vasectomy in the male sex partner ≥ 3 months prior to first 
vaccination. 
v.  Same sex relationships. 
 
                                                 
vii Participants are considered generally healthy if they have (1) no active disease (acute illness, exacerbation of 
a chronic condition or a chronic – progressive illness) which requires treatment and/or follow-up, and (2) no 
disease that is identified as an exclusion criterion or (3) if they are healthy and have a preexisting stable disease, 
defined as disease not requiring significant change in therapy or hospitalization for worsening disease during the 
6 weeks before screening/ before Day 208. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 51 / 109 
 
11.3.2 Exclusion Criteria for Booster Phase: 
Participant who meet ANY of the following criteria are NOT eligible for the Booster phase: 
B1. Clinically significant infection or other acute illness, including fever ≥ 38°C within 48 
hours prior to the planned Booster vaccination. 
B2. Participant has an acute or recent infection not due to SARS-CoV-2 and is not 
symptom-free in the week prior to the Booster vaccination (Visit 7). 
B3. Participant has received any vaccine within 30 days prior Visit 7, with the exception 
of the seasonal influenza vaccination. Participants will be encouraged to receive this 
vaccination at least 7 days after their Booster vaccine.  
B4. Participant has abnormal findings in any required study investigations (including 
medical history, physical examination, and clinical laboratory) that is considered 
clinically relevant by the Investigator.  
B5. Participant has received immuno-suppressive therapy within 4 weeks prior to Visit 7 
or is expected to receive immunosuppressive therapy during the study. Immuno-
suppressive therapy is defined as administration of chronic (longer than 2 weeks) 
prednisone or equivalent ≥ 0.05 mg/kg/day within 4 weeks prior to Visit 7 (topical and 
inhaled steroids are allowed), radiation therapy or immunosuppressive cytotoxic 
drugs or monoclonal antibodies in the previous 3 years. 
B6. Participant has clinical conditions representing a contraindication to intramuscular 
vaccination and blood draws. 
B7. Participant is pregnant (positive urine pregnancy test at Visit 7, respectively), has 
plans to become pregnant up to 3 months after the Booster vaccination. 
B8. Participant has a rash, dermatological condition that would, in the opinion of the 
Investigator, interfere with injection site reaction rating. 
B9. Participant has a known or suspected problem with alcohol or drug abuse as 
determined by the Investigator. 
B10. 
Participant has any condition that, in the opinion of the Investigator, may 
compromise the Participant’s well-being, might interfere with evaluation of study 
endpoints, or would limit the Participant’s ability to complete the study.  
B11. 
Participant is committed to an institution (by virtue of an order issued either by 
the judicial or the administrative authorities). 
B12. 
Participant has participated in another clinical study involving an investigational 
medicinal product (IMP) or device within 4 weeks prior to Visit 7 or is scheduled to 
participate in another clinical study involving an IMP, or device during the course of 
this study. 
 
11.4 Delay Criteria 
Vaccination will be delayed if: 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 52 / 109 
 
1. Participant has current febrile illness (body temperature equal or greater 38.0°C) or 
other acute illness within 48 hours prior vaccination.  
2. An illness which in the judgement of the investigator may interfere with tolerability/ 
Day1-8 safety assessment 
3. Participant has received antipyretics within 6 hours prior to the scheduled time of 
vaccination. 
4. Receipt of any vaccine within 30 days prior to study intervention, with the exception 
of the seasonal influenza vaccine. Participants will be encouraged to receive this 
vaccination at least 7 days before or after their study vaccine. 
 
In addition, for a rescheduled first vaccination all inclusion and none of the exclusion criteria 
must be met; in case not all of these criteria are met, the Participant will be excluded from 
further vaccination.  
The rescheduled visit should be within the specified time window for the vaccination visit. In 
case the time window for a rescheduled first vaccination cannot be met, the Participant might 
be invited for a re-screening. Only a single re-screening is allowed in the study. Re-screened 
Participants are required to sign a new Informed Consent Form and will be assigned a new 
participant number.  
11.5 Pregnancy Testing and Birth Control  
 Women of childbearing potential presenting with a negative pregnancy test and practicing 
the use of adequate birth control before conduct and during the first 3 months of the study 
are eligible for inclusion into the study. 
A woman is considered of childbearing potential if fertile, following menarche and until 
becoming post-menopausal unless permanently sterile.  
Women of childbearing potential must have practiced an adequate contraceptive method 
during the 30 days before Visit 0 (Screening Visit) and the first 3 months until Visit 5 (Day 
106) and present with a negative serum pregnancy test at Visit 0 (Screening Visit), a 
negative urine pregnancy test prior to any vaccination. In addition, a urine pregnancy test 
will need to be performed at the Early Termination Visit (if applicable).  
Women of childbearing potential are required to practice an acceptable method of birth 
control for the first 3 months post-vaccination. An acceptable method of birth control is 
defined as those, which result in a low failure rate (i.e. less than 1% per year) when used 
consistently and correctly.  
This includes one of the following measures: 
 
Hormonal contraceptives (e.g. implants, birth control pills, patches). 
 
Intrauterine hormone-releasing system or intrauterine device. 
 
Barrier type of birth control measure (e.g. diaphragms, cervical caps). 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 53 / 109 
 
 
Vasectomy in the male sex partner ≥ 3 months prior to first vaccination. 
 
Same-sex relationships. 
 
Women without childbearing potential are not required to perform any birth control measure. 
A woman is considered of non-childbearing potential, if she is: 
 
Surgically sterilized for ≥ 3 months prior to Visit 1 (permanent sterilization methods 
include hysterectomy, bilateral salpingectomy or bilateral oophorectomy, or transcervical 
sterilization [Essure and Adiana procedures], or tubal ligation). 
 
Postmenopausal for ≥ 1 year prior to Screening as historically confirmed by a 
gynaecologist.  
 
If a Participant becomes pregnant during the study, she must immediately inform the 
Investigator and the Participant is asked to attend all remaining visits according to schedule. 
11.6 Participant Withdrawal or Discontinuation 
Any participant has the right to withdraw from the study at any time for any reason, without 
the need to justify. A Participant who considers withdrawing from the study must be informed 
by the investigator about modified follow-up options (e.g telephone contact, a contact with a 
relative or treating physician or information from medical records). The Investigator and 
Sponsor also have the right to prematurely terminate a Participant’s further participation in 
the study, e. g. in the case of non-compliance or if – in the judgment of the Investigator and/or 
Sponsor – continued participation would pose an unacceptable risk for the Participant. 
Additionally, a participant will be withdrawn from further vaccination (either second 
vaccination or booster vaccination) if any of the following criteria are met: 
 
If participant has ongoing symptoms of COVID-19 disease as defined per protocol (see 
15.2.4. Assessment of Symptoms Relating to SARS-CoV-2) and a positive SARS-CoV-
2 test. 
Please Note: Participants with a positive test should visit the study site and a COVID-19 
illness Visit should be performed. 
 
If a Participant becomes pregnant prior to study completion study vaccine exposure will 
be discontinued. Attempts will be made to follow her through completion of the pregnancy 
and the first 3 months of life of the newborn. The Investigator will record a narrative 
description of the course of the pregnancy and infant. For further information on 
pregnancy reporting procedures see Section 16.11.3. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 54 / 109 
 
 
If a Participant has symptoms, or abnormal laboratory values, which are considered 
unacceptable by the Participant or the Investigator. 
 
If a Participant experiences an SAE or AESI with no likelier alternative cause than the 
study vaccine (i.e. possibly or probably related). In such cases, study vaccinations and 
further enrolment will be suspended for all Participants pending DSMB review and 
assessment (see Section 11.6). 
 
If a Participant experiences a severe systemic allergic reaction, e.g. generalized urticaria 
within 10 days after vaccine administration or anaphylaxis within 24 hours following 
vaccine administration, with no likelier alternative cause than the study vaccine. 
 
If a Participant experiences a Grade 3viii solicited injection site reaction that (1) occurs 
within 7 days following vaccination and (2) lasts longer than 3 days. 
 
If a Participant experiences a Grade 3 solicited systemic reaction that (1) occurs within 
7 days following vaccination and (2) lasts longer than 3 days. However, the Participant 
may receive further vaccination if there is a more plausible alternative cause for the 
reaction. 
 
If a Participant experiences a Grade 3 unsolicited AE, including Grade 3 laboratory 
abnormality that is assessed to be clinically relevant by the Investigator, that (1) occurs 
within 36 days after vaccination, and (2) has no likelier alternative cause than the study 
vaccine or has not resolved prior to the next scheduled study vaccination. 
The primary reason for withdrawal/discontinuation of a Participant from treatment and/or 
from the study should be documented in the electronic Case Report Form (eCRF) (e.g. 
withdrawal of consent, withdrawal due to AE, Investigator/Sponsor recommended 
withdrawal, lost to follow up, death). 
Participants withdrawn from further vaccination (i.e. did not receive their second vaccination) 
should perform their remaining regular study visits as scheduled if there are no other reasons 
for premature withdrawal from the study.  
In case of premature withdrawal from the study, all attempts should be made to have the 
Participant perform an Early Termination (ET) visit (see Section 14.4.2 for 
procedures/assessments to be performed at an ET visit). Data collected on withdrawn 
Participants will be used in the analysis and included in the Clinical Study Report (CSR). 
                                                 
viii Note: for the purpose of this study, AEs graded as potentially life threatening (Grade 4) will be 
reported as SAEs (see Section 16.1.2) and will thus fall under the first criterion in Section 11.6. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 55 / 109 
 
Participants who have not received study interventions regardless of reason, will not be 
followed. 
Participants who do not complete the entire study due to withdrawal or discontinuation for 
any reason will not be replaced. 
11.7 Lost to Follow-up 
A Participant will be considered lost to follow-up if she or he repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions should be taken if a Participant fails to return to the study site (clinic) 
for a required visit: 
 
The study site must attempt to contact the Participant and reschedule the missed 
visit as soon as possible and counsel the Participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the Participant wishes to 
and/or should continue in the study. 
 
Before the Participant is deemed lost to follow-up, the investigator or designee must 
take every effort to regain contact with the Participant (e.g. telephone call). These 
contact attempts should be documented in the medical record. 
 
Should the Participant continue to be unreachable, she/he will be considered to have 
withdrawn from the study.  
11.8 Re-screening of Participants 
A Participant is eligible for re-screening if (s)he completed the screening visit and met in- 
and exclusion criteria but cannot be randomized or vaccinated for administrative reasons 
within the given time window (e.g. having served as back-up Participant in the staggered 
recruitment phase). 
 
 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 56 / 109 
 
12. INVESTIGATIONAL MEDICINAL PRODUCT 
12.1 Description of the IMPs  
VLA2001 is a highly purified, inactivated, whole virus SARS-Cov-2 vaccines grown on Vero 
cells. The vaccine production platform, developed by Valneva, uses an inactivated whole-
virus approach where live wild-type virus is grown in cell culture and then inactivated (i.e. 
making it unable to replicate and infect cells) via chemical treatment. Valneva uses β-
propiolactone inactivation in order to preserve the native surface structure of the S protein. 
VLA2001 has similar biological, physical and chemical properties as the approved vaccine 
IXIARO, produced using the same platform.  
The final administered dose of VLA2001 is 0.5 mL. 
12.1.1 Primary Immunization – composition of VLA2001 
Table 1 
Composition of VLA2001 (primary immunization) 
 
Active substance 
 
 
SARS-CoV-2 
inactivated 
with 
β-
propiolactone 
Target Antigen Units  
Low dose: 3 AU/dose  
Medium dose: 7 AU/dose  
High dose: 35 AU/dose 
Excipients and buffer components 
Aluminium hydroxide  
0.5 mg/dose 
Dulbecco's Phosphate Buffered Saline (DPBS) 
HSA 
25 ug/dose 
Concentrations per final administered dose of 0.5ml (i.e. post bed-side mixing) 
 
Bed side mixed with 
 
 
 
CpG 1018 
1 mg/dose 
Tris buffered saline 
Concentrations per final administered dose of 0.5ml (i.e. post bed-side mixing) 
 
VLA2001 will be administered in combination with CpG 1018 enriched oligodeoxynucleotide 
phosphorothioate immunostimulatory adjuvant (CpG 1018 adjuvant; licensed by FDA, 
marketing authorisation by EMA pending). The CpG 1018 adjuvant used is a 22-mer 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 57 / 109 
 
oligodeoxynucleotide in a Tris buffered saline (20 mM Tris, 100 mM Sodium Chloride, pH 
7.5 (HEPLISAV-B SmPC). For this clinical study, one part of the vaccine (labelled VLA2001) 
will be presented as a liquid formulation containing aluminium hydroxide in glass vials at 
three dose levels and has to be mixed bedside with CpG 1018 prior to vaccination (volume 
for administration is 0,5ml). 
The bed-side mixing procedure is described in detail in section 13.3.2.  
12.1.2 Booster Phase - composition of VLA2001:  
For the Booster Phase, there will be no bed-side mixing necessary. For the Booster Phase, 
VLA2001 will be provided in multi-dose glass vials as a liquid formulation containing 
aluminium hydroxide and CpG 1018.  
Table 2 
Composition of VLA2001 (booster vaccination) 
Active substance 
 
 
SARS-CoV-2 inactivated:  
 
Antigen Units/dose, 
antigen dose level equivalent to high 
dose 
Excipients and buffer components 
Aluminium Hydroxide  
0.5 mg Al3+/dose 
CpG 1018  
 1 mg/dose 
Dulbecco's Phosphate Buffered Saline (DPBS) 3) 
rHA 
  ≤25 µg/dose 
 
12.2 IMP Labelling and Packaging 
Packaging and labelling of IMP is performed by Almac. Labels will be written in accordance 
to local law. Valneva will provide one kit containing one vial of VLA2001 and one vial of CpG. 
Booster Phase:  
Packaging and labelling of IMP is performed by a central manufacturing organization located 
in the UK (Almac). Labels will be written in accordance to local law. Valneva will provide one 
kit containing one multi-dose vial of VLA2001. 
12.3 IMP Storage, Dispensing and Accountability 
12.3.1 IMP Storage 
The IMP should be stored in a refrigerator at +2 to +8°C in a room with access limited to 
study personnel. Temperature monitoring systems will be used. 
PLEASE DO NOT FREEZE THE VACCINE! 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 58 / 109 
 
12.3.2 Dispensing and Accountability of Investigational Medicinal Product 
A drug shipment log will be kept current by the site, detailing the date and quantity of IMP 
received from and returned to the Sponsor. In addition, a current drug dispensing log has to 
be maintained, detailing the dates and quantities of IMP administered to each Participant. 
This documentation will be available to the designated CRA to verify drug accountability 
during the study and to perform overall drug accountability. 
Any unused IMP and empty vials will be accounted for and returned to the Sponsor. 
Details of IMP handling, including the procedure for Booster Phase are described in the 
updated study-specific IMP manual. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 59 / 109 
 
