The purpose of this Phase III study is to assess the efficacy, safety, and immunogenicity of two CoV2 preS dTM-AS03 vaccines (monovalent and bivalent) as part of primary series vaccinations in a multi-stage approach, as well as a booster injection of a CoV2 preS dTM-AS03 vaccine, in adults 18 years of age and older. A total of approximately 21 046 participants are planned to be enrolled (5080 per study intervention group in Stage 1 and 5443 per study intervention group in Stage 2). Initial, double-blind, primary series study design is planned for 365 days post-last Initial injection (ie, approximately 386 days total) for each participant. Based on decisions of the Study Oversight Group, Stage 1 and Stage 2 participants will be invited to participate in an unblinded Crossover / Booster study design with duration as follows: * For participants who initially received vaccine: 12 months post-booster (ie, approximately 18 to 24 months) * For participants who initially received placebo: ≥ 4 months post-last dose of the primary series + 12 months post-booster (ie, approximately 28 to 34 months) * For participants who do not consent to continue in the unblinded Crossover / Booster part of the study, all study procedures will be stopped and participants will be discontinued from the study.
The duration of participation in the initial, double-blind, primary series design of the study will be approximately 365 days post-last injection (ie, approximately 386 days total) for each participant. Based on decisions of the Study OG, Stage 1 and Stage 2 participants will be invited to participate in an unblinded Crossover / Booster study design with duration as follows: * For participants who initially received vaccine: 12 months post-booster (ie, approximately 18 to 24 months) * For participants who initially received placebo: ≥ 4 months post-last dose of the primary series + 12 months post-booster (ie, approximately 28 to 34 months) * For participants who do not consent to continue in the unblinded Crossover / Booster part of the study, all study procedures will be stopped and participants will be discontinued from the study.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
QUADRUPLE
Enrollment
23,670
Pharmaceutical form: emulsion for injection. Route of administration: intramuscular injection
Pharmaceutical form: emulsion for injection. Route of administration: intramuscular injection.
Pharmaceutical form: liquid. Route of administration: intramuscular administration.
Pharmaceutical form: emulsion for injection. Route of administration: intramuscular injection.
Pharmaceutical form: emulsion for injection. Route of administration: intramuscular injection.
AES - DRS - Simon Williamson Clinic, PC - Birmingham- Site Number : 8400004
Birmingham, Alabama, United States
Optimal Research Alabama- Site Number : 8400019
Huntsville, Alabama, United States
Peninsula Research Associates, Inc.- Site Number : 8400021
Rolling Hills Estates, California, United States
Synexus Clinical Research US, Inc. Site Number : 8400013
Centennial, Colorado, United States
Optimal Research, LLC-Melbourne- Site Number : 8400002
Melbourne, Florida, United States
Stage 1 and Stage 2: Number of Participants With Onset of Symptomatic Coronavirus Disease 2019 (COVID-19) Episode
Symptomatic COVID-19 was defined as virologically-confirmed SARS-CoV-2 infection accompanied by protocol-defined COVID-19-like illness (CLI).
Time frame: From Day 36 up to Day 387
Stage 1 and Stage 2: Number of Participants With Solicited Injection Site and Systemic Reactions
A solicited reaction was defined as an "expected" adverse reaction (AR) (sign or symