Clinical trial NCT05004181: Safety and Immunogenicity of RNA-based Vaccines Against SARS-CoV-2 Variants in Healthy Participants
Official title: A Phase II Trial to Evaluate the Safety and Immunogenicity of SARS-CoV-2 Monovalent and Multivalent RNA-based Vaccines in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: SARS-CoV-2 Infection
COVID-19
SARS-CoV-2 Acute Respiratory Disease
SARS (Disease)
Lead sponsor: BioNTech SE
Sponsor class: INDUSTRY
First posted: 2021-08-13
Enrollment: 1380
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: This trial consisted of three parts, Part A, Part B, and Part C, and evaluated the safety and immunogenicity of a third (booster) injection of the multivalent vaccine BNT162b2 (B.1.1.7 + B.1.617.2), and the safety and immunogenicity of a third booster injection of the monovalent vaccine BNT162b2 (B.1.617.2) or BNT162b2 (B.1.1.7), in participants who had received two doses of the parent vaccine BNT162b2 at 30 µg, at least 6 months after the second dose of BNT162b2. It also evaluated the safety and immunogenicity of a three-dose regimen of BNT162b2 (B.1.1.7 + B.1.617.2) in participants who had not received prior Coronavirus Disease 2019 (COVID-19) vaccination. In addition, the safety and immunogenicity of BNT162b2 (B.1.1.529.1) or BNT162b2 given as a third or fourth vaccine dose to RNA COVID-19 vaccine-experienced participants with history of SARS-CoV-2 Omicron variant infection was evaluated and contrasted with the natural immune response reached after infection with the SARS-CoV-2 Omicron variant in RNA COVID-19 vaccine-experienced participants.

Detailed description: Trial participants in Part A were assigned to one of 6 cohorts (Cohort 1-6). Trial participants in Part B were assigned to one of 3 cohorts (Cohort 1, 4, and 6). Trial participants in Part C were randomized in a 2:2:1 ratio into 3 cohorts (Cohort 7-9).

Eligibility criteria: Inclusion Criteria:

* Had given informed consent by signing the informed consent form (ICF) before initiation of any trial-specific procedures.
* Volunteers who at the time of consent were:
* Part A: 18 to 55 years old.
* Part B and Part C: 18 to 85 years old (\~60% should be 18 to 55 years old and \~40% 56 to 85 years old).
* For Cohorts 1 to 5: In Part A, who had received BNT162b2 vaccine (30 µg, two-dose regimen) in either a clinical trial or as part of the governmental vaccination programs at least 6 months before Visit 0. Participants who were currently enrolled in the Phase III BNT162-02 / C4591001 (NCT04368728) trial, had already been unblinded, and had previously received two doses of BNT162b2 at least 6 months earlier could be included (for Cohorts 1 and 4 in Part B, prior enrollment and dosing in the C4591001 trial was mandatory). At enrollment into Part B of this trial, their participation in the C4591001 trial was terminated. Participants should have not had experienced COVID-19 based on medical history.
* For Cohort 6: Were COVID-19 vaccine-naïve and had not experienced COVID-19 based on their medical history.
* Were willing and able to comply with all scheduled visits, vaccination plan, laboratory tests, lifestyle considerations, and other trial procedures.
* Were overall healthy at Visit 0 in the clinical judgment of the investigator based on the medical history, clinical assessment (including physical examination, vital signs, blood and urine clinical laboratory tests, 12-lead electrocardiogram (ECG), and oral swab for Nucleic Acid Amplification-based Test (NAAT)-based Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) testing).
* Note: Healthy volunteers with pre-existing stable disease, defined as disease not requiring significant change in therapy or hospitalization for worsening disease during the 12 weeks before Visit 0, could be included.
* Note: Volunteers who had hepatitis C (HCV) infection, but had completed curative treatment based on the medical history could be included. Volunteers who had or have hepatitis B (HBV) or human immunodeficiency virus (HIV) based on the medical history could not be included.
* Agreed not to enroll in another trial of an Investigational Medicinal Product (IMP), starting after Visit 0 and continuously until the last planned visit in this trial.
* Women of childbearing potential (WOCBP) had to test negative in a urine beta-human chorionic gonadotropin (β-HCG) test at Visits 0 and 1.
* WOCBP had to agree to practice a highly effective form of contraception starting at Visit 0 and continuously until 28 days after their last IMP administration in this trial.
* WOCBP had to confirm that they practiced an acceptable form of contraception for the 14 days prior to Visit 0.