13. STUDY PROCEDURES 
13.1 Informed Consent and Enrolment 
Any healthy volunteer who provides informed consent (i.e., signs and dates the informed 
consent form) is considered enrolled in the study.  
The Investigator will inform the Participant about the procedures, risks and benefits of the 
study. Fully informed, written consent must be obtained from each Participant prior to any 
assessment being performed. It is important that the Participant is allowed sufficient time to 
decide on his/her participation in the study. 
13.2 Participant Identification Code 
At Visit 0, a 10-digit Participant identification code will be assigned to each Participant. The 
first four digits are the product identifier (e.g. 2001 for this product) provided by the Sponsor. 
The fifth digit is the study identifier (i.e. 2001-1 for this phase I/II study); the sixth and seventh 
digit is the site identification number (i.e. 2001-1-01). The last three digits are assigned in 
ascending order as the Participants are enrolled (i.e., signing the informed consent form, e.g. 
2001-1-01-001).  
13.3 Investigational Treatment 
13.3.1 Description of Treatment 
The vaccination schedule consists of two doses of VLA2001 for each study Participant, 
administered by intramuscular (IM) injection in the deltoid region of non-dominant arm 
preferably 21 days apart, on Day 1 and Day 22 [Low dose, Medium dose, High dose]. 
Booster Phase: 
The booster vaccination will be administered IM in the deltoid region of the non-dominant 
arm; please refer to the updated study-specific IMP manual. 
13.3.2 Vaccine Preparation and Administration 
Primary immunization: 
One part of the vaccine (labelled VLA2001) will be presented as a liquid formulation 
containing aluminium hydroxide in glass vials at three dose levels (each vial is pre-filled with 
0.4ml) and has to be mixed bedside with CpG 1018 (0.2ml) prior to vaccination (volume for 
administration is 0.5ml). 
Preparation of IMP will be done according to the following procedure:  

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 60 / 109 
 
1. CAUTION: Preservatives, antiseptics, detergents, and other anti-viral substances 
may inactivate the vaccine. Use only sterile syringes that are free of preservatives, 
antiseptics, detergents or other anti-viral substances for injection of VLA2001. 
2. The VLA2001 glass vial and CpG vials should be removed from the fridge (2-8°) and 
allowed to reach room temperature before administration 
3. The VLA2001 and CpG vials should be gently swirled (5 to 10 seconds) to obtain a 
homogeneous suspension (no vortex or shaking); 
4. The VLA2001 and CpG vials should be inspected visually for any foreign particulate 
matter and/or variation in physical appearance (e.g. discoloration) prior to withdrawal 
of the appropriate volume into a syringe. Vials found to contain foreign particulate 
matter, to be discolored or to leak must be discarded and may not be used; the 
Sponsor must be informed immediately of such events. 
5. Withdraw 0.2ml CpG 1018 with a syringe (the prefilled volume in the CpG vials is 
approximately 0.7ml). Transfer the 0.2ml CpG 1018 into the VLA2001 vial, the 
resulting volume is 0.6ml.  
6. The mixed vaccine vial should be gently swirled (5 to 10 seconds) to obtain a 
homogeneous suspension (no vortex or shaking). 
7. Take a new needle and withdraw the injection volume of 0.5 mL. The injection site 
should be prepared according to standard clinical procedures. 
8. Injection of 0.5ml mixed vaccine intramuscularly into deltoid region of non-dominant 
arm by study staff as soon as possible.  
9. The used vials and syringes should be kept within the empty kits for drug 
accountability purposes. Used needles should be disposed in accordance with local 
requirements. 
Under no circumstances should the VLA2001 vaccine be administered intravascularly, as 
this could lead to hypersensitivity reactions such as shock. 
Booster Phase: 
For the Booster Phase there will be no bed-side mixing necessary. VLA2001 will be provided 
in multi-dose vials to the study sites where each multi-dose vial will have a unique kit number. 
In addition, the site will receive unlabelled syringes together with an aspiration and an 
administration needle and specific syringe labels. Once the pharmacist gets the treatment 
for a participant, they will retrieve 0.5 mL from the respective multi-dose vial with a syringe. 
Immediately afterwards this syringe will be labelled with a syringe label (participant identifiers 
will be added manually on the label). With this process the identification of and allocation of 
the syringe to a specific multi-dose vial and participant is ensured. 
The details of the procedure for Booster Phase are described in the updated IMP manual. 
 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 61 / 109 
 
Anaphylaxis or other possible severe acute, post-vaccination adverse reactions to 
vaccines, including VLA2001 vaccine, are very rare, but can occur. Therefore, 
appropriate emergency equipment and medication as well as adequately trained 
personnel must be on site whenever a vaccination is performed. 
13.3.3 Post- Vaccination Observation 
The first Participant of a sentinel dosing group will be observed for 3 hours at the study site 
following vaccination; all remaining 4 Participants of the sentinel dosing group will be 
observed for 60 minutes (see Section 10.1) at the study site. All remaining 135 Participant 
in the randomized and blinded part of the study will be observed at the study site for 30 
minutes after each vaccination. This is in order to provide appropriate emergency treatment 
should this be necessary. In addition, vital signs including pulse rate and blood pressure 
while seated and at rest will be measured prior to discharge. Any injection site and systemic 
reactions will be recorded. 
Booster Phase: 
For the Booster vaccination, participants should be observed in the clinic for 30 minutes after 
administration.  
Prior to leaving the study site, the Participant will be instructed how to complete the 
respective electronic diary for documentation of AEs (for further information see 
Section 15.3), will be given a digital thermometer for measuring oral body temperature and 
a measuring device for assessing injection site reactions (at the vaccination visit only). 
13.4 Screening and Study Visits 
The overall study design is illustrated in Section 22.1. Please refer to the Schedule of Study 
Procedures and Assessments in section 22.2 and section 22.3 (specific to the Booster 
Phase), for the timings of all procedures to be carried out during the study. 
Please note: 
Study Changes in Response to the COVID-19 Pandemic Situation 
Authorities worldwide have issued guidance for Industry, Investigators, and Institutional 
Review Boards on conducting clinical studies during the COVID-19 pandemic. 
Competent health authorities and agencies, including the FDA, the MHRA* and the HRA**, 
support the implementation of remote activities to ensure continuation of study activities 
should the COVID 19 situation limit/forbid access to clinical sites. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 62 / 109 
 
Valneva will continuously monitor and evaluate the development of the COVID-19 pandemic 
in the area of study sites to determine if any measures should be implemented to mitigate 
undue risks to the Participants or in response to local governmental recommendations. 
Such measures can include (but not limited to):  
 
remote monitoring,  
 
switching in-person visits to telephone call and/or home visits (including appropriate 
documentation of the phone call/home visit),  
 
sending of ‘Dear Investigator’ Letters to inform investigator sites of changes to trial 
conduct 
 
self-isolation of trial Participants as a precaution or as a result of confirmed infection, 
limiting or inhibiting the required clinical trial activities. 
Explicit instructions from Valneva and CRO as to what can be accessed where, will be 
available and communicated in a timely manner to ensure fulfilment of protocol activities 
during the trial.  
Trial participants will be consented to any identifiers leaving the site and be assured that their 
confidentiality will be protected. 
Furthermore, care will be taken that no extra burdens are placed on investigators and site 
staff around scanning and uploading many documents. 
 
The safety of the Participants participating in the trial remains our priority.  
 
*MHRA Guidance. (see literature) 
 
13.4.1 Unscheduled Visit 
An unscheduled visit can be held at any time during the study if deemed necessary by the 
Investigator (e.g. follow-up on unexpected AEs or SAEs) or the DSMB. Assessments 
performed at an unscheduled visit will be at the Investigator’s or DSMB’s discretion. 
Unscheduled visits and any procedures/assessments performed during such a visit (e.g. 
physical examination, laboratory test) should be documented in the source data and the 
eCRF. 
In any case a phone call will only take place if a) data are not being entered; b) grade 3 
events are reported, c) if a serious AE is reported via the diary, d) if Participants indicate 
symptoms towards potential COVID-19 infection. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 63 / 109 
 
13.4.2 Early Termination Visit 
Participants who terminate participation or who are withdrawn from the study prematurely 
will undergo investigations during an ET visit, if possible. Every effort should be made to 
have discontinued Participants complete the study ET Visit (see Table 3).  
Table 3 Study VLA2001-201 Study Visit Schedule – Early Termination 
TIME 
ACTION 
unscheduled 
1. 
Review/Collect Participant diary (Section 15.3) 
2. 
AE/AESI/SAE documentation (Section 15.2) 
3. 
Concomitant medication (Section 15.4) 
4. 
Symptom-driven physical examination and Vital Signs (Section 15.6 and 15.5) 
5. 
Blood draw a: 
a. 
Immunogenicity evaluation (Section 14) 
b. 
Clinical chemistry, haematology, coagulation assessments (Section 15.7) 
6. 
Urine samples: 
a. 
Urine pregnancy test (if applicable) b 
b. 
Urinalysis (Section 15.7) 
7.  Documentation of reason for early termination 
AE=adverse event; AESI=adverse event of special interest; SAE=serious adverse event 
a The following amounts of blood will be drawn: HIV/HBsAg/HCV screening – 3 mL; serum pregnancy test – 3.5 mL; 
immunogenicity – 15 mL; clinical chemistry – 7.5 mL; haematology – 5 mL; coagulation – 3 mL. 
b A pregnancy test will be performed on all female Participants of child bearing potential at screening (serum 
pregnancy test), and prior to each vaccination and upon study completion (urine pregnancy test). 
If an ET Visit is not possible, a follow-up safety phone call should be made as soon as 
possible after termination to capture at least concomitant medications and solicited and 
unsolicited AEs since the last study visit.  
The reason for early termination should be clarified in as much detail as possible. If an AE 
was the reason for early study termination, details of the specific AE(s) should be captured 
(see Section 11.6). The reason for discontinuation will be recorded on the eCRF, and data 
collected up to the time of discontinuation will be used in the analysis and included in the 
clinical study report. 
In the event of Participant discontinuation due to an AE, clinical and/or laboratory 
investigations that are beyond the scope of the required study observations/assessments 
may be performed as part of the evaluation of the event. These investigations will take place 
under the direction of the Investigator in consultation with the Sponsor, and the details of the 
outcome may be reported to the appropriate regulatory authorities by the Sponsor.  

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 64 / 109 
 
13.5 Procedures for Monitoring Participant Compliance 
In general, study procedures are to be performed under the supervision of the Investigator 
or designee at the study site. Participant compliance will be monitored by reviewing the 
Participant's entries in the e-Diary.  
14. ASSESSMENT OF IMMUNOGENICITY 
All serum samples obtained for the determination of neutralizing antibodies and IgG 
antibodies against SARS-CoV-2 will be handled according to the procedures supplied to 
each investigative site for the preparation, storage and shipment of samples (refer to 
Laboratory Manual). Immunogenicity samples will be collected from all Participants at the 
time points indicated in section 22.2 and 22.3. Each clinical study site will be responsible for 
the separation of serum from whole blood samples and the safe and controlled storage of 
serum samples prior to shipment to the central laboratory.  
Immunogenicity sample (10ml) will be drawn for SARS-CoV-2-specific neutralizing antibody 
titre evaluation and ELISA antibody titre evaluation. 
Serum samples to measure SARS-CoV-2 neutralizing antibody levels will be collected from 
Participants on Day 1 (prior vaccination), Day 8, Day 22 (prior vaccination), Day 36, Day 106 
and Day 208. An authorized laboratory will measure neutralizing antibodies to SARS-CoV-2 
using wild-type virus neutralizing assay. In addition to the functional assays, samples will be 
analysed for IgG against SARS-CoV-2 by ELISA.  
The cell-mediated immune response (T-cell response) will be assessed on Day 1, Day 36 
and Day 208 by characterizing PBMCs; methods may include T-cell ELISpot assays to 
SARS-CoV-2 antigens. 
Booster Phase: 
During the Booster Phase, a blood sample (10 ml) will be collected at Visit 7 (before 
vaccination), Visit 8 and Visit 9, to measure SARS-CoV-2-specific neutralizing antibody titre 
and ELISA antibody titre. 
Similarly, cell-mediated immune response (T-cell response) will be assessed by 
characterizing PBMCs at Visit 7 and Visit 8. 
More details about the Booster Phase assessments can be found in section 22.3.  
At the end of the study, results of immunogenicity assessments will be provided to the 
Investigator. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 65 / 109 
 
14.1 Additional Testing Procedures 
Instructions for obtaining and processing saliva sampling are provided in the Laboratory 
Manual.  
Self-swabbing samples will be assessed by validated assays for the detection of SARS-CoV-
2. 
Samples obtained in this study may, in addition to its use for assessment of SARS-CoV-2 
specific antibody and cellular immune responses, also be used for further development of 
the vaccine, including but not limited to the following assays: 
 Development of additional neutralization assays (e.g. pseudovirion neutralization 
assay)  
 Detection of antibodies by enzyme linked immunosorbent assay (ELISA) against 
different SARS-CoV-2 antigens 
 Detection of cellular immune responses using different test methods (e.g. ELISpot, 
intracellular cytokine staining) 
 Clinical diagnostic work-up. 
Such development may occur at laboratories other than the central analytical laboratory used 
for this study. 
A blood sample for use in passive transfer studies will be collected to support the 
establishment of a robust clinical endpoint for identification of neutralizing antibody levels 
associated with protection from COVID-19. These samples may also be used for the 
preparation of assay controls. 
 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 66 / 109 
 
15. ASSESSMENT OF SAFETY 
15.1 Definitions 
15.1.1 Adverse Events 
An AE is defined as any untoward medical occurrence in a Participant administered an 
investigational product that does not necessarily have a causal relationship with the 
treatment. All new abnormalities or any exacerbation in intensity or frequency (worsening) of 
a pre-existing condition during or after vaccination must be documented as AEs. 
15.1.2 Serious Adverse Event 
A SAE is defined as any untoward medical occurrence that at any dose meets one or more 
of the following criteria: 
 
Outcome is fatal/results in death (including foetal death). 
 
Is life-threatening – defined as an event in which the Participant was, in the judgment of 
the Investigator, at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death had it been more severe. 
 
Requires inpatient hospitalisation or results in prolongation of an existing hospitalisation. 
 
Results in persistent or significant disability/incapacity (i.e., a substantial disruption of a 
person’s ability to conduct normal life functions). 
 
Results in congenital anomaly/birth defect. 
 
