Dose Finding Study to Evaluate The Safety, Tolerability and Immunogenicity of an Inactiviated, Adjuvanted SARS-CoV-2 Virus Vaccine Candidate Against Covid-19 in Healthy Subjects

• ClinicalTrials.gov Identifier: NCT04671017
• Recruitment Status: Completed
• First Posted: December 17, 2020
• Results First Posted: March 24, 2022
• Last Update Posted: April 22, 2022
• Sponsor: Valneva Austria GmbH
• Collaborator: National Institute for Health Research, United Kingdom
• Information provided by (Responsible Party): Valneva Austria GmbH

Tracking Information

• First Submitted Date: December 15, 2020
• First Posted Date: December 17, 2020
• Results First Submitted Date: March 7, 2022
• Results First Posted Date: March 24, 2022
• Last Update Posted Date: April 22, 2022
• Actual Study Start Date: December 16, 2020
• Actual Primary Completion Date: February 26, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 22, 2022)

• Frequency of Solicited AEs (Local and Systemic Reactions) Within 7 Days After Any Vaccination of the Primary Vaccination Series [ Time Frame: within 7 days after any vaccination ]
• Geometric Mean Titre (GMT) for Neutralizing Antibodies Against SARS-CoV-2 Determined by Wild-type Virus Neutralizing Assay [ Time Frame: Day 36 ]

Original Primary Outcome Measures (submitted: December 15, 2020)

• Frequency and severity of solicited AEs (local and systemic reactions) within 7 days after any vaccination [ Time Frame: until Day 29 ]
• Geometric mean titre (GMT) for neutralizing antibodies against SARS-CoV-2 [ Time Frame: Day 36 ]

Current Secondary Outcome Measures (submitted: March 22, 2022)

• Frequency of Any Unsolicited AE [ Time Frame: until Day 36 ]
• Frequency of Any Vaccine-related AE [ Time Frame: until Day 36 ]
• Frequency and Severity of Any AE [ Time Frame: until Day 208 ]
• Frequency and Severity of Any Vaccine-related AE [ Time Frame: until Day 208 ]
• Frequency of Any SAE [ Time Frame: until Day 36 ]
  All Adverse Events of Special Interest (AESIs) were treated as important medical event and were therefore be treated as SAE according to protocol.
• Frequency of Any AESI [ Time Frame: until Day 36 ]
• Frequency and Severity of Any SAE [ Time Frame: until Day 208 ]
• Frequency and Severity of an AESI [ Time Frame: until Day 208 ]
• Frequency and Severy of Solicited AEs (Local and Systemic Reactions) After the Booster Vaccination [ Time Frame: until Visit 7 plus 6 days ]
• Frequency and Severity of Any Unsolicited AE [ Time Frame: until Visit 9 ]
• Frequency and Severity of Any Vaccine-related AE [ Time Frame: until Visit 9 ]
• Frequency and Severity of Any SAE [ Time Frame: until Visit 10 ]
• Frequency and Severity of Any AESI [ Time Frame: until Visit 10 ]
• Immune Response as Measured by Neutralizing Antibody Titres Against SARS-CoV-2 [ Time Frame: until Day 208 ]
• Proportion of Participants With Seroconversion in Terms of Neutralizing Antibodies [ Time Frame: until Day 208 ]
• Fold Increase of SARS-CoV-2 Neutralizing Antibody Titres Compared With Baseline [ Time Frame: until Day 208 ]
• GMTs for IgG Antibodies Against SARS-CoV-2 Determined by ELISA [ Time Frame: until Day 208 ]
• Proportion of Participants With Seroconversion in Terms of IgG Antibodies Against SARS-CoV-2, as Determined by ELISA in Participants Negative for SARS-CoV-2 at Screening [ Time Frame: until Day 208 ]
• Geometric Mean Fold Rise (GMFR) From Pre-booster Time Point (Visit 7) to 2 Weeks After Booster Dose With Regards to Neutralizing Antibodies [ Time Frame: until Visit 8 ]
• Geometric Mean Fold Rise (GMFR) From Pre-booster Time Point (Visit 7) to 4 Weeks After Booster Dose With Regards to Neutralizing Antibodies [ Time Frame: until Visit 9 ]
• Proportion of Participants With 4-fold Increase From Pre-booster Time Point (Visit 7) to 2 Weeks After Booster Dose With Regards to Neutralizing Antibodies [ Time Frame: until Visit 8 ]
• Proportion of Participants With 4-fold Increase From Pre-booster Time Point (Visit 7) to 4 Weeks After Booster Dose With Regards to Neutralizing Antibodies [ Time Frame: until Visit 9 ]
• Geometric Mean Titres (GMT) Measured as Neutralizing Antibody Titres Against SARSCoV-2 [ Time Frame: until Visit 9 ]
• Geometric Mean Fold Rise (GMFR) From Pre-booster Time Point (Visit 7) to 2 Weeks After Booster Dose With Regards to S-protein Binding Antibodies (ELISA) [ Time Frame: until Visit 8 ]
• Geometric Mean Fold Rise (GMFR) From Pre-booster Time Point (Visit 7) to 4 Weeks After Booster Dose With Regards to S-protein Binding Antibodies (ELISA) [ Time Frame: until Visit 9 ]
• Proportion of Participants With 4-fold Increase From Pre-booster Time Point (Visit 7) to 2 Weeks After Booster Dose in Regards to S-protein Binding Antibodies (ELISA) [ Time Frame: until Visit 8 ]
• Proportion of Participants With 4-fold Increase From Pre-booster Time Point (Visit 7) to 4 Weeks After Booster Dose in Regards to S-protein Binding Antibodies (ELISA) [ Time Frame: until Visit 9 ]
• Geometric Mean Titres (GMT) Measured as IgG Antibodies Against SARS-CoV-2 (ELISA [ Time Frame: until Visit 9 ]

Original Secondary Outcome Measures (submitted: December 15, 2020)

• Frequency and severity of any unsolicited AE [ Time Frame: until Day 36 ]
• Frequency and severity of any vaccine-related AE [ Time Frame: until Day 36 ]
• Frequency and severity of any AE [ Time Frame: until Day 208 ]
• Frequency and severity of any vaccine-related AE [ Time Frame: until Day 208 ]
• Frequency and severity of any SAE [ Time Frame: until Day 36 ]
• Frequency and severity of any AESI [ Time Frame: until Day 36 ]
• Frequency and severity of any SAE [ Time Frame: until Day 208 ]
• Frequency and severity of an AESI [ Time Frame: until Day 208 ]
• Immune response as measured by neutralizing antibody titres against SARS-CoV-2 [ Time Frame: until Day 208 ]
• Proportion of subjects with seroconversion in terms of neutralizing antibodies [ Time Frame: until Day 208 ]
• Fold increase of SARS-CoV-2 neutralizing antibody titres compared with baseline [ Time Frame: until Day 208 ]
• GMTs for IgG antibodies against SARS-CoV-2 [ Time Frame: until Day 208 ]
• Proportion of subjects with seroconversion in terms of IgG antibodies against SARS-CoV-2 in subjects negative for SARS-CoV-2 at screening [ Time Frame: until Day 208 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Dose Finding Study to Evaluate The Safety, Tolerability and Immunogenicity of an Inactiviated, Adjuvanted SARS-CoV-2 Virus Vaccine Candidate Against Covid-19 in Healthy Subjects
• Official 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
• Brief Summary: A multicenter, 3-arm randomized dose finding study in the UK to evaluate safety, tolerability and immunogenicity of a vaccine candidate against Covid-19. 150 healthy volunteers will be enrolled and receive two shots of the vaccine candidate. All participants who receive two doses of the vaccine candidate will be invited to participate in the Booster phase.

Detailed Description

The multicenter, dose finding Phase 1/2 study starts off with an open-label, dose-escalation part, thereafter, during the double-blind part of study, participants will be randomized 1:1:1 to receive the low, medium or high dose of the vaccine (VLA2001). All participants will received a total of two vaccinations intramuscularly, on day 1 and day 22.

The first 5 participants in each dose group will receive VLA2001 open label, starting with the low dose of VLA2001. If no safety concerns are identified, the next 5 subjects will receive the medium dose of the vaccine. Again, if no safety issues are identified, 5 participants will be vaccinated with the high dose of the vaccine. A Data Safety and Monitoring Board (DSMB) will review accrued safety data before randomization of the remaining 135 subjects across all sites will be initiated.

All study participants will be followed up for safety and immunogenicity up to approximately 6 months after receiving their second vaccination.