* WOCBP had to agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction starting after Visit 0 and continuously until 28 days after their last IMP injection in this trial.
* Men who are sexually active with a WOCBP and had not had a vasectomy had to agree to use a highly effective form of contraception with their female partner of childbearing potential starting after Visit 0 and continuously until 28 days after their last IMP injection in this trial.
* Men had to be willing to refrain from sperm donation, starting after Visit 0 and continuously until 28 days after their last vaccination.
* For Part C, Cohorts 7, 8, and 9: Had received two or three documented doses of any authorized COVID-19 RNA-based vaccine (e.g., BNT162b2 \[Comirnaty\] or the Moderna vaccine \[Spikevax\]) prior to being diagnosed with SARS-CoV-2 infection from January 2022 onwards (and limited to a period when there was a high prevalence of SARS-CoV-2 Omicron infections).
* Note: The interval between the last COVID-19 RNA-based vaccine administered and randomization should have been \>4 months. The latest prior diagnosed SARS-CoV-2 infection should have been at least 2 months before randomization. The latest SARS-CoV-2 infection should have been documented with a result from a NAAT (as a preferable option). In case no historic NAAT result was available proving prior SARS-CoV-2 infection, the local positive result of SARS-CoV-2 N-binding antibodies done at screening was sufficient.

Exclusion Criteria:

* Any existing condition which could have affected vaccine injection and/or assessment of local reactions assessment, e.g., tattoos, severe scars, etc.
* Any bleeding diathesis or condition associated with prolonged bleeding that could have, in the opinion of the investigator, contraindicated intramuscular injection.
* Any medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that, in the investigator's judgment, made the participant inappropriate for the trial.
* Any current febrile illness (body temperature ≥38.0°C/≥100.4°F) or other acute illness within 48 h prior to Day 1/IMP injection in this trial.
* Any current or history of cardiovascular diseases, e.g., myocarditis, pericarditis, myocardial infarction, congestive heart failure, cardiomyopathy or clinically significant arrhythmias, unless such disease was not considered relevant for participation in this trial in the investigator's judgment.
* History of COVID-19 and/or clinical (based on COVID-19 symptoms/signs alone, if a SARS CoV 2 NAAT result was not available) or microbiological (based on COVID-19 symptoms/signs and a positive SARS CoV 2 NAAT result) evidence of prior infection with SARS CoV 2 at screening (Visit 0).
* Note: not applicable for Part C.
* History of Guillain-Barré syndrome.
* Known or suspected immunodeficiency.
* History of severe adverse reaction associated with a vaccine and/or severe allergic reaction (e.g., anaphylaxis) to any component of the trial IMPs.
* History or known allergy, hypersensitivity, or intolerance to the trial IMP including any excipients of the IMPs in this trial.
* Had received any SARS CoV 2 vaccination other than BNT162b2 (30 µg BNT162b2 given as a course of two doses approximately 21 days apart).
* Note: not applicable for Part C.
* Had received a live or live attenuated vaccine within 28 days prior to Day 1/IMP injection.
* Had received any other vaccines within 14 days before or after any IMP injection, e.g., influenza, tetanus, pneumococcal, hepatitis A or B. When possible standard of care vaccinations should been planned with the trial IMP administrations in mind.
* Individuals who received treatment with radiotherapy or immunosuppressive therapy, including cytotoxic agents or systemic corticosteroids (if systemic corticosteroids were administered for ≥14 days at a dose of ≥20 mg/day of prednisone or equivalent), e.g., for cancer or an autoimmune disease, or planned receipt throughout this trial. Inhaled/nebulized, intra-articular, intrabursal, or topical (skin or eyes) corticosteroids were permitted.
* Receipt of blood/plasma products or immunoglobulin, from 60 days before IMP administration or planned receipt throughout this trial.
* Participation in other trials involving IMP within 28 days or 5 half-lives (whichever was longer) prior to Visit 1 and/or during trial participation, besides participation in trials with BNT162b2.
* Were pregnant or breastfeeding or are planning pregnancy within 28 days after last IMP treatment.
* Were vulnerable individuals as per International Conference on Harmonisation (ICH) E6 definition, i.e., are individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate.
* For Part C, Cohorts 7, 8, and 9: Vaccination with other non-RNA or unauthorized COVID-19 vaccines.
* For Part C, Cohorts 7, 8, and 9: Vaccination with any COVID-19 vaccine after SARS-CoV-2 infection from January 2022 onwards (and limited to a period when there was a high prevalence of SARS-CoV-2 Omicron infections).

Primary outcomes:
measure: All Parts - Percentage of Participants Reporting Local Reactions at the Injection Site (Pain, Tenderness, Erythema/Redness, Induration/Swelling)
timeFrame: from Day 1 to Day 7 after each IMP dose
measure: All Parts - Percentage of Participants Reporting Systemic Events (Fever, Fatigue, Headache, Chills, Vomiting, Nausea, Diarrhea, New or Worsened Muscle Pain, and New or Worsened Joint Pain)
timeFrame: from Day 1 to Day 7 after each IMP dose
measure: All Parts - Percentage of Participants Reporting Adverse Events (AEs)
timeFrame: Dose 1 up to 1 month after each dose (all parts)
measure: All Parts - Percentage of Participants Reporting Serious Adverse Events (SAEs)
timeFrame: Dose 1 up to 6 months after the last dose
measure: Part B - GMR of B.1.1.7 NT 1 Month After 1 Dose of BNT162b2 (B.1.1.7 + B.1.617.2) in BNT162b2-experienced Participants to the Reference Strain NT 1 Month After 2 Doses of BNT162b2 in Participants From the Phase III C4591001 (NCT04368728) Trial
timeFrame: 1 month after booster dose in BNT162-17 participants and 1 month post Dose 2 in participants from the C4591001 (NCT04368728) trial
measure: Part B - GMR of B.1.617.2 NT 1 Month After 1 Dose of BNT162b2 (B.1.1.7 + B.1.617.2) in BNT162b2-experienced Participants to the Reference Strain NT 1 Month After 2 Doses of BNT162b2 in Participants From the Phase III C4591001 (NCT04368728) Trial
timeFrame: 1 month after booster dose in BNT162-17 participants and 1 month post Dose 2 in participants from the C4591001 (NCT04368728) trial
measure: Part B - GMR of B.1.617.2 NT 1 Month After 1 Dose of BNT162b2 (B.1.617.2) in BNT162b2-experienced Participants to the Reference Strain NT 1 Month After 2 Doses of BNT162b2 in Participants From the Phase III C4591001 (NCT04368728) Trial
timeFrame: 1 month after booster dose in BNT162-17 participants and 1 month post Dose 2 in participants from the C4591001 (NCT04368728) trial
measure: Part B - Difference in Seroresponse (SR) to B.1.1.7 NT 1 Month After 1 Dose of BNT162b2 (B.1.1.7 + B.1.617.2) in BNT162b2-experienced Participants to the Reference Strain NT 1 Month After 2 Doses of BNT162b2 in Participants From C4591001 (NCT04368728)
timeFrame: 1 month after booster dose in BNT162-17 participants and 1 month post Dose 2 in participants from the C4591001 (NCT04368728) trial
measure: Part B - Difference in SR to B.1.617.2 NT 1 Month After 1 Dose of BNT162b2 (B.1.1.7 + B.1.617.2) in BNT162b2-experienced Participants to the Reference Strain NT 1 Month After 2 Doses of BNT162b2 in Participants From C4591001 (NCT04368728)
timeFrame: 1 month after booster dose in BNT162-17 participants and 1 month post Dose 2 in participants from the C4591001 (NCT04368728) trial
measure: Part B - Difference in SR to B.1.617.2 NT 1 Month After 1 Dose of BNT162b2 (B.1.617.2) in BNT162b2-experienced Participants to the Reference Strain NT 1 Month After 2 Doses of BNT162b2 in Participants From C4591001 (NCT04368728)
timeFrame: 1 month after booster dose in BNT162-17 participants and 1 month post Dose 2 in participants from the C4591001 (NCT04368728) trial
measure: Part B - GMR of B.1.1.7 NT 1 Month After 2 Doses of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 Vaccine-naïve Participants to the Reference Strain NT 1 Month After 2 Doses of BNT162b2 in Participants From the C4591001 (NCT04368728) Trial
timeFrame: 1 month
measure: Part B - GMR of B.1.617.2 NT 1 Month After 2 Doses of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 Vaccine-naïve Participants to the Reference Strain NT 1 Month After 2 Doses of BNT162b2 in Participants From the C4591001 (NCT04368728) Trial
timeFrame: 1 month
measure: Part B - The Difference in SR to B.1.1.7 NT 1 Month After 2 Doses of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 Vaccine-naïve Participants to the Reference Strain NT 1 Month After 2 Doses of BNT162b2 in Participants From the C4591001 (NCT04368728) Trial
timeFrame: 1 month