Is a medically important condition – a medical event that may not be immediately life-
threatening or result in death or require hospitalisation but may jeopardize the Participant 
or may require medical or surgical intervention to prevent one of the other outcomes 
listed in the definitions above. This definition also applies to progression of disease 
leading to a serious outcome. 
In case of hospitalisation or prolonged hospitalisation for diagnostic or elective medical 
procedures that were planned prior to vaccination to treat a pre-existing condition that did 
not change in severity, neither the condition leading to the hospitalisation or prolonged 
hospitalisation, nor the actual medical procedure need to be reported as an SAE. In this 
case, the underlying diagnosis or condition should be reported in the medical history section 
of the eCRF and the corresponding medical procedure should be documented as a comment 
to the underlying diagnosis or condition in the medical history section of the eCRF. 
The Sponsor will classify the SAEs as either expected or unexpected: 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 67 / 109 
 
Expected: 
An AE that is listed in the current Investigator's Brochure (IB) 
Unexpected: 
An AE that is not listed in the current IB, or it differs because of 
greater severity or greater specificity 
For the purpose of this study, AEs graded as potentially life-threatening (Grade 4) (see 
Section 15.2.3 for solicited AEs) will be reported as SAEs. 
15.1.3 Adverse Events of Special Interest 
An AESI (serious or non-serious) is an event of scientific and medical concern specific to the 
Sponsor's product. Please refer to Sections 15.10 and 22.5, where symptoms/illnesses 
considered as an AESI for this study are described. 
15.1.4 Medically-Attended Adverse Event 
All AEs where Participants are seeking medical care (i.e. doctor’s office, emergency service, 
hospital, but not including use of self-medication). 
15.1.5 Pre-existing Diseases 
Pre-existing diseases that are present before entry into the study, that are described in the 
medical history, and that manifest with the same severity, frequency, or duration after 
vaccine exposure, will not be recorded as AEs. Furthermore, routine health checks required 
due to pre-existing diseases will not be recorded. However, when there is an increase in the 
severity of a pre-existing disease, the event must be described on the AE CRF page. 
15.1.6 Untoward Medical Occurrences Not Considered Adverse Events 
Each untoward medical occurrence experienced before vaccine exposure (for example, from 
the time of signed informed consent up to but not including vaccine exposure) will be 
described in the medical history.  
15.2 Collection, Documentation and Assessment of Adverse Events 
15.2.1 Unsolicited Adverse Events 
Participants will be provided and trained to use an electronic diary to make notes on 
unsolicited AEs up to D36 (Visit 4, see Section 15.3). Additionally, the Investigator will enquire 
about AEs during study visits. Clinically relevant laboratory parameter changes constitute 
unsolicited AEs, too, unless they are considered a symptom of an underlying AE or part of a 
syndrome that is reported as AE (e.g. presence of blood cells in urine in a person diagnosed 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 68 / 109 
 
with urinary tract infection). In addition, symptoms noted during the symptom-driven physical 
exams (unless already covered by an AE) constitute AEs.  
All unsolicited AEs need to be documented in the respective AE section of the eCRF during 
the applicable study visit (Visits 1 to 6 or unscheduled visit(s), if applicable), regardless of 
their source (AEs noted in the Participant diary [see Section 15.3], open question to 
Participant, laboratory parameters, symptom-driven physical examination). Serious adverse 
events will continue to be documented until the end of the study. 
Any symptom is regarded as a separate AE. However, if the Investigator considers several 
symptoms to be in the context of one underlying diagnosis, the Investigator may merge these 
symptoms into one single appropriate AE. The AE term entered into the eCRF should contain 
all symptoms summarized to one event (e.g. ‘Influenza with flu-like-symptoms, fever and 
headache’). 
The Investigator will follow-up each AE until it is resolved or until the medical condition of the 
Participant is stable. All relevant follow-up information will be reported to the Sponsor until 
the end of the study for each Participant. Serious adverse events ongoing at the time of 
Visit 8 will be followed until resolution or achievement of stable clinical conditions, latest until 
the overall end of the study.  
Beyond study end, SAEs that are fatal, life-threatening or suspected to be related to 
study treatment will be followed up to be reported until 6 months after the last study 
visit of the respective Participant. 
The following information will be documented for each AE: severity, causality, outcome, and 
seriousness, medically-attended, action taken to treat AE, action taken on IMP, start and 
stop dates. 
Booster Phase: 
Participants taking part in the Booster Phase will use the electronic diary to collect solicited 
AEs and make notes on unsolicited AEs occurring until Visit 10. 
 
15.2.1.1 Severity 
The Investigator will assess the severity of AEs using his/her clinical expertise and judgment 
based on the most appropriate description below: 
Mild (Grade 1):
Awareness of signs or symptoms, but easily tolerated, does not 
interfere with daily activities. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 69 / 109 
 
Moderate (Grade 2):
Discomfort enough to interfere with usual activity and with or 
without requiring medical intervention. 
Severe (Grade 3):
Incapable of work or usual activity and requiring medical 
intervention. 
15.2.1.2 Causality 
Causality is a determination of whether there is a reasonable possibility that the vaccine 
administration is aetiologically related to/associated with the AE.  
Solicited adverse events of vaccination site reactions will be considered causally related to 
study treatment. 
For all other adverse events, the Investigator will determine a causal relationship to the 
study vaccine. Several factors will be considered in making this assessment, including: 1) 
the temporal relationship of the event to the administration of the study vaccine 2) whether 
an alternative etiology has been identified and 3) biological plausibility.  
Causality of all adverse events should be assessed by the Investigator using the following 
question: 
“Is there a reasonable possibility that the adverse event may have been caused by the 
study vaccine?” 
 
YES (related): There is a reasonable possibility that the study vaccine contributed to the 
adverse event 
 
NO (not related): There is no reasonable possibility that the adverse event is causally 
related to the administration of the study vaccine. There are other, more likely causes 
and administration of the study vaccine is not suspected to have contributed to the 
adverse event 
Probable: 
 
Reaction that follows a reasonable temporal sequence from 
administration of the IMP, or that follows a known or expected 
response pattern to the suspected treatment; and that could not 
reasonably be explained by known characteristics of the 
Participant’s clinical state. 
Possible:  
Reaction 
that 
follows 
a 
reasonable 
temporal 
sequence 
from administration of the IMP, or that follows a known 
or 
expected 
response 
pattern 
to 
the 
suspected 
treatment; but that could readily have been produced by 
a number of other factors. 
Unlikely: 
 
Reports not following a reasonable temporal sequence from 
administration of the IMP; an event, which may have been 
produced by the Participant’s clinical state or by other 
environmental factors. A more likely alternative aetiology exists. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 70 / 109 
 
Not related (unrelated): Events for which sufficient information exists to conclude that the 
aetiology is unrelated to the IMP. 
 
Adverse events with a causality reported as probable or possible will be considered related 
to the IMP. Adverse events with missing causality assessment will be regarded as related 
unless further specified. All other AEs will be considered as not related to IMP. 
15.2.2 Assessment and Outcome of Adverse Events 
Each AE that occurs from first vaccination to study completion/termination will be described 
in the eCRF (i.e. one AE per form) using the medical diagnosis (preferred), symptom, or sign, 
in standard medical terminology in order to avoid the use of vague, ambiguous, or colloquial 
expressions. Adverse events will be evaluated by the Investigator for: 
 
Seriousness as defined in Section 15.1.2. 
 
Severity as defined in Section 15.2.1.1. 
 
Causal relationship to vaccine exposure as defined in Section 15.2.1.2. 
For each AE, the outcome will also be documented as either: 
 
Recovered/Resolved 
 
Recovered/Resolved with sequelae 
 
Recovering/Resolving 
 
Not recovered/not resolved 
 
Fatal 
 
Unknown 
If the severity rating for an ongoing AE changes before the event resolves, the AE will not 
be reported a second time. Instead the original AE report will be revised. For purposes of 
data capture the highest severity rating during the course of a single AE will be the severity 
rating entered on the AE CRF. 
NOTE: A Participant's death per se is not an event, but an outcome. The event that resulted 
in the Participant's death must be fully documented and reported, regardless of being 
considered related to treatment or not. 
15.2.3 Solicited Adverse Events 
Solicited AEs will be collected in the e-Diary by the Participant for 7 consecutive days after 
each vaccination, starting on the day of vaccination. They will be graded by the investigator 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 71 / 109 
 
or the designee according to the FDA’s Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, see Table 4, Table 5 
and Table 6. 
For solicited AEs which are serious and/or medically attended, the investigator carries out 
more detailed assessments are performed for unsolicited AEs (causality, outcome, action 
taken) and documents them in the eCRF. For solicited local and systemic AEs persisting 
beyond 6 days after vaccination, stop date is also documented in the eCRF (AE section). 
15.2.3.1 Injection Site Reaction – Measurement and Evaluation 
Solicited injection site reactions include injection site pain, itching, tenderness, redness and 
swelling/induration. Participants will be provided with a measuring tool to measure the size 
of any measurable injection site reaction (longest diameter). 
Table 4 Grading of Injection Site Reactions 
15.2.3.2 Systemic Reactions – Measurement and Evaluation 
Solicited systemic reactions include fever/body temperature (Section 15.2.3.3), fatigue, 
headache, nausea/vomiting, muscle pain. 
Vaccine-specific 
Criteria 
Mild  
(Grade 1) 
Moderate  
(Grade 2) 
Severe  
(Grade 3) 
Potentially 
Life 
Threatening 
(Grade 4)c 
Pain 
Does not interfere 
with activity 
Repeated use of 
non-narcotic 
pain 
reliever > 24 hours 
or interferes with 
activity 
Any use of narcotic 
pain 
reliever 
or 
prevents daily activity
Emergency 
room 
visit 
or 
hospitalisation 
Tenderness 
Mild discomfort to 
touch 
Discomfort 
with 
movement 
Significant discomfort 
at rest 
Emergency 
room 
visit 
or 
hospitalisation 
Erythema 
/ 
Redness a 
2.5–5.0 cm 
0.98–1.96 inch  
5.1–10.0 cm 
1.97–3.94 inch  
> 10.0 cm 
> 3.94 inch  
Necrosis 
or 
exfoliative 
dermatitis 
Induration 
/ 
Swelling b 
2.5–5.0 cm  
(0.98–1.96 inch) 
and 
does 
not 
interfere 
with 
activity 
5.1–10.0 cm  
(1.97–3.94 inch) or 
interferes 
with 
activity 
> 10.0 cm 
(> 
3.94 
inch) 
or 
prevents daily activity
Necrosis 
a 
In addition to grading the measured local reactions at the greatest single diameter. 
b 
Induration/swelling should be evaluated and graded using the functional scale as well as the actual 
measurement. 
c 
Any Grade 4 injection site reaction will be reported as SAE, Grade 3 severity should be documented. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 72 / 109 
 
Table 5 
Grading of Systemic Reactions 
15.2.3.3 Fever and Body Temperature 
Participants will be provided with a digital thermometer to individually measure their body 
temperature orally once every evening from vaccination until Day 7 after each vaccination. 
In case fever (oral body temperature ≥ 38.0°C occurs, Participants should measure their 
body temperature every 4 to 8 hours until fever resolves (oral body temperature < 38.0°C . 
The time at which the first body temperature of < 38.0°C is recorded is considered to be the 
end of the fever episode. All fever measurements should be recorded by the Participant in 
the Participant diary including the first value that shows a return to normal body temperature. 
If more than one body temperature value is recorded in the Participant diary on a given day, 
the highest daily temperature reading will be recorded in the eCRF. 
Table 6 
Grading of Fever 
Mild 
38.0°C – 38.4°C  
Moderate 
38.5°C – 38.9°C  
Severe  
39.0°C – 40.0°C 
Potentially Life-Threatening 
>40.0°C  
 
15.2.4 Assessment of Symptoms Relating to SARS-CoV-2 
 
Vaccine-specific 
Criteria 
Mild  
(Grade 1) 
Moderate  
(Grade 2) 
Severe  
(Grade 3) 
Potentially 
Life 
Threatening 
(Grade 4)d 
Nausea/vomiting 
No 
interference 
with activity or one 
to two episodes/ 
24 hours 
Some interference 
with activity or > 2 
episodes/24 hours 
Prevents 
daily 
activity, 
requires 
outpatient 
IV 
hydration 
Emergency 
room 
visit 
or 
hospitalisation 
for 
hypotensive shock 
Headache 
No 
interference 
with activity 
Repeated use of 
non-narcotic 
pain 
reliever > 24 hours 
or 
some 
interference 
with 
activity 
Significant; any use 
of 
narcotic 
pain 
reliever or prevents 
daily activity 
Emergency 
room 
visit 
or 
hospitalisation 
Fatigue 
No 
interference 
with activity 
Some interference 
with activity 
Significant; prevents 
daily activity 
Emergency 
room 
visit 
or 
hospitalisation 
Myalgia 
No 
interference 
with activity 
Some interference 
with activity 
Significant; prevents 
daily activity 
Emergency 
room 
visit 
or 
hospitalisation 
a
Any Grade 4 systemic reaction will be reported as SAE, Grade 3 severity should be documented. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 73 / 109 
 
Participants who present at least one of the below mentioned symptoms during the study 
must contact their study team:  
 
Fever or chills   
 
Persistent cough (as defined by NHS, as a lot of coughing for more than 1 hour, or three or 
more coughing episodes in 24 hours. If the participant usually has a cough, it may be worse than 
usual. 
 
Shortness of breath, difficulty breathing  
 
Fatigue  
 
Muscle or body aches   
 
A loss of smell and taste 
 
Headache   
 
Sore throat  
 
Congestion  
 
Nausea or vomiting (more than one episode and/or persisting) 
 
Diarrhoea  
With the exception of fever, shortness of breath, or difficulty breathing, the symptom must 
be present for 2 or more consecutive days.  
 
15.2.5 Procedures in the Event of COVID-19 like Signs and Symptoms 
As a risk mitigation strategy, all enrolled participants will be intensively monitored during the 
conduct of the study to rapidly diagnose COVID-19 and referred for treatment according to 
local site procedures, if applicable. 
Participant who presents with at least one of the above-mentioned symptoms during the 
study, must contact the study team. In case of confirmed COVID-19 symptoms Participants 
will be tested on site by a validated test.  
In case of a negative test result, Participants will be invited for a second confirmatory test on 
site. In the event the result is still negative, the Participant will continue with scheduled visits. 
If either or both tests are positive, the participant will be performing a COVID-19 illness visit 
at site. Where supported, home or mobile visits may be substituted for this site visit As part 
of these visits, samples (a saliva sample and blood samples) will be taken for antigen and 
antibody assessment as well as recording of COVID-19-related clinical and laboratory 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 74 / 109 
 
information. During the Booster Phase, saliva samples will not be collected in line with the 
schedule of assessment (section 22.3) 
Participant should continue for 14 days after symptoms onset or until resolution of the 
COVID-19 episode, whichever comes last, with the home-collection self-swab kit every 2 
days. Resolution of COVID-19 is defined as having 2 consecutive SARS-CoV-2 negative 
swabs and 2 consecutive days with no COVID-19 related signs and symptoms.  
All confirmed COVID-19 episodes will be communicated to the respective participant and to 
other authorities according to local regulations. In addition, participants will be educated 
about current applicable public health guidances for confirmed COVID-19 cases. 
15.3 Electronic Diary 
Electronic diaries (e-Diary) will be used to record solicited AEs within 7 days after each 
vaccination and to make notes on unsolicited AEs until D36 and until V10 in the Booster 
Phase. Assessments by the Participant should occur at the same time each day, starting 
approximately 8 hours after vaccination. The Participant will be properly instructed on the 
reporting requirements and how to complete and use the Participant diaries, thermometer 
and measuring ruler (for assessment of measurable injection site reactions).  
The following information will be collected:  
 
Oral body temperature. 
 
