Clinical trial NCT04671017: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: SARS-CoV-2 Virus Infection
Keywords: VLA2001
SARS-CoV-2 Virus Infection
Covid-19
inactivated-adjuvanted SARS-CoV-2 virus vaccine
Lead sponsor: Valneva Austria GmbH
Sponsor class: INDUSTRY
Collaborators: name: National Institute for Health Research, United Kingdom
First posted: 2020-12-17
Enrollment: 153
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
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)
Primary purpose: PREVENTION

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.

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.

Primary outcomes:
measure: Frequency of Solicited AEs (Local and Systemic Reactions) Within 7 Days After Any Vaccination of the Primary Vaccination Series
timeFrame: within 7 days after any vaccination
measure: Geometric Mean Titre (GMT) for Neutralizing Antibodies Against SARS-CoV-2 Determined by Wild-type Virus Neutralizing Assay
timeFrame: Day 36
Secondary outcomes:
measure: Frequency of Any Unsolicited AE
timeFrame: until Day 36
measure: Frequency of Any Vaccine-related AE
timeFrame: until Day 36
measure: Frequency and Severity of Any AE
timeFrame: until Day 208
measure: Frequency and Severity of Any Vaccine-related AE
timeFrame: until Day 208
measure: Frequency of Any SAE
timeFrame: until Day 36
measure: Frequency of Any AESI
timeFrame: until Day 36
measure: Frequency and Severity of Any SAE
timeFrame: until Day 208
measure: Frequency and Severity of an AESI
timeFrame: until Day 208
measure: Frequency and Severy of Solicited AEs (Local and Systemic Reactions) After the Booster Vaccination
timeFrame: until Visit 7 plus 6 days
measure: Frequency and Severity of Any Unsolicited AE
timeFrame: until Visit 9
measure: Frequency and Severity of Any Vaccine-related AE
timeFrame: until Visit 9
measure: Frequency and Severity of Any SAE
timeFrame: until Visit 10
measure: Frequency and Severity of Any AESI
timeFrame: until Visit 10
measure: Immune Response as Measured by Neutralizing Antibody Titres Against SARS-CoV-2
timeFrame: until Day 208
measure: Proportion of Participants With Seroconversion in Terms of Neutralizing Antibodies
timeFrame: until Day 208
measure: Fold Increase of SARS-CoV-2 Neutralizing Antibody Titres Compared With Baseline
timeFrame: until Day 208
measure: GMTs for IgG Antibodies Against SARS-CoV-2 Determined by ELISA
timeFrame: until Day 208
measure: 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
timeFrame: until Day 208
measure: Geometric Mean Fold Rise (GMFR) From Pre-booster Time Point (Visit 7) to 2 Weeks After Booster Dose With Regards to Neutralizing Antibodies
timeFrame: until Visit 8
measure: Geometric Mean Fold Rise (GMFR) From Pre-booster Time Point (Visit 7) to 4 Weeks After Booster Dose With Regards to Neutralizing Antibodies
timeFrame: until Visit 9
measure: 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
timeFrame: until Visit 8
measure: 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
timeFrame: until Visit 9
measure: Geometric Mean Titres (GMT) Measured as Neutralizing Antibody Titres Against SARSCoV-2
timeFrame: until Visit 9
measure: 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)
timeFrame: until Visit 8
measure: 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)
timeFrame: until Visit 9
measure: 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)
timeFrame: until Visit 8
measure: 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)
timeFrame: until Visit 9
measure: Geometric Mean Titres (GMT) Measured as IgG Antibodies Against SARS-CoV-2 (ELISA
timeFrame: until Visit 9
Other outcomes:
Locations:
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
city: Bristol
country: United Kingdom
facility: University Hospital Bristol and Weston NHS Foundation Trust
city: Newcastle
country: United Kingdom
facility: Newcastle University Medical School
city: Southampton
country: United Kingdom
facility: Southampton NIHR Clinical Research Facility
Study officials:
affiliation: Valneva Austria GmbH
name: Valneva Clinical Development
role: STUDY_CHAIR
References:
citation: 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.