measure: Part B - The Difference in SR to B.1.617.2 NT 1 Month After 2 Doses of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 Vaccine-naïve Participants to the Reference Strain NT 1 Month After 2 Doses of BNT162b2 in Participants From the C4591001 (NCT04368728) Trial
timeFrame: 1 month
measure: Part B - GMR of Reference Strain NT After One Dose of BNT162b2 (B.1.1.7 + B.1.617.2) in Participants With Evidence of Prior Infection to the Reference Strain NT After 2 Doses of BNT162b2 in Participants Without Evidence of Infection
timeFrame: 3 weeks post Dose 1 in BNT162-17 participants and 1 month post Dose 2 in participants from the C4591001 (NCT04368728) trial
measure: Part B - The Difference in SRs to the Reference Strain NT in Subjects With Evidence of Prior Infection and to the Reference Strain NT in Participants Without Evidence of Infection (COVID-19 Vaccine-naïve Participants)
timeFrame: 3 weeks post Dose 1 in BNT162-17 participants and 1 month post Dose 2 in participants from the C4591001 (NCT04368728) trial
measure: Part C - GMR of B.1.1.529.1 NT 1 Month After One Dose of BNT162b2 (B.1.1.529.1) in RNA-based COVID-19 Vaccine-experienced Participants With History of SARS-CoV-2 Infection to Those at 1 Month After One Dose of BNT162b2 for Cohorts 7 and 8.
timeFrame: 1 month after 1 dose of BNT162b2 or BNT162b2 (B.1.1.529.1)
measure: Part C - The Difference in SR of B.1.1.529.1 NT 1 Month After One Dose of BNT162b2 (B.1.1.529.1) in RNA-based COVID-19 Vaccine-experienced Participants With History of SARS-CoV-2 Infection to Those at 1 Month After One Dose of BNT162b2 for Cohorts 7 & 8.
timeFrame: 1 month after 1 dose of BNT162b2 or BNT162b2 (B.1.1.529.1)
Secondary outcomes:
measure: Part A - Geometric Mean Titer (GMT) at Each Timepoint
timeFrame: Day 1 up to Day 421
measure: Part A - Geometric Mean Fold Rises (GMFR) From Before Vaccination to Each Subsequent Time Point After Vaccination
timeFrame: Day 1 to Day 421
measure: Part A - Percentage of Participants Achieving SR in Terms of NT at Each Post Vaccination Time Point
timeFrame: Day 1 to Day 421
measure: Part B - GMT of VOCs and Reference Strains in Part B Cohort 1 and Control
timeFrame: 1 month after booster dose in BNT162-17 participants and 1 month post Dose 2 in participants from the C4591001 (NCT04368728) trial
measure: Part B - SR of of VOCs and Reference Strains in Part B Cohort 1 and Control
timeFrame: 1 month after Dose 1 in BNT162-17 participants and 1 month post Dose 2 in participants from the C4591001 (NCT04368728) trial
measure: Part B - GMT of VOCs and Reference Strains in Part B Cohort 4 and Control
timeFrame: 1 month after booster dose in BNT162-17 participants and 1 month post Dose 2 in participants from the C4591001 (NCT04368728) trial
measure: Part B - SR of of VOCs and Reference Strains in Part B Cohort 4 and Control
timeFrame: 1 month after Dose 1 in BNT162-17 participants and 1 month post Dose 2 in participants from the C4591001 (NCT04368728) trial
measure: Part B - GMT of VOCs and Reference Strain in Part B Cohort 6 1 Month After Dose 2 and 1 Month After Dose 3
timeFrame: 1 month after Dose 2 and 1 month after Dose 3
measure: Part B - Cohort 6 - Percentages With SRs to VOCs (B.1.1.7, B.1.617.2) and Reference Strain
timeFrame: 1 month after Dose 2 and 1 month after Dose 3
measure: Part B - GMTs of VOC in COVID-19 Vaccine-naïve Participants With and Without Evidence of Prior Infection in Part B C6 (1 and 2 Primary Doses Respectively) and in BNT162b2-Experienced Participants Without Evidence of Infection in Part B C1 (1 Booster Dose)
timeFrame: Day 1 up to 1 month after 1 booster dose in Part B Cohort 1 without evidence of infection, up to 1 month after 2 doses in Part B Cohort 6 without evidence of infection and up to 3 weeks after 1 dose in Part B Cohort 6 with evidence of prior infection
measure: Part B - GMRs of VOC in COVID-19 Vaccine-naïve Participants With and Without Evidence of Prior Infection (1 and 2 Primary Doses Respectively) and in BNT162b2-Experienced Participants Without Evidence of Infection (1 Booster Dose)
timeFrame: Day 1 to Day 29