Solicited injection site reactions. 
 
Solicited systemic reactions. 
 
Symptoms Relating to SARS-CoV-2 infection. 
 
Other AEs. 
 
Any new medication or changes in medication taken after vaccination. 
Study staff will be prompted to perform a phone call visit if a) no diary data are being reported 
by the Participant, b) a grade three solicited event has been reported, c) criteria for serious 
adverse event have been met and/ or d) symptoms relating to SARS-CoV-2 have been 
reported. 
 
Access to ePRO: 
Participants need to download “Patient Cloud” app from their APP Store 
 
Site need to register the patient in the EDC (Patient Cloud module) to generate the 
´Activation code´ and provide the same to Participant. Once Participant enters the 
activation code in the Patient Cloud App, the access is granted. This is just one time 
activity (no need to repeat it if ePRO has multiple visits). 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 75 / 109 
 
 
Note that the Site personnel (CRC/PI) should also be granted access to Patient Cloud 
in EDC so they can generate the activation codes for the Participants. 
 
During investigator meeting and site initiation visit the CRO will provide training on 
how to use ePRO App. So the Site personnel can train the Participants as need be. 
As well, an ePRO manual will be created that clearly explain how to use the App. 
 
The electronic diary will serve as source documentation. Entries in the diaries will be 
transcribed onto the appropriate eCRFs. Any entry on the eCRF that does not correspond 
with an entry in the diary will be explained by the Investigator on the relevant diary page. 
 
15.4 Medical, Medication, and Non-Drug Therapy History 
15.4.1 Medical history 
At screening, the Participant’s medical history will be described for the following body 
systems including severity (mild, moderate, or severe as defined in Section 15.2.1.1) or 
surgery and start and end dates, if known: eyes, ears, nose, and throat; respiratory; 
cardiovascular; gastrointestinal; musculoskeletal; neurological; endocrine; metabolic; 
hematopoietic/lymphatic; dermatological; and genitourinary. 
In addition, the medical history prior to screening will include the following: 
 
Previous SARS-CoV-2 infection.  
 
Information on planned hospitalisations (including elective surgery) during the study for 
medical conditions existing prior to or at study entry. Such planned hospitalisations do 
not need to be reported as SAEs. 
Booster Phase: 
During the Booster Phase, the Medical history will be reviewed in line with the Inclusion and 
Exclusion criteria and according to the schedule of assessments (section 22.3) 
15.4.2 Concomitant Medications and Non-Drug Therapies 
All medications or vaccines (including over-the-counter or prescription medicines) received 
from 2 weeks prior to study enrolment until completion/termination must be recorded in the 
eCRF along with the information listed below. Vitamins and/or herbal supplements are not 
to be recorded.  
 
Product name 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 76 / 109 
 
 
Reason for use 
 
Dates and routes of administration including start and end date 
 
Dosage information including dose frequency 
The Study Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
In addition, medications to treat SAEs will be reported to the Sponsor on SAE Report Forms 
as described in Section 3. In the context of this study, information on non-drug therapies will 
only be collected in relation to SAEs. 
The following medications are not permitted if administered within the specified study 
periods (unless such treatment has to be administered in an emergency situation): 
 
NOTE: for Participants who become hospitalized with COVID-19, receipt of licensed 
treatment options and/or participation in investigational treatment studies is permitted 
 
Receipt of any vaccine (licensed or investigational) other than licensed influenza 
vaccines within 30 days prior to and after administration of study intervention (except in 
medical emergencies such as tetanus or rabies exposure). 
 
Investigational products indicated for the treatment or prevention of SARS-CoV-2 or 
COVID-19 
 
Another IMP. 
 
Immunosuppressive treatmentix during the course of the study (unless such treatment 
has to be administered in an emergency situation). 
• 
Glucocorticoids at a dose ≥20 mg/day of prednisone or equivalent given daily 
or on alternate days for ≥14 consecutive days between randomization and the 
Participant´s schedule 
• 
Other systemically administered drugs with significant immunosuppressive 
activity, such as azathioprine, tacrolimus, cyclosporine, methotrexate, or 
cytotoxic chemotherapy between randomization and the Participant´s schedule 
 
Any blood products or immunoglobulins. 
                                                 
ix Treatment that can be expected to influence immune response. Such treatment includes, but is not 
limited to, systemic or high dose inhaled (> 800 μg/day of beclomethasone dipropionate or equivalent) 
corticosteroids, radiation treatment or other immunosuppressive or cytotoxic drugs. Use of inhaled 
(low dose), intranasal or topical steroids is permitted. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 77 / 109 
 
For documentary purposes, any of the treatments listed above (including emergency 
treatment) given within these time periods requires special documentation and is to be 
documented as a protocol deviation. 
The following medications and procedures will delay vaccination: 
 
Participant has current febrile illness (body temperature equal or greater 38.0°C) or other 
acute illness within 48 hours prior vaccination.  
 
Receipt of any vaccine within 30 days prior to study intervention, with the exception of 
the seasonal influenza vaccine. Participants will be encouraged to receive this 
vaccination at least 7 days before or after their study vaccine. 
 
Antipyretics received within 6 hours prior to vaccination. 
Use of any other medications or non-drug therapies is not restricted. 
Additionally, medications that are not permitted prior to study enrolment, resulting in 
exclusion from the study, are reflected in the exclusion criteria in Section 11.2. 
Booster Phase: 
During the Booster Phase prior and concomitant medications will be reviewed throughout 
the study according to the schedule of assessment (section 22.3). 
15.5 Vital Signs 
Vital signs will include body temperature (°C) measured orally, pulse rate (beats/min), and 
systolic and diastolic blood pressure (mmHg) while seated and at rest.  
Vital signs will be measured at screening (Visit 0), on Day 8, Day 36, Day 106 and Day 208. 
At both vaccinations visits (Day 1 and Day 22) these data should be recorded prior to 
vaccination and in addition, pulse rate and blood pressure should be assessed after 
vaccination while seated and at rest after a 30-minute observation period. In addition, for the 
sentinel dosing group, pulse rate and blood pressure should be recorded shortly before 
discharge from study site (3 hours or respectively, 60 min minutes after vaccination). 
Vital sign values are to be recorded on the appropriate eCRF. For each vital sign value, the 
Investigator will determine whether the value is considered an AE (see definition in 
Section 15.1.1). If assessed as an AE, the medical diagnosis (preferably), symptom, or sign, 
will be recorded on the AE CRF. Additional tests and other evaluations required to establish 
the significance or etiology of an abnormal result, or to monitor the course of an AE should 
be obtained when clinically indicated. Any abnormal value that persists should be followed 
at the discretion of the Investigator. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 78 / 109 
 
Booster Phase: 
During the Booster Phase, vital signs will be measured according to the schedule of 
assessment (section 22.3). 
15.6 Physical Examinations 
At screening (Visit 0), a physical examination will include, but will not be limited to 
assessment of height and weight, general appearance, head and neck, eyes and ears, nose 
and throat, chest, lungs, heart, abdomen, extremities and joints, lymph nodes, skin, and 
neurological. They will be described as normal or abnormal in the e-CRF 
A symptom-driven physical examination will be performed at all study visits except the 
Screening Visit (Visit 0), i.e. only if the Participant reports a symptom. In this case, a system-
based assessment will be performed for a detailed check of the affected body system(s). A 
symptom-driven examination should also be performed in case the Participant has 
complaints within the observation time after vaccination (See Section 22.2 and 22.3 for 
Booster Phase). 
Abnormal conditions detected at screening or prior to vaccination at Visit 1 will be recorded 
as medical history. At all other study visits, if a new abnormal or worsened abnormal pre-
existing condition is detected, the condition will be recorded as an AE. 
Booster Phase: 
During the Booster Phase, a symptom-driven physical examination will be performed 
according to the schedule of assessment (section 22.3) 
15.7 Clinical Laboratory Parameters 
Blood and urine samples will be obtained for assessment of clinical laboratory parameters 
as outlined in the Schedule of Study Procedures and Assessments (see Section 22.2 and 
22.3 for Booster Phase). Parameters will be analysed by central laboratories according to 
the applicable laboratory standard operating procedure (SOP). 
For women of childbearing potential, a urine sample and a serum test for pregnancy tests 
for beta-HCG should be performed at the site using a licensed test (dipstick).  
A baseline safety laboratory blood [30.0 mL] and urine sample will be obtained at Visit 0 
(screening visit) from all Participants for standard clinical chemistry, haematology, 
coagulation panel and urinalysis as well as for HIV/HBsAg/HCV testing. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 79 / 109 
 
Clinical chemistry 
(approx. 8.0 mL) 
Creatinine, sodium, potassium, calcium, aspartate transaminase 
(AST), alanine aminotransferase (ALT), alkaline phosphatase, 
bilirubin and C-reactive protein (CRP). 
Haematology panel 
(approx. 9.0 mL) 
Haemoglobin, haematocrit, erythrocyte count, white blood cell 
(WBC) count, differential WBC count (basophils, eosinophils, 
lymphocytes, monocytes, neutrophils), platelets, erythrocyte 
sedimentation rate (ESR). 
Coagulation panel 
(approx. 5 mL) 
Small blood coagulation (prothrombin time, activated partial 
thromboplastin time and fibrinogen). 
Urinalysis 
Standard urine dipstick for determining pH-value, specific gravity, 
leucocytes, nitrite, protein, glucose, ketones, urobilinogen, 
bilirubin, erythrocytes. 
HBsAg/ HCV / HIV test 
(approx. 8.0 mL) 
A positive HIV test obtained by enzyme-linked immunosorbent 
assay (ELISA) will have to be confirmed by a second method 
[e.g. Western blotting or PCR], at Visit 0 only. No 
HIV/HBsAg/HCV test needs to be performed if negativity has 
been established within the last 30 days prior to Visit 0. 
Pregnancy test 
approx. 2.0 mL 
A serum pregnancy test will be performed for all female 
Participants of childbearing potential at the screening visit only 
and a beta-human chorionic gonadotropin urine pregnancy test 
will be done prior to vaccination at Visit 1 and Visit 3  
Baseline serology will be drawn for detection of antibodies against SARS-CoV-2, HIV, HBV 
and HCV at the local lab. The results of SARS-CoV-2 tests that were performed up to 7 days 
before Visit 0 are acceptable. The results of negative HIV tests that were performed up to 30 
days before Visit 0 are acceptable. A positive HIV test obtained by ELISA will have to be 
confirmed by a second method (e.g. Western blot or PCR) [blood (for all tests): 5 mL]. In 
addition, an HLA typing test will be done at Screening (20 mL) 
Laboratory values will be evaluated according to the Toxicity Grading Scale for Healthy Adult 
and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (FDA). For the 
individual toxicity criteria refer to section 22.4.  
Laboratory assessments for which no severity grading is described in section 22.4 are 
graded as described in Section 15.2.1.1 upon the Investigator’s judgement. 
The Investigator’s assessment of each abnormal laboratory value, including its clinical 
significance, is to be recorded in the eCRF:  

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 80 / 109 
 
 
Abnormal laboratory assessments that are considered clinically relevant, in the opinion 
of the Investigator, need to be documented as unsolicited AEs and assessed further for 
severity according to the toxicity grading scale provided in Section 22.4, causality and 
other assessments done for unsolicited AE (see Section 15.2.1).  
 
Abnormal laboratory assessments that are considered a symptom of an underlying AE 
or part of a syndrome that is reported as AE (e.g. presence of blood cells in urine in a 
person diagnosed with urinary tract infection) do NOT additionally need to be 
documented as unsolicited AE, but a respective comment should be added to the 
underlying AE. 
Additional tests and other evaluations required to establish the significance or aetiology of 
an abnormal laboratory result or to monitor the course of an AE should be obtained when 
clinically indicated. Any abnormal value that persists should be followed at the discretion of 
the Investigator. 
Booster Phase: 
During the Booster Phase, clinical laboratory parameters will be assessed according to the 
schedule of assessment (section 22.3). 
15.8 Saliva Samples 
Saliva samples will be taken from ALL Participants at the time points indicated in the 
Schedule of Procedures (section 22.3) for future investigation of mucosal immune responses 
to VLA2001. 
Booster Phase: 
During the Booster Phase, saliva samples will not be collected in line with the schedule of 
assessment (section 22.3). 
15.9 Case Definitions 
A COVID-19 case is defined as follows:  
Virologically (SARS-CoV-2 positive) confirmed SARS-CoV-2 infection with one or more of 
the following symptoms listed below:  
 
Fever or chills  
 
Persistent of cough, as defined by NHS, as a lot of coughing for more than 1 hour, or three or 
more coughing episodes in 24 hours. If the participant usually has a cough, it may be worse than 
usual. 
 
Shortness of breath or difficulty breathing  

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 81 / 109 
 
 
Fatigue   
 
Muscle or body aches   
 
Headache   
 
New loss of taste or smell  
 
Sore throat  
 
Congestion  
 
Nausea or vomiting (more than one episode and/or persisting) 
 
Diarrhoea 
 
With the exception of fever, shortness of breath, or difficulty breathing, the symptom must 
be present for 2 or more consecutive days.  
Cases 
are 
defined 
by 
laboratory 
confirmation 
of 
SARS-CoV-2 
and 
signs/symptoms/examinations that occur within 14 calendar days of the initial symptom(s).  
A case of severe COVID-19 is defined as follows: 
Virologically confirmed SARS-CoV-2 infection with any of the following:  
 
Clinical signs at rest indicative of severe systemic illness (respiratory rate ≥ 30 per 
minute, heart rate ≥ 125 per minute, SpO2x ≤ 93% on room air at sea level or PaO2/FiO2  
< 300 mm Hg).   
 
Respiratory failure (defined as needing high-flow oxygen, non-invasive ventilation, 
mechanical ventilation or extra corporal membrane oxygenation).  
 
Evidence of shock (systolic blood pressure < 90 mm Hg, diastolic blood pressure  
< 60 mm Hg, or requiring vasopressors). 
 
Significant acute renal, hepatic, or neurologic dysfunction.  
 
Admission to an intensive care unit. 
 
Death. 
 
                                                 
x Oximetry parameters: SpO2=oxygen saturation; PaO2=partial pressure of oxygen; FiO2=fraction of 
inspired oxygen 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 82 / 109 
 
15.10 Adverse Events of Special Interest 
Enhanced respiratory disease has been reported in animal models for SARS-CoV-1 
vaccines. Although several NHP studies for SARS-CoV-2 vaccines including inactivated 
vaccines showed no evidence of enhanced disease, disease enhancement remains a 
theoretical safety concern. Therefore, COVID-19 manifestations and complications 
associated with COVID-19 (such as but not limited to pneumonia, neurological or vascular 
complications, severe pneumonia, severe neurological or vascular events, acute respiratory 
distress syndrome, renal complications, sepsis, septic shock, death) will be closely 
monitored as AESIs. In addition, because the vaccine contains a relatively novel adjuvant 
(CpG 1018) for which immune-mediated disorders are considered AESI (Munoz et al, 2020), 
those will also receive particular attention. All AESIs will be treated as medically 
significant and will therefore be treated as SAEs. A list of AESIs can be found in Annex 
22.5. 
15.11 Adverse Event Reporting Procedures 
All AEs will be reported from the time a signed and dated informed consent form (ICF) is 
obtained until the end of the study/early withdrawal. Clinically relevant medical events not 
meeting the above criteria and occurring between ICF signature and the first vaccination will 
be collected on the medical history electronic case report form (eCRF) page as pre-existing 
conditions. The sponsor will evaluate any safety information that is spontaneously reported 
by an Investigator beyond the time frame specified in the protocol. All AEs will be followed 
until resolution or until clinically stable. 
15.11.1 Serious Adverse Event 
Any SAE should be reported via the Safety Gateway within EDC-system within 24 hours 
after the Investigator has become aware of the event.  
Under certain circumstances the initial notification could be done by phone, but nevertheless 
a written SAE Report Form must be submitted to the Safety Officer within 24 hours (see 
Section 2). 
The study centre will be provided with specific reporting procedures. SAEs will be entered 
into the SAE eCRF page using a recognized medical term or diagnosis that accurately 
reflects the event. All identified patient’s documents supporting the SAE should be sent to 
the CRO as soon as they are requested by the Medical Monitor/Drug Safety Officer by e-
mail (preferable) or by fax using the contact information on Page 3. Fatal or life-threatening 
SAEs that the Investigator suspects are related to the study vaccine should be telephoned 
to the local Medical Monitor immediately upon the Investigator’s awareness of the event. 
All SAEs are reported to the Sponsor for the entire study period and for 30 days after the last 
visit for each participant. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 83 / 109 
 
SAE term should represent diagnosis. Only in case no diagnosis can be identified, each 
symptom should be reported separately. 
Medical or diagnostic procedures due to an underlying disease or symptom are not 
considered an AE but a consequent measure following an AE. A correct SAE report will 
therefore have to specify the disease or symptom as the reportable AE and the medical or 
diagnostic procedure as action taken. 
In addition, expedited and periodic reporting to Competent Authorities and ECs will be 
performed in accordance with local requirements. Further reporting details can be found in 
the study-specific SAE procedure which is in accordance with respective EU requirements, 
ICH GCP, national laws and site-specific requirements. Serious adverse events that are 
considered as probably or possibly related and additionally are unexpected need to be 
reported according to the requirements for suspected unexpected serious adverse reactions 
(SUSARs). 
Serious adverse event reports will be reviewed by the study site’s physician, the Safety 
Officer, the study medical monitor, the Sponsor and the independent DSMB. 
All AESIs will be treated as medically significant and will therefore be treated as SAEs. Thus, 
SAE reporting procedures are also to be applied for AESIs. 
Beyond study end, SAEs that are fatal events, life-threatening or suspected to be 
related to study treatment will be followed up until 6 months after the last vaccination 
of the respective Participant. 
15.11.2 Pregnancy 
The risk of maternal to foetal transmission of SARS-CoV-2 during pregnancy cannot be 
excluded. Thus, women must not become pregnant during the first 3 months post-
vaccination until Visit 5 (Day 106) as well as the first 3 months after the Booster vaccination.  
Reporting requirements start with administration of the vaccination until study completion (or 
ET Visit). All pregnancies that occur during the clinical study period will be followed-up for 3 
months after delivery or termination of the pregnancy. Any effect on either mother or foetus 
should be determined. A pregnancy which led to a congenital anomaly/birth defect must be 
followed-up by the Investigator longer or until resolution or stabilization. Duration of 
prolonged follow-up will be decided on an individual basis and in accordance with the 
Sponsor. The Investigator will prepare a narrative on the course of the pregnancy and the 
outcome. 
The Investigator should report pregnancies within 24 hours of being notified using the 
Pregnancy Report Form. Reporting procedures are similar to SAE reporting procedures 
(contacts and processing), although a pregnancy is not considered an SAE.  

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 84 / 109 
 
If a seriousness criterion applies in addition to the pregnancy (e.g. hospitalisation, congenital 
anomaly/birth defect) the pregnancy qualifies as an SAE. In such case a Pregnancy Report 
Form and an SAE Report Form must be filled out. 
 
15.11.3 Data Safety Monitoring Board 
An independent DSMB, consisting of experts that will be selected based upon their expertise 
in infectious diseases (preferably clinical experience with COVID-19) vaccines clinical 
research and/or clinical medicine, will be utilised in this study to provide independent 
monitoring of safety data/issues during the course of the study and make recommendations 
to the Sponsor regarding further conduct of the study, further vaccinations in the study and/or 
protocol modifications to be installed for safety reasons. A DSMB charter including a detailed 
description will be prepared. 
Responsibilities of the DSMB 
 
Review of accrued safety data of the 15 sentinel Participants including safety data at 
least 3 days post vaccination of the high dose group to decide whether it is safe to 
proceed with recruitment. 
 
Review of accrued safety data of the first 60 randomised Participants (overall 20 
Participants per dose group) including safety data at least 7 days post vaccination. 
 
Review of any case reports of SAEs/AESIs on an ad-hoc basis. 
 
Periodically review unblinded listings and summary tabulations of SAEs, deaths, solicited 
AEs, unsolicited AEs and AEs leading to withdrawal from further vaccinations.  
 
All cases of COVID-19 and severe COVID-19 will be assessed by the Sponsor and 
presented to the DSMB for adjudication against the case definitions.  
 
Participate in ad-hoc DSMB reviews initiated if enrolment is interrupted by the principal 
Investigator, the Sponsor or the medical monitor at the CRO for any safety reasons, or if 
a pre-specified study stopping rule applies. 
 
The DSMB can issue a recommendation to stop the study during ad-hoc DSMB meetings, 
or to discontinue a treatment group, e.g. in response to an excess rate of AEs with the same 
suspected underlying pathological mechanism. 
 
Booster phase: 
During the Booster Phase, a scheduled DSMB review will be performed once all vaccinated 
Participants have completed their Visit 7. 
 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 85 / 109 
 
15.11.4 Sponsor 
Listings of available blinded safety data will be closely reviewed by the Sponsor to identify 
any potential safety concerns until the last Participant reaches Day 36 and during the Booster 
Phase. 
15.11.5 Investigator 
To ensure information exchange on safety across sites, Investigators will be provided with 
safety information pertaining to all severe (Grade 3) AEs and all SAEs reported in the eCRF.  

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 86 / 109 
 
16. STATISTICS  
16.1 Sample Size and Power Calculations 
A total of 150 Participants is considered sufficient to obtain initial safety data for VLA2001, 
especially since inactivated vaccines are a well-established, safe vaccine technology. Fifty 
Participants per group will allow for 95% confidence that an AE with a true underlying 
incidence of about 2% would be observed in the present study.  
In addition, assuming 10% of Participants with protocol deviations, about 45 Participants per 
dose group will be evaluable for immunogenicity. This sample size is in a range generally 
expected to allow selection of an appropriate dose level. 
Booster Phase: 
For the Booster Phase of this study no formal sample size calculation has been performed 
and no minimal or maximal number of participants is defined. Based on operational 
considerations the total number of participants is expected to be up to approximately 80 
Participants. 
16.2 Datasets and Analysis Cohorts 
Safety Analysis Set (SAS) 
The Safety Analysis Set (SAS) includes all Participants who entered into the study and 
received at least one vaccination. The SAS will be used for all baseline, safety and tolerability 
analyses including demographic data, local/systemic tolerability, laboratory data, (S)AEs and 
AESIs. All analyses based on the SAS will be carried out using the actual treatment received.  
Full Analysis Set (FAS) 
The Full Analysis Set (FAS) is defined to include all Participants enrolled who received at 
least one vaccination. Participants will be analysed according to the treatment group they 
had been allocated to, rather than by the actual treatment they received. 
Per-Protocol Analysis Set (PPAS) 
The Per-Protocol Analysis Set (PPAS) will consist of the FAS population excluding 
Participants that meet one of the following criteria, which possibly have an impact on the 
immunogenicity read-out:   
 
Participants with less than two vaccinations. 
 
Participants who received the wrong study medication.  
 
Participants who fulfilled exclusion criteria  

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 87 / 109 
 
These criteria for potential protocol violations are identified at the time of study planning. 
However, during the course of the trial unforeseen events may occur or new scientific 
knowledge may become available, therefore final decisions on all protocol violations will be 
made on a case by case decision in a data review meeting. 
Immunogenicity analysis will be primarily carried out on the PPAS. 
16.3 Handling of Missing, Unused, and Spurious Data 
All immunogenicity analysis will be based on observed values. Missing values will neither be 
replaced nor estimated. For missing data in AE evaluation (e.g. severity information) a worst 
case approach will be applied. 
16.4 Methods of Analysis 
A Statistical Analysis Plan (SAP) will be provided describing in more detail, how the study 
results will be evaluated. The SAP will be finalized prior to the Blind Data Review Meeting 
for Part A analysis 
Data will be summarized by treatment group and, where appropriate, by visit and SARS-
CoV-2 baseline serostatus. Descriptive statistics (number of observations, mean, standard 
deviation, minimum, median, and maximum) will be provided for continuous variables (e.g. 
age and weight). Frequency counts and percentages will be presented for categorical 
variables (e.g. gender). 
All data exclusions, including premature terminations, will be detailed and tabulated. Data 
listings will include enrolled Participants.  
Baseline characteristics including demographic variables, medical and vaccination history 
and concomitant medications will be subject to descriptive analyses. 
AEs and medical history will be coded using the MedDRA coding dictionary. Concomitant 
medications (including vaccinations) will be coded using the WHO Drug Dictionary.  
More detailed criteria to identify Participants in each analysis set, other research questions 
of interest not covered in this protocol, the definition of endpoints and details of their 
calculation, as well as further details on how to deal with missing, unused and spurious data 
will be covered in the SAP. If a change of the planned analyses is considered necessary 
after protocol finalization, this will be described and justified in the SAP. If a change is made 
after the statistical analysis has been performed, this will be described and justified in the 
CSR. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 88 / 109 
 
16.4.1 Primary Safety Endpoint 
The number and percentage of Participants with solicited local and systemic AEs within 
7 days after each and after any vaccination will be presented. Differences between the 
treatment groups will be assessed for significance using Fisher’s exact test, a significant 
overall test will be amended by pair-wise tests. 
This analysis will be repeated stratified by baseline SARS-CoV-2 serostatus. 
16.4.2 Primary Immunogenicity Endpoint  
The primary immunogenicity analysis will be a comparison of GMTs for SARS-CoV-2 
neutralizing antibodies at 14 days after the second dose (i.e. Day 36). 
Therefore, GMTs and GMT ratios will be estimated by applying an analysis of variance 
(ANOVA) including the factor treatment group and study site. This will be done using log10 
transformed data and taking the anti-log of the resulting point estimates for the least squares 
means, least squares means differences and the corresponding 95% CIs. Tukey’s HSD test 
will be applied for pair wise comparisons. 
16.4.3 Secondary Endpoints  
16.4.3.1 Secondary Safety Endpoints 
The number and percentage of Participants with unsolicited AEs (including those with 
clinically relevant laboratory parameter changes), related AEs, AESIs and SAEs will be 
presented for each study arm, overall, by system organ class/preferred term and by severity. 
Differences between study groups will be assessed for significance using Fisher’s exact 
(Fisher-Freeman-Halton) test, whereby a significant overall test will be amended by pair-wise 
tests, and 95% confidence interval (CI) will be presented for all AE rates.  
The number and percentage of Participants with abnormal laboratory parameters will be 
presented for each study arm, overall and by parameter. 
Further details will be provided in the Statistical Analysis Plan (SAP).  
All analyses of safety data will be based on the SAS. 
16.4.3.2 Secondary Immunogenicity Endpoints 
Secondary immunogenicity analysis will include the comparison of the GMTs as well as 
comparison of geometric mean fold increase (GMFI) between study groups on other study 
days. ANOVA models as described for the primary immunogenicity endpoint will be applied. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 89 / 109 
 
Seroconversion rates for various study days as well as rates of Participants reaching certain 
fold-increase will be compared between the study groups using Fisher’s exact (Fisher-
Freeman-Halton) test, whereby a significant overall test will be amended by pair-wise tests, 
and 95% confidence intervals will be calculated. Immunogenicity analysis will be repeated 
stratified by serostatus for SARS-CoV-2 at screening.  
Immunogenicity analysis will generally be based on the PPAS. Immunogenicity analysis 
conducted on the FAS will be defined in the SAP. 
16.4.4 Exploratory Endpoints 
Results of the cellular immune response will be analysed descriptively by treatment group. 
16.5 Planned Data Analysis of the Study 
The following data analyses will be performed:  
 
Part A includes safety and immunogenicity data after all Participants have completed 
Visit 4 (Day 36).  
 
Part B includes safety and immunogenicity data after all Participants have completed 
Visit 6 (Day 208). 
 
An additional data analysis will be performed during part B after all Participants have 
completed Visit 5 (Day 106) 
 Part C includes Visits 7 to 10. An analysis of Part C will be done when all participants 
have completed visit 9.  
 Final analysis will be done when all participants have completed the last visit (visit 10) 
Individual study parts will be analysed sequentially.  
Part A analysis will be performed once the last Participant has completed Day 36 (Visit 4) 
and will comprise the primary immunogenicity and safety endpoints; the study will be 
unblinded at this time. Part B analysis will be performed once the last Participant has 
completed Day 208 (Visit 6). 
16.6 Clinical Study Report 
Interim 
Clinical 
Study 
reports 
will be 
published 
after part 
B 
and 
part C. 
A final Clinical Study Report will be published upon availability of all data. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 90 / 109 
 
17. ETHICS AND REGULATORY ASPECTS 
17.1 Compliance Statement 
This study will be conducted in accordance with this protocol, current ICH GCP guidelines, 
Declaration of Helsinki, and with the applicable national and local regulatory requirements. 
17.2  Ethics Committee and Regulatory Authorities 
Before enrolment of healthy volunteers into this study, the protocol, informed consent form, 
any promotional material/advertisements, and any other requested information will be 
reviewed and approved/given favourable opinion by the EC and applicable regulatory 
authorities in accordance with local requirements. The study will commence only upon the 
Sponsor’s receipt of approval/favourable opinion from the EC.  
If the protocol and/or any other information given to the Participant is/are amended, the 
revised document(s) will be reviewed and approved/given favourable opinion by the EC and 
applicable regulatory authorities in accordance with local requirements, where applicable. 
The protocol amendment will only be implemented upon the Sponsor’s receipt of approval. 
Amendments that are intended to eliminate an apparent immediate hazard to Participants 
may be implemented prior to receiving EC and authority approval. However, in this case, 
approval must be obtained as soon as possible after implementation. 
17.3 Participant Information and Informed Consent 
It is the Investigator’s responsibility to obtain freely given, written, informed consent from the 
Participant before the Participant is exposed to any study-related procedures, including 
screening tests for eligibility.  
The informed consent form will include a comprehensive explanation of the proposed 
treatment without any exculpatory statements, in accordance with the elements required by 
ICH GCP and applicable regulatory requirements. Volunteers will be allowed sufficient time 
to consider participation in the study after having the nature and risks of the study explained 
to them. By signing the informed consent form, volunteers agree that all evaluations required 
by the study will be completed, unless they withdraw voluntarily or are terminated from the 
study for any reason. 
The Investigator will explain that the Participants are completely free to refuse to enter the 
study or to withdraw from it at any time, without any prejudice and need for justification. The 
Participants will be informed that representatives of the Sponsor and health authority 
inspector may review their source records, and that these persons are bound by 
confidentiality obligations. 
The Participant will be given a copy or a second original of the ICF. An original of the signed 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 91 / 109 
 
and dated ICF must be retained in the site’s records and is subject to inspection by 
representatives of the Sponsor or representatives from regulatory agencies. 
The Sponsor will provide to the Investigator in written form any new information that 
significantly bears on the Participants’ risks associated with study vaccine exposure. The 
informed consent form will be updated, if necessary. This new information and/or revised 
informed consent form, which has been approved by the applicable EC and regulatory 
authorities, will be provided by the Investigator to the Participants who consented to 
participate in the study. 
18. QUALITY CONTROL AND QUALITY ASSURANCE 
18.1 Source Data and Records 
Source data are defined as all information related to clinical findings, observations or other 
activities in the study, captured in original records or certified copies of original records. The 
Investigator will permit study-related monitoring, audits, EC review and regulatory 
inspections, by providing direct access to source data/records. Source records should be 
preserved for the maximum period of time required by local regulations. 
Source data entries must be made in accordance with local requirements. Signed and dated 
copies of the laboratory result reports must be kept within the Participant’s source data file. 
For data collected via the electronic Participant diary (e-Diary), the e-Diary is regarded as 
source document. 
18.2 Investigator’s Responsibility 
The Investigator will comply with the protocol (which has been approved/given favourable 
opinion by the EC), ICH GCP, and applicable regulatory requirements. The Investigator is 
ultimately responsible for the conduct of all aspects of the study at the study site and verifies 
by signature the integrity of all data transmitted to the Sponsor. The term ‘Investigator’, as 
used in this protocol and in study documents, refers to the Investigator or authorized study 
personnel whom the Investigator has designated to perform certain duties. Sub-Investigators 
or other authorized study personnel are eligible to sign for the Investigator, except where the 
Investigator’s signature is specifically required. 
18.3 Training 
The study monitor will ensure that the Investigator and study site personnel understand all 
requirements of the protocol, the investigational status of the vaccine, and his/her regulatory 
responsibilities as an Investigator. Training may be provided at an Investigator’s meeting, at 
the study site, web-based, and/or by instruction manuals. In addition, the study monitor will 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 92 / 109 
 
be available for consultation with the Investigator and will serve as the liaison between the 
study site and the Sponsor. 
18.4 Monitoring 
A designated monitor will check electronic system data and source data at regular intervals 
throughout the study to verify completeness, accuracy and consistency of the data, protocol 
adherence, and adherence to GCP guidelines. The monitor will work and perform Source 
Data Verification according to the Monitoring Plan. The Investigator will cooperate with the 
monitor to ensure that any discrepancies identified are resolved. 
18.5 Audit and Inspection 
Upon request, the Investigator will make all study-related source data and records available 
to a qualified quality assurance auditor mandated by the Sponsor or to regulatory inspectors. 
The main purposes of an audit or inspection are to confirm that the rights and welfare of the 
Participants have been adequately protected, and that all data relevant for the assessment 
of safety and efficiency of the investigational product have appropriately been reported to 
the Sponsor.  
18.6 Non-Compliance with the Protocol/Deviations from the Protocol 
Any deviations from the protocol will be tracked, actions defined, as feasible, and reviewed 
in Data Review meetings for the study part analysis and the final analysis for assessment of 
their influence on the quality of the study analysis.  
18.7 Confidentiality of Participant’s Data 
The Investigator will exercise all reasonable precautions within the constraints of the 
applicable regulatory requirements to maintain the confidentiality of Participants’ identities. 
On exported electronic source data or any other documents submitted to the Sponsor, 
Participants will only be identified by Participant number. Documents not for submission to 
the Sponsor, e.g. Participant identification log and original ICF, will be maintained by the 
Investigator in strict confidence. 
19. DATA HANDLING AND RECORD KEEPING 
19.1 Information of Investigators 
An Investigator Brochure (IB) containing all important data relating to the safe use of the IMP 
will be supplied to the Investigator prior to study start. 
The Investigator will be kept informed on new relevant safety data as the study proceeds. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 93 / 109 
 
19.2 Electronic Case Report Forms 
19.2.1 Data Recorded Directly on Case Report Forms 
An eCRF will be used for this study. Data will be recorded directly onto source documents 
before documentation in the eCRF. 
19.2.2 Electronic Case Report Form Entries 
Electronic case report form entries and corrections will only be performed by study site staff 
authorized by the Investigator. Each user is informed of the clinical study’s web-site internet 
address and is allocated to a user account with personal password to access the confidential 
website. The personal password must be kept confidential and must only be used by the 
person to whom it was assigned. For additional authorized users at the site, a new user 
account must be requested to ensure that each entry/change can be allocated to the person 
who performed the entry/change. 
All visit data need to be recorded in the eCRF database as soon as possible after each study 
visit, no later than 1 business day after data have been collected.  
 
19.2.3 Changes to Electronic Case Report Form Data 
Corrections may be requested as follows: 
 
Investigators’ responses are checked as they are entered and are rejected if they do not 
fulfil quality criteria. A message will specify the type of error or syntax error and assist in 
its correction. 
 
If required, the CRA can ask for information to be corrected during monitoring.  
 
Computerized data-check programs and manual checks will identify clinical data 
discrepancies for resolution. Corresponding queries will be created within the data 
capturing system and the site will be informed about new issues to be resolved on-line. 
All discrepancies will be solved on-line directly by the Investigator or by authorized staff. 
Corrections of eCRF data may be performed by authorized staff only. The person performing 
the changes in the eCRF is required to confirm electronically the changes made.  
 
19.2.4 Electronic Case Report Form Entry Validation 
The Investigator will thoroughly review the data on the eCRF and will finally certify the 
contents of the eCRF by electronic signature after completion of each Participant. If a 
correction is made to the eCRF data after the Investigator’s final approval, the certification 
must be repeated after the changes have been performed. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 94 / 109 
 
 
19.2.5 Data Collection 
All visits and assessments are entered into an interactive form. Electronic case report forms 
will be source document verified following guidelines established before study onset and 
detailed in the Monitoring Plan. The study database will be maintained. Details of eCRF 
handling are provided in a study specific eCRF manual. 
 
19.3 Coding of Adverse Events, Drugs and Diseases 
After data entry, AEs and medical history will be coded according to the latest version of the 
Medical Dictionary for Regulatory Activities (MedDRA). The same version will be applied to 
all study parts. Previous and concomitant medication and vaccines will be coded according 
to the latest version of the WHO Drug Reference List and Anatomical Therapeutic Chemical 
Classification System.  
 
19.4 Investigator File 
19.4.1 Maintenance 
The Investigator will maintain complete and accurate study documentation in a separate file 
(i.e. Investigator File) provided during the initiation visit. The Investigator is responsible for 
maintaining complete, up to date and accurate study records to enable the conduct of the 
study to be fully documented. The records should include the clinical protocol as well as any 
amendments, study approval letters, all original ICFs, drug dispensing and accountability 
logs and all relevant correspondence pertaining to the study. 
 
19.4.2 Archiving and destruction 
All study-related documents should be kept by the Investigator for the maximum period of 
time required by local regulations. No study document should be destroyed without prior 
written agreement between the Investigator and the Sponsor. Should the Investigator elect 
to assign the study documents to another party, or move them to another location, the 
Sponsor must be notified. 
 
19.4.3 Provision of Additional Information 
On request, the Investigator will supply the Sponsor with additional data relating to the study 
or copies of relevant source records, duly anonymized. In case of particular issues or 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
 
Valneva Austria GmbH 
CONFIDENTIAL 
 
page 95 / 109 
 
governmental queries, it is also necessary to have access to the complete study records, 
provided that the Participant's confidentiality is protected in accordance with applicable 
regulations. 
20. PUBLICATION POLICY 
All results generated in this study will be considered to be strictly confidential. The 
Investigator may not submit the results for publication or presentation without prior written 
permission of the Sponsor. Authorship for any publication will be determined in mutual 
agreement. Within the scope of publication, co-authorship may be offered, at the sole 
discretion of the Sponsor, on a case-by-case basis taking scientific contribution into 
consideration. This is according to uniform requirements for manuscripts submitted to 
biomedical journals proposed by the International Committee of Medical Journal Editors. 
21. LIABILITIES AND INSURANCE 
In case of any damage or injury occurring to a Participant in association with the participation 
in the study, insurance has been contracted. 
The name, address and the insurance policy number will be given to both the Investigator 
prior to enrolment. Moreover a copy of the insurance conditions will be filed on site. 
The Investigator is responsible for dispensing the investigational product according to this 
protocol, and for its secure storage and safe handling throughout the study. 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
Valneva Austria GmbH 
CONFIDENTIAL 
page 96 / 109 
 
22. SUPPLEMENTS 
22.1 Study Flow Chart 
Figure 1 
Study Design for First-in-Human Clinical Study VLA2001-201 
 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
Valneva Austria GmbH 
CONFIDENTIAL 
page 97 / 109 
 
22.2 Schedule of Study Procedures and Assessments 
The investigator may schedule visits (unplanned visits in addition to those listed in the table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant 
Procedures/Assessments 
Visit 0 
Scree-
ning 
(Day -7 to 
Day 0) 
Visit 1 l 
Day 1 
 
 
Safety 
phone 
calls for 
sentinel 
group* 
Visit 2 
Day 8 
 
(+/- 1d) 
Visit 3 
Day 22 
 
(+/- 2d) 
Visit 4 
Day 36 
 
(+/- 2d) 
Visit 5 
Day 106 
 
(+/- 7d) 
Visit 6 
Day 208 
M7 
(+/- 14d) 
Unplanned
COVID-
19 
Illness 
Visit 
Ad hoc Safety 
Call in case of 
e-Diary 
entry 
(Grade 3 AE or 
SAE)
Visit
ET 
 
Informed consent a 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria check 
X 
X 
(Review) 
 
 
 
 
 
 
 
 
 
Delay criteria check 
 
X 
 
 
X 
 
 
 
 
 
 
Demographics b 
X 
 
 
 
 
 
 
 
 
 
 
Medical 
history 
c
(including vaccination history) 
X 
X 
(Update) 
 
 
 
 
 
 
 
 
 
Physical/Symptom-driven 
examination d 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
Prior/Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs e 
X 
X 
 
 
X 
 
X 
X 
 
 
X 
Baseline serology f 30 mL] 
X 
 
 
 
 
 
 
 
 
 
 
Serum/Urine Pregnancy test g [ 2 
mL] 
X 
X 
 
 
X 
 
 
 
 
 
 
Safety labs h [10 mL] 
X 
 
 
X 
X 
X 
 
X 
X 
 
X m 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
 
Immunogenicity sample i [10 mL] 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
Blood for PBMC Isolation j [50 mL] 
 
X 
 
 
 
X 
 
X 
 
 
 
Saliva Sample k 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
Blood for passive transfer studies n 
[50 mL] 
 
 
 
 
 
X 
 
 
 
 
 
VACCINATION 
 
X 
 
 
X 
 
 
 
 
 
 
Electronic Participant Diary 
 
E 
R 
R 
R/E 
R 
 
 
 
R 
R 
AE/AESI/SAE Assessment  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
(S)AE=(serious) adverse event; AESI=adverse event of special interest; PBMC=peripheral blood mononuclear cells; R=review  

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
Valneva Austria GmbH 
CONFIDENTIAL 
page 98 / 109 
 
 
*Safety call sentinel group: first Participant per dosing group approx. 24 hours, Participants 2 to 5 approx. 48 hours after vaccination 
 
a Occurs at enrolment before Screening. 
b Demographics include year of birth, height, weight, BMI, gender, race and ethnicity. 
c Symptoms noted at Visit 1 (prior to first vaccination) are not considered AEs but will be recorded as medical history.  
d At the screening visit, a physical examination will be performed on the following body systems being described as normal or abnormal: general appearance, 
head and neck, eyes and ears, nose and throat, chest, lungs, heart, abdomen, extremities and joints, lymph nodes, skin, and neurological. At subsequent 
visits, and prior to discharge after vaccinations on Visits 1 and 2, a symptom-driven physical examination will be performed, i.e. only in case symptom is 
reported by the Participant, an assessment of the affected body system(s) will be performed.  
e Vital signs will include systolic and diastolic blood pressure and pulse rate while seated and at rest, and body temperature measured orally before vaccination. 
In addition, after an observation period of 30 minutes (60 minutes for the 15 sentinel Participants) following vaccination pulse rate as well as blood pressure 
while seated and at rest will again be assessed. 
f A baseline serology will be drawn for detection of antibodies against SARS-CoV-2, HIV, HBV and HCV at the local lab. The results of SARS-CoV-2 tests that 
were performed up to 7 days before Visit 0 are acceptable. The results of negative HIV tests that were performed up to 30 days before Visit 0 are acceptable. 
A positive HIV test obtained by ELISA will have to be confirmed by a second method (e.g. Western blot or PCR) [blood (for all tests): 5 mL].  
g A serum pregnancy test will be performed for all female Participants of childbearing potential at the screening visit only and a urine pregnancy test will be done 
prior to vaccination at Visit 1 and Visit 3 [blood: 2 mL].  
h Baseline safety labs for standard clinical chemistry (i.e. creatinine, sodium, potassium, calcium, aspartate aminotransferase, alanine aminotransferase, alkaline 
phosphatase, bilirubin, CRP), haematology (i.e. haemoglobin, haematocrit, erythrocyte count, white blood count, differential white blood cell count, platelets, 
erythrocyte sedimentation rate , coagulation panel (i.e. prothrombin time, aPTT, fibrinogen) [EDTA blood: 30 mL] and urinalysis (i.e. pH, specific gravity, 
leucocytes, nitrite, protein, glucose, ketones, urobilinogen, bilirubin, erythrocytes. 
i An immunogenicity sample will be drawn [10mL] for SARS-CoV-2-specific neutralizing antibody titre evaluation and ELISA testing, development or performance 
of further assays related to development of this vaccine candidate and/or retrospective safety analysis if deemed necessary by the Data Safety Monitoring 
Board upon clinical indication or on demand if requested later by regulatory authorities. 
j A blood sample [approx. 50mL] will be collected to isolate PBMCs from all Participants except sentinel Participants for future investigation of cellular immune 
responses to VLA2001. PBMCs may also be used for further research activities considered relevant to SARS-CoV-2, e.g., HLA typing.  
k Saliva samples will be obtained from all Participants for future investigation of mucosal immune responses to VLA2001.  
l All procedures/assessments (apart from e-Diary explanation and AE assessment) occur prior to vaccination (unless stated otherwise). 
m A safety lab sample will be obtained if early termination occurs before Day 36 (Visit 4). 
n A blood sample [approx. 50mL] will be collected to isolate serum from all Participants consenting to the additional blood volume for studies to support the 
establishment of a robust clinical endpoint for identification of neutralizing antibody levels associated with protection from COVID-19.  
 
Please note: 
 
Due to local requirements, medical history should be checked with Participants’ medical records (GP / hospital) prior Day 1 
 
 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
Valneva Austria GmbH 
CONFIDENTIAL 
page 99 / 109 
 
22.3 Schedule of Study Procedures and Assessments for the Booster Phase 
The investigator may schedule visits (unplanned visits in addition to those listed in the table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant 
Procedures/Assessments 
Visit 6 
Day 
208 
M7 
(+/- 
14d) 
Visit 7 i 
Planned for 
mid-end 
September 
2021 for all 
participants
(+/- 14d) 
 
Visit 8 
14 days after 
booster 
vaccination 
(Visit7)  
 
 
 
(+/- 2d) 
Visit 9 
28 days after 
booster 
vaccination 
(Visit7)  
 
 
 
(+/- 7d) 
Visit 10 
Safety follow-
up call 6 
months after 
booster 
vaccination 
(Visit 7)  
 
 
(+/- 14d) 
Unplanned
COVID-
19 
Illness 
Visit 
Ad hoc 
Safety Call 
in case of e-
Diary entry 
(Grade 3 AE 
or SAE) 
Visit
ET 
 
Informed consent  
X 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
check 
X 
X 
 
 
 
 
 
 
Delay criteria check 
 
X 
 
 
 
 
 
 
Symptom-driven 
physical 
examination a 
X 
X 
X 
X 
 
X 
 
X 
Prior/Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs b 
X 
X 
 
 
 
 
 
 
Urine Pregnancy test c  
 
X 
 
 
 
 
 
 
Safety labs d [10 mL] 
X 
X 
X 
X 
 
X 
 
X 
Immunogenicity sample e [10 
mL] 
X 
X 
X 
X 
 
X 
 
X 
Blood for PBMC Isolation f [50 
mL] 
X 
X 
X 
 
 
 
 
 
Saliva Sample k 
X 
 
 
 
 
 
 
 
VACCINATION 
 
X 
 
 
 
 
 
 
Electronic Participant Diary 
 
E 
R 
R 
 
 
R 
R 
AE/AESI/SAE Assessment  
X 
X 
X 
X 
X 
X 
X 
X 
 
(S)AE=(serious) adverse event; AESI=adverse event of special interest; PBMC=peripheral blood mononuclear cells; R=review  

VLA2001
Clinical Study Protocol VLA2001-201 Version 7.0
31-Aug-21
Valneva Austria GmbH
CONFIDENTIAL
page 100 / 109
a A symptom-driven physical examination will be performed, i.e. only in case symptom is reported by the Participant, an assessment of the affected body 
system(s) will be performed. 
b Vital signs will include systolic and diastolic blood pressure and pulse rate while seated and at rest, and body temperature measured orally before vaccination. 
In addition, after an observation period of 30 minutes following vaccination pulse rate as well as blood pressure while seated and at rest will again be assessed. 
c A urine pregnancy test will be done prior to vaccination at Visit 7. 
d Safety labs for standard clinical chemistry (i.e. creatinine, sodium, potassium, calcium, aspartate aminotransferase, alanine aminotransferase, alkaline 
phosphatase, bilirubin, CRP), haematology (i.e. haemoglobin, haematocrit, erythrocyte count, white blood count, differential white blood cell count, platelets, 
erythrocyte sedimentation rate , coagulation panel (i.e. prothrombin time, aPTT, fibrinogen) [EDTA blood: 30 mL] and urinalysis (i.e. pH, specific gravity, 
leucocytes, nitrite, protein, glucose, ketones, urobilinogen, bilirubin, erythrocytes. 
e An immunogenicity sample will be drawn [10mL] for SARS-CoV-2-specific neutralizing antibody titre evaluation and ELISA testing, development or performance 
of further assays related to development of this vaccine candidate and/or retrospective safety analysis if deemed necessary by the Data Safety Monitoring 
Board upon clinical indication or on demand if requested later by regulatory authorities. 
f A blood sample [approx. 50mL] will be collected to isolate PBMCs from all Participants for future investigation of cellular immune responses to VLA2001. PBMCs 
may also be used for further research activities considered relevant to SARS-CoV-2, e.g., HLA typing. 
 k Saliva samples will be obtained from all Participants for future investigation of mucosal immune responses to VLA2001.
i All procedures/assessments (apart from e-Diary explanation and AE assessment) occur prior to vaccination.

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
Valneva Austria GmbH 
CONFIDENTIAL 
page 101 / 109 
 
22.4 Toxicity Grading Scale for Abnormal Laboratory Assessments  
 
Mild 
(Grade 1) a 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially 
life 
threatening 
(Grade 4) b,e 
Haematology Parameters 
Haemoglobin (Female) –
gm/dL 
11.0–12.0 
9.5–10.9 
8.0–9.4 
< 8.0 
Haemoglobin 
(Male) 
–
gm/dL 
12.5–13.5 
10.5–12.4 
8.5–10.4 
< 8.5 
Haematocrit
Outside normal range c 
Erythrocyte count
Outside normal range c 
WBC Increase – cell/mm3
10,800–15,000 
15,001–20,000 
20,001–25,000 
> 25,000 
WBC Decrease – cell/mm3
2,500–3,500 d 
1,500–2,499 
1,000–1,499 
< 1,000 
Neutrophils 
Decrease 
–
cell/mm3 
1,500–2,000 
1,000–1,499 
500–999 
< 500 
Lymphocytes Decrease –
cell/mm3 
750–1,000 
500–749 
250–499 
< 250 
Monocytes
Outside normal range c 
Eosinophils 
–
cell/mm3 
650–15004 
1501–5000 
> 5000 
Hyper-
eosinophilic 
Basophils
Outside normal range c 
Platelets 
Decreased 
–
cell/mm3  
125,000 
– 
140,000 d 
100,000 
– 
124,000 
25,000–99,000 
< 25,000 
ESR
Outside normal range c 
Clinical Chemistry Parameters
Creatinine – mg/dL 
1.5–1.7 d 
1.8–2.0 
2.1–2.5 
> 2.5 or requires 
dialysis 
Sodium –
Hyponatremia 
mEq/L  
132–134 
130–131 
125–129 
< 125 
Sodium –
Hypernatremia 
mEq/L  
144–145 d 
146–147 
148–150 
> 150 
Potassium 
–
Hyperkalaemia mEq/L  
5.1–5.2 d 
5.3–5.4 
5.5–5.6 
> 5.6 
Potassium – Hypokalaemia 
mEq/L  
3.5–3.6 d 
3.3–3.4 
3.1–3.2 
< 3.1 
Calcium – Hypocalcaemia 
mg/dL  
8.0–8.4 d 
7.5–7.9 
7.0–7.4 
< 7.0 
Calcium – Hypercalcaemia 
mg/dL  
10.5–11.0 
11.1–11.5 
11.6–12.0 
> 12.0 
AST – increase by factor
1.1–2.5 x ULN 
2.6–5.0 x ULN 
5.1–10 x ULN 
> 10 x ULN 
ALT – increase by factor
1.1–2.5 x ULN 
2.6–5.0 x ULN 
5.1–10 x ULN 
> 10 x ULN 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
Valneva Austria GmbH 
CONFIDENTIAL 
page 102 / 109 
 
 
Mild 
(Grade 1) a 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially 
life 
threatening 
(Grade 4) b,e 
Alkaline 
phosphatase 
– 
increase by factor
1.1–2.0 x ULN 
2.1–3.0 x ULN 
3.1– 10 x ULN 
> 10 x ULN 
Bilirubin 
– 
when 
accompanied 
by 
any 
increase in Liver Function 
Test increase by factor
1.1–1.25 x ULN 
1.26–1.5 x ULN 
1.51–1.75 x ULN 
> 1.75 x ULN 
Bilirubin 
– 
when 
Liver 
Function Test is normal; 
increase by factor
1.1–1.5 x ULN 
1.6–2.0 x ULN 
2.0–3.0 x ULN 
> 3.0 x ULN 
CRP
Outside normal range c 
Coagulation Factors
PT – increase by factor  
1.0–1.10 x ULN 
1.11–1.20 x ULN 
1.21–1.25 x ULN 
> 1.25 ULN 
PTT (aPTT) – increase by 
factor  
1.0–1.2 x ULN 
1.21–1.4 x ULN 
1.41–1.5 x ULN 
> 1.5 x ULN 
Fibrinogen 
increase 
-
mg/dL  
400–500 d 
501–600 
> 600 
– 
Fibrinogen 
decrease 
-
mg/dL  
 
150–200 d 
125–149 
100–124 
< 100 or 
associated with 
gross bleeding or 
disseminated 
intravascular 
coagulation 
 
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; aPTT=activated partial 
thromboplastin time; CRP=C reactive protein; ESR=erythrocyte sedimentation rate; FDA=Food and Drug 
Administration; PT=prothrombin time; SAE=serious adverse event; ULN=upper limit of normal; WBC=white 
blood cell 
a In case the laboratory’s normal ranges and absolute Grade 1 limits overlap, Grade 1 limits will prevail, i.e. 
 the value will be classified as Grade 1 abnormality even if it is within central laboratory normal ranges. 
 Values between the central laboratory normal ranges and absolute Grade 1 limits will be reported as no 
 abnormality (Grade 0).  
b The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of 
 the laboratory abnormalities as potentially life threatening (Grade 4). For example, a low sodium value 
 that falls within a grade 3 parameter (125–129 mE/L) should be recorded as a grade 4 hyponatremia 
 unsolicited AE if the Participant had a new seizure associated with the low sodium value. 
c As neither the FDA Scale nor the Division of AIDS Table for Grading the Severity of Adult and Pediatric 
 Adverse Events (December 2004) provide any grading for haematocrit, erythrocyte count, monocytes, 
 Basophils, ESR and CRP, these will only be analysed as ‘outside normal range’, as determined by central 
 laboratory standards and graded as described in Section 15.2.1.1 upon Investigator’s judgement. 
d Central laboratory values should be adjusted to FDA toxicity grading scale. Specifically, if central 
 laboratory reference range is more stringent than FDA toxicity grading scale the central laboratory values 
 should be reported as no abnormality (Grade 0). Similarly, if laboratory values are within the central 
 laboratory normal reference range, but fall into FDA toxicity grading scale, the values should be reported 
 as indicated by the FDA toxicity grading scale. 
e  Any Grade 4 abnormal laboratory value should be reported as an SAE (see Section 16.1.2). 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
Valneva Austria GmbH 
CONFIDENTIAL 
page 103 / 109 
 
22.5 Adverse Events of Special Interest 
Neuroinflammatory 
Disorders: 
Acute disseminated encephalomyelitis (including site specific variants: 
eg, 
non-infectious 
encephalitis, 
encephalomyelitis, 
myelitis, 
myeloradiculomyelitis), anosmia, ageusia, cranial nerve disorders 
including paralyses/paresis (eg, Bell’s palsy), generalized convulsion, 
Guillain-Barre syndrome (including Miller Fisher syndrome and other 
variants), immune-mediated peripheral neuropathies and plexopathies 
(including 
chronic 
inflammatory 
demyelinating 
polyneuropathy, 
multifocal motor neuropathy and polyneuropathies associated with 
monoclonal gammopathy), meningoencephalitis, myasthenia gravis, 
multiple sclerosis, narcolepsy, optic neuritis, transverse myelitis, uveitis
Musculoskeletal 
and 
Connective 
Tissue 
Disorders 
Antisynthetase syndrome, dermatomyositis, juvenile chronic arthritis 
(including 
Still’s disease), mixed connective tissue disorder, 
polymyalgia rheumatic, polymyositis, psoriatic arthropathy, relapsing 
polychondritis, rheumatoid arthritis, scleroderma (including diffuse 
systemic form and CREST syndrome), spondyloarthritis (including 
ankylosing spondylitis, reactive arthritis [Reiter's Syndrome] and 
undifferentiated spondyloarthritis), systemic lupus erythematosus, 
systemic sclerosis, Sjogren’s syndrome 
Vasculitides 
Large vessels vasculitis (including giant cell arteritis such as 
Takayasu's arteritis and temporal arteritis), medium sized and/or small 
vessels vasculitis (including polyarteritis nodosa, Kawasaki's disease, 
microscopic polyangiitis, Wegener's granulomatosis, Churg–Strauss 
syndrome [allergic granulomatous angiitis], Buerger’s disease 
[thromboangiitis obliterans], necrotizing vasculitis and anti-neutrophil 
cytoplasmic antibody [ANCA] positive vasculitis [type unspecified], 
Henoch-Schonlein purpura, Behcet's syndrome, leukocytoclastic 
vasculitis) 
Gastrointestinal 
Disorders 
Crohn’s disease, celiac disease, liver injury, ulcerative colitis, ulcerative 
proctitis 
Hepatic Disorders 
Autoimmune hepatitis, autoimmune cholangitis, primary sclerosing 
cholangitis, primary biliary cirrhosis 
Renal Disorders 
Acute kidney injury, autoimmune glomerulonephritis (including IgA 
nephropathy, glomerulonephritis rapidly progressive, membranous 
glomerulonephritis, membranoproliferative glomerulonephritis, and 
mesangioproliferative glomerulonephritis, 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
Valneva Austria GmbH 
CONFIDENTIAL 
page 104 / 109 
 
Cardiac Disorders 
Autoimmune myocarditis/cardiomyopathy 
Acute cardiac injury including: 
 
Microangiopathy 
 
Heart failure and cardiogenic shock 
 
Stress cardiomyopathy 
 
Coronary artery disease 
 
Arrhythmia 
 
Myocarditis, pericarditis 
 
Skin Disorders 
Alopecia areata, psoriasis, vitiligo, Raynaud’s phenomenon, erythema 
nodosum, autoimmune bullous skin diseases (including pemphigus, 
pemphigoid 
and 
dermatitis 
herpetiformis), 
cutaneous 
lupus 
erythematosus, morphoea, lichen planus, Stevens-Johnson syndrome, 
Sweet’s syndrome 
Haematologic 
Disorders 
Autoimmune haemolytic anaemia, autoimmune thrombocytopenia, 
antiphospholipid syndrome, thrombocytopenia 
Coagulation disorder 
 
Deep vein thrombosis 
 
Pulmonary embolus 
 
Cerebrovascular stroke 
 
Limb ischemia 
 
Haemorrhagic disease 
 
Metabolic Disorders 
Autoimmune thyroiditis, Grave’s or Basedow’s disease, Hashimoto´s 
thyroiditis, diabetes mellitus type 1, Addison’s disease 
Other Disorders 
Goodpasture syndrome, idiopathic pulmonary fibrosis, pernicious 
anaemia, sarcoidosis 
Immunologic 
Enhanced disease following immunization, cytokine release syndrome 
related to COVID-19 disease 
Respiratory 
Acute respiratory distress syndrome (ARDS) 
Dermatologic 
Chilblain-like lesions, single organ cutaneous vasculitis, erythema 
multiforme 
Infection 
severe COVID-19 (see Section 15.9) 
 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
Valneva Austria GmbH 
CONFIDENTIAL 
page 105 / 109 
 
23. REFERENCES 
Arabi YM, Alothman A, Balkhy HH et al. Treatment of Middle East Respiratory Syndrome 
with a combination of lopinavir-ritonavir and interferon-beta1b (MIRACLE trial): study 
protocol for a randomized controlled trial. Trials 2018;19:81 
Arabi YM, Mandourah Y, Al-Hameed F et al. Corticosteroid therapy for critically Ill 
patients with Middle East respiratory syndrome. Am J Respir Crit Care Med. 
2020;197:757–767 
Astuti I, Ysrafil. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): An 
overview of viral structure and host response. Diabetes Metab Syndr 
2020;14(4):407-412 
Chaolin H, Yeming W, Xingwang L. Clinical features of patients infected with 2019 novel 
coronavirus in Wuhan, China. Lance. 2020;(395):497–506 
Gao Q, Bao L, Mao H et al. Development of an inactivated vaccine candidate for SARS-
CoV-2. Science 369(6499):77–81 
Guan W, Ni Z, Hu Y et al. Clinical Characteristics of Coronavirus Disease 2019 in China. 
N Eng J Med 2020;382:1708–1720 
HEPLISAV-B Summary of product characteristics 
https://rsc.niaid.nih.gov/sites/default/files/1-14-2-2-package-insert-heplisav-b.pdf 
(Accessed 28 Aug 2020) 
IXIARO Clinical Review Memorandum, 2018 
https://www.fda.gov/files/vaccines,%20blood%20&%20biologics/published/Clinical-
Review--IXIARO.pdf (accessed 29 Aug 2020) 
John Hopkins Resource Center https://coronavirus.jhu.edu/ (accessed 28 Aug 2020) 
Li Q, Guan X, Wu P et al. Early transmission dynamics in Wuhan, China, of novel 
coronavirus-infected pneumonia. N Engl J Med 2020;382(13): 1199–1207 
Joshua G. Liang, Danmei Su, Tian-Zhang Song et al.  S-Trimer, a COVID-19 subunit 
vaccine candidate, induces protective immunity in nonhuman primates 
https://doi.org/10.1101/2020.09.24.311027 
Munoz FM, Cramer JP, Dekker CL et al. Vaccine-associated Enhanced Disease: Case 
Definition and Guidelines for Data Collection, Analysis, and Presentation of 
Immunization Safety Data. Submitted. 
Sinovac Press Release from 13.06.2020; Sinovac Announces Positive Preliminary 
Results of Phase I/II Clinical Trials for Inactivated Vaccine Candidate Against COVID-19; 
http://www.sinovac.com/?optionid=754&auto_id=904 (accessed 28 Aug 2020) 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
Valneva Austria GmbH 
CONFIDENTIAL 
page 106 / 109 
 
Wang D., Hu B., Hu C. Clinical characteristics of 138 hospitalized patients with 2019 
novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020;323(11): 
1061-1069 
Williamson E, Walker AJ, Bhaskaran KJ et al. OpenSAFELY: factors associated with 
COVID-19-related hospital death in the linked electronic health records of 17 million 
adult NHS patients.medRxiv2020.05.06.20092999;doi: 
https://doi.org/10.1101/2020.05.06.20092999 
World Health Organisation. Report of the WHO: China Joint Mission on Coronavirus 
Disease 2019 (COVID-19); 16–24 February 2020. https://www.who.int/docs/default-
source/coronaviruse/who-china-joint-mission-on-covid-19-final-report.pdf (accessed 
28 Aug 2020) 
World Health Organization. Draft landscape of COVID-19 candidate 
vaccines. July 20, 2020 https://www.who.int/publications/m/item/draft-landscape-of-
covid-19-candidate-vaccines (accessed 28 Aug 2020) 
World Health Organisation. A Coordinated Global Research Roadmap: 2019 Novel 
Coronavirus. 2020 https://www.who.int/blueprint/priority-diseases/key-
action/Coronavirus_Roadmap_V9.pdf (accessed 28 Aug 2020) 
Xia et al. Effect of an Inactivated Vaccine Against SARS-CoV-2 on Safety and 
Immunogenicity Outcomes Interim Analysis of 2 Randomized Clinical Trials JAMA 2020; 
doi:10.1001/jama.2020.15543 
Xia et al. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-
CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial Lancet 2020; 
DOI:https://doi.org/10.1016/S1473-3099(20)30831-8 
Yang D, Leibowitz JL. The structure and functions of coronavirus genomic 3’ and 5’ 
ends. Virus Res. 2015;206:120–133 
Zumla A, Hui DS, Azhar EI, Memish ZA, Maeurer M. Reducing mortality from 
2019-nCoV: host-directed therapies should be an option. Lancet. 2020;395:e35–e36 
Agrawal AS, Tao X, Algaissi a, et al Immunization with inactivated Middle East 
Respiratory Syndrome coronavirus vaccine leads to lung immunopathology on challenge 
with live virus. Hum Vaccin Immunother. 2016;12(9):2351-2356 
Hondo-okubo Y, Barnard D, Ong CH, Peng BH; Tseng CT Severe acute respiratory 
syndrome associated vaccines formulated with delta inulin adjuvants provide enhances 
protection while ameliorating lung eosinophilic immunopathology. J. Virol. 
2015;89(6):2995-3007. 
 *MHRA Guidance: 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
Valneva Austria GmbH 
CONFIDENTIAL 
page 107 / 109 
 
https://www.gov.uk/guidance/managing-clinical-trials-during-coronavirus-covid-
19#remote-monitoring-for-trials 
 
MHRA Blog: 
https://mhrainspectorate.blog.gov.uk/2020/03/12/advice-for-management-of-clinical-
trials-in-relation-to-coronavirus/ 
 
**HRA Guidance: 
https://www.hra.nhs.uk/covid-19-research/covid-19-guidance-sponsors-sites-and-
researchers/ 
 
Curran J, Dol J, Boulos L, et al. Transmission characteristics of SARS-CoV-2 variants of 
concern Rapid Scoping Review. medRxiv. Published online January 1, 
2021:2021.04.23.21255515. doi:10.1101/2021.04.23.21255515 
Tegally H, Wilkinson E, Giovanetti M, et al. Emergence of a SARS-CoV-2 variant of 
concern with mutations in spike glycoprotein. Nature. Published online 2021. 
https://doi.org/10.1038/s41586-021-03402-9 
Cherian S, Potdar V, Jadhav S, et al. Convergent evolution of SARS-CoV-2 spike 
mutations, L452R, E484Q and P681R, in the second wave of COVID-19 in Maharashtra, 
India. bioRxiv. Published online January 1, 2021:2021.04.22.440932. 
doi:10.1101/2021.04.22.440932 
Public Health England. SARS-CoV-2 Variants of Concern and Variants under 
Investigation in England. Technical Briefing 10. Public Health England; 2021. 
https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment
_data/file/984274/Variants_of_Concern_VOC_Technical_Briefing_10_England.pdf 
Bager P, Wohlfahrt J, Fonager J, Albertsen. Increased Risk of Hospitalisation 
Associated with Infection with SARS-CoV-2 Lineage B.1.1.7 in Denmark. doi:Bager, 
Peter and Wohlfahrt, Jan and Fonager, Jannik and Albertsen, Mads and Yssing 
Michaelsen, Thomas and Holten Møller, Camilla and Ethelberg, Steen and Legarth, 
Rebecca and Fischer Button, Mia Sara and Gubbels, Sophie Madeleine and 
Voldstedlund, Marianne and Mølbak, Kåre and Skov, Robert Leo and Fomsgaard, 
Anders and Grove Krause, Tyra, Increased Risk of Hospitalisation Associated with 
Infection with SARS-CoV-2 Lineage B.1.1.7 in Denmark. Available at SSRN: 
https://ssrn.com/abstract=3792894 or http://dx.doi.org/10.2139/ssrn.3792894 
NERVTAG paper on COVID-19 variant of concern B.1.1.7. GOVUK. Published online 
2021. https://www.gov.uk/government/publications/nervtag-paper-on-covid-19-variant-of-
concern-b117, http://files/64/nervtag-paper-on-covid-19-variant-of-concern-b117.html 
%[2021/02/08/18:37:19 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
Valneva Austria GmbH 
CONFIDENTIAL 
page 108 / 109 
 
Pearson CA, Eggo. Estimates of severity and transmissibility of novel South Africa 
SARS-CoV-2 variant 501Y.V2. https://cmmid.github.io/topics/covid19/reports/sa-
novelvariant/2021_01_11_Transmissibility_and_severity_of_501Y_V2_in_SA.pdf 
Jassat W MC. Increased Mortality among Individuals Hospitalised with COVID-19 during 
the Second Wave in South Africa.; 2021. 
https://www.medrxiv.org/content/10.1101/2021.03.09.21253184v1 
Funk T, Pharris A, Spiteri G, et al. Characteristics of SARS-CoV-2 variants of concern 
B.1.1.7, B.1.351 or P.1: data from seven EU/EEA countries, weeks 38/2020 to 10/2021. 
Eurosurveillance.2021;26(16).doi:https://doi.org/10.2807/1560-
7917.ES.2021.26.16.2100348 
Muik A, Wallisch A-K, Sänger B, et al. Neutralization of SARS-CoV-2 lineage B.1.1.7 
pseudovirus by BNT162b2 vaccine–elicited human sera. Science. Published online 
2021:eabg6105. 
https://science.sciencemag.org/content/sci/early/2021/01/28/science.abg6105.full.pdf 
Gallais F, Gantner P, Bruel T, et al. Anti-SARS-CoV-2 Antibodies Persist for up to 13 
Months and Reduce Risk of Reinfection. medRxiv. Published online January 1, 
2021:2021.05.07.21256823. doi:10.1101/2021.05.07.21256823 
Graham MS, Sudre CH, May A, et al. Changes in symptomatology, reinfection, and 
transmissibility associated with the SARS-CoV-2 variant B.1.1.7: an ecological study. 
Lancet Public Health. 2021;6(5):e335-e345. doi:10.1016/S2468-2667(21)00055-4 
Wibmer CK, Ayres F, Hermanus T, et al. SARS-CoV-2 501Y.V2 escapes neutralization 
by South African COVID-19 donor plasma. Nat Med. Published online March 2021. 
https://www.ncbi.nlm.nih.gov/pubmed/33654292 
Li R, Ma X, Deng J, et al. Differential efficiencies to neutralize the novel mutants B.1.1.7 
and 501Y.V2 by collected sera from convalescent COVID -19 patients and RBD 
nanoparticle-vaccinated rhesus macaques. Cell Mol Immunol. Published online February 
2021. https://www.ncbi.nlm.nih.gov/pubmed/33580167 
Cele S, Gazy I, Jackson L, et al. Escape of SARS-CoV-2 501Y.V2 variants from 
neutralization by convalescent plasma. :19. 
https://www.medrxiv.org/content/10.1101/2021.01.26.21250224v1 
Sabino EC, Buss LF, Carvalho MPS, et al. Resurgence of COVID-19 in Manaus, Brazil, 
despite high seroprevalence. The Lancet. 2021;397(10273):452-455. 
https://linkinghub.elsevier.com/retrieve/pii/S0140673621001835 

VLA2001 
Clinical Study Protocol VLA2001-201 Version 7.0  
31-Aug-21 
 
Valneva Austria GmbH 
CONFIDENTIAL 
page 109 / 109 
 
Naveca F, Nasciment V, Souza V, et al. Phylogenetic relationship of SARS-CoV-2 
sequences from Amazonas with emerging Brazilian variants harboring mutations E484K 
and N501Y in the Spike protein. Virological. Published online 2021. 
https://virological.org/t/phylogenetic-relationship-of-sars-cov-2-sequences-from-
amazonas-with-emergingbrazilian-variants-harboring-mutations-e484k-and-n501y-in-
the-spike-protein/585 
SARS-CoV-2 lateral flow antigen tests: evaluation of VUI-202012/01. GOVUK. 
https://www.gov.uk/government/publications/sars-cov-2-lateral-flow-antigen-
testsevaluation-of-vui-20201201/sars-cov-2-lateral-flow-antigen-tests-evaluation-of-vui-
20201201, http://files/62/sars-cov-2-lateral-flow-antigen-tests-evaluation-of-
vui20201201.html %[2021/02/08/16:54:26 
Weekly epidemiological update on COVID-19 - 25 May 2021 Edition 41, published 25 
May 2021. https://www.who.int/publications/m/item/weekly-epidemiological-update-on-
covid-19---25-may-2021. 
Harvey, W.T., Carabelli, A.M., Jackson, B. et al. SARS-CoV-2 variants, spike mutations 
and immune escape. Nat Rev Microbiol (2021). https://doi.org/10.1038/s41579-021-
00573-0 
Collier, D. A. et al. Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited 
antibodies. Nature https://doi.org/10.1038/s41586-021-03412-7 (2021). 
Gupta, R.K. Will SARS-CoV-2 variants of concern affect the promise of vaccines? Nat 
Rev Immunol 21, 340–341 (2021). https://doi.org/10.1038/s41577-021-00556-5