This study was extended to investigate the tolerability, safety and immungenicity of a booster vaccination with VLA2001. All study participants, in the Booster phase, will be followed up for safety and immunogenicity up to 6 months after receiving their Booster vaccination.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

1. st phase Sequential (open-label phase)
2. nd phase Parallel Assignment (double-blinded randomized phase )
3. rd phase Parallel Assignment (open-label phase)

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

1. st phase is open-label
2. nd phase is double-blind randomized (Participant, Investigator )
3. rd phase is open-label phase

Primary Purpose: Prevention

• Condition: SARS-CoV-2 Virus Infection

Intervention

Biological: VLA2001

whole virus inactivated SARS-CoV-2 vaccine adjuvanted with cytosine phospho-guanine (CpG) 1018 in combination with aluminium hydroxide

Study Arms

• Experimental: Low Dose: VLA2001
  Intervention: Biological: VLA2001
• Experimental: Medium Dose: VLA2001
  Intervention: Biological: VLA2001
• Experimental: High Dose: VLA2001
  Intervention: Biological: VLA2001
• Experimental: Booster: High Dose: VLA2001
  Intervention: Biological: VLA2001

• Publications *: Lazarus R, Taucher C, Brown C, Corbic Ramljak I, Danon L, Dubischar K, Duncan CJA, Eder-Lingelbach S, Faust SN, Green C, Gokani K, Hochreiter R, Wright JK, Kwon D, Middleditch A, Munro APS, Naker K, Penciu F, Price D, Querton B, Riaz T, Ross-Russell A, Sanchez-Gonzalez A, Wardle H, Warren S, Finn A; Valneva Phase 1 Trial Group. Safety and immunogenicity of the inactivated whole-virus adjuvanted COVID-19 vaccine VLA2001: A randomized, dose escalation, double-blind phase 1/2 clinical trial in healthy adults. J Infect. 2022 Sep;85(3):306-317. doi: 10.1016/j.jinf.2022.06.009. Epub 2022 Jun 16.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 29, 2021): 153
• Original Estimated Enrollment (submitted: December 15, 2020): 150
• Actual Study Completion Date: April 6, 2022
• Actual Primary Completion Date: February 26, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria - Subjects who meet ALL of the following criteria are eligible for the study:

1. Participant is 18 to 55 years of age
2. Participant who has a smart phone and is willing and able to install and use the eDiary.
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 healthy as determined by the Investigator
5. Participant has a Body Mass Index (BMI) of 18.0-30.0 kg/m2

6. If subject is of childbearing potential:

   1. Participant has practiced an adequate method of contraception during the 30 days before screening (Visit 0).
   2. Participant has a negative serum or urine pregnancy test at screening (Visit 0) or Visit 1, respectively.
   3. Participant agrees to employ adequate birth control measures up to Day 106 (Visit 5).

Inclusion Criteria for Booster Phase - Subjects 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 healthy as determined by the Investigator's clinical judgement

• B5. If a participant is of childbearing potential:

  1. Participant has a negative urine pregnancy test at Visit 7 prior to booster vaccination.
  2. Participant agrees to employ adequate birth control measures up to 3 months after the Booster vaccination.

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 24 hours prior to the planned study vaccination.
2. History of laboratory-confirmed SARS-CoV-2 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.
5. Participant has an acute or recent infection not due to SARS-CoV-2
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.
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 that pose a risk for participation or completion of the study, based on Investigator's clinical judgement.
11. Participants with underlying diseases with a high risk of developing severe COVID-19 symptoms if infected
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 subject 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
14. Participant received immuno-suppressive therapy within 4 weeks prior to Visit 1 or receipt of immunosuppressive therapy is expected during the study.
15. Participant has a history of any vaccine related contraindicating event
16. Participant presents with clinical conditions representing a contraindication to intramuscular vaccination and blood draws.
17. Participant is pregnant, 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 venepuncture.
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.

Exclusion Criteria for Booster Phase - Participants who meet ANY of the following criteria are NOT eligible for 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. Immunosuppressive 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 55 Years (Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United Kingdom

Administrative Information

• NCT Number: NCT04671017
• Other Study ID Numbers: VLA2001-201
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Valneva Austria GmbH
• Original Responsible Party: Same as current
• Current Study Sponsor: Valneva Austria GmbH
• Original Study Sponsor: Same as current
• Collaborators: National Institute for Health Research, United Kingdom

Investigators

• Study Chair: Valneva Clinical Development; Valneva Austria GmbH

• PRS Account: Valneva Austria GmbH
• Verification Date: April 2022