measure: Part B - Difference in SRs to VOCs in COVID-19 Vaccine-naïve Participants With and Without Evidence of Prior Infection (1 and 2 Primary Doses Respectively) and in BNT162b2-Experienced Participants Without Evidence of Infection (1 Booster Dose)
timeFrame: Day 1 to Day 29
measure: Part B - SR of VOC in COVID-19 Vaccine-naïve Participants With and Without Evidence of Prior Infection (1 and 2 Primary Doses Respectively) and in BNT162b2-Experienced Participants Without Evidence of Infection (1 Booster Dose)
timeFrame: 3 weeks after one dose in participants with evidence of prior infection (Cohort 6), 1 month after two doses in participants without evidence of infection (Cohort 6), and 1 month after one booster dose (Cohort 1)
measure: Part C - GMT - B.1.1.529.1 in RNA Based COVID-19 Vaccine-experienced Participants With History of SARS-CoV-2 Infection
timeFrame: Day 1 to Day 360
Other outcomes:
Locations:
city: Long Beach
country: United States
facility: Collaborative Neuroscience Network LLC
state: California
city: San Diego
country: United States
facility: California Research Foundation
state: California
city: Milford
country: United States
facility: Clinical Research Consulting, Llc
state: Connecticut
city: Stamford
country: United States
facility: Stamford Therapeutics Consortium
state: Connecticut
city: Atlanta
country: United States
facility: Atlanta Center for Medical Research
state: Georgia
city: Savannah
country: United States
facility: Meridian Clinical Research
state: Georgia
city: Gulfport
country: United States
facility: Medpharmics, LLC
state: Mississippi
city: Warren
country: United States
facility: Amici Clinical Research
state: New Jersey
city: Rochester
country: United States
facility: Rochester Clinical Research
state: New York
city: Columbus
country: United States
facility: Aventiv Research Inc.
state: Ohio
city: Austin
country: United States
facility: ARC Clinical Research
state: Texas
city: Dallas
country: United States
facility: North Texas Infectious Diseases Consultants
state: Texas
city: San Antonio
country: United States
facility: Clinical Trials of Texas Inc.
state: Texas
city: San Antonio
country: United States
facility: Diagnostics Research Group
state: Texas
city: Berlin
country: Germany
facility: CRS Clinical Research Services Berlin
city: Frankfurt am Main
country: Germany
facility: IKF Institut fuer klinische Forschung Frankfurt
city: Mannheim
country: Germany
facility: CRS Clinical Research Services Mannheim GmbH
city: Stuhr
country: Germany
facility: Studienzentrum Brinkum Dr. Lars Pohlmeier und Torsten Drescher
city: Bloemfontein
country: South Africa
facility: JOSHA Research
state: Free State
city: Kraaifontein
country: South Africa
facility: Langeberg Medicross Medical Centre
state: Western Cape
city: Paarl
country: South Africa
facility: Paarl Research Centre
state: Western Cape
city: Somerset West
country: South Africa
facility: Synexus Helderberg Clinical Trial Centre
state: Western Cape
city: Benoni
country: South Africa
facility: Worthwhile Clinical Trials
city: Cape Town
country: South Africa
facility: Tiervlei Trial Centre
city: Halfway House
country: South Africa
facility: Midrand Medical Centre
city: Johannesburg
country: South Africa
facility: Newtown Clinical Research
city: Pretoria
country: South Africa
facility: Global Clinical Trials
city: Pretoria
country: South Africa
facility: Botho ke Bontle Health Service
city: Pretoria
country: South Africa
facility: Synexus SA Stanza Clinical Research Centre
city: Pretoria
country: South Africa
facility: Jongaie Research, Medicross Pretoria West
city: Ankara
country: Turkey
facility: Ankara University Faculty of Medicine, Avicenna Hospital
city: Ankara
country: Turkey
facility: Hacettepe University Hospital
city: Istanbul
country: Turkey
facility: Bagcilar Medipol Mega University Hospital
city: Istanbul
country: Turkey
facility: Istanbul University Medical Faculty
city: Kocaeli
country: Turkey
facility: Kocaeli Universitesi Tip Fakultesi
Study officials:
affiliation: BioNTech SE
name: BioNTech Responsible Person
role: STUDY_DIRECTOR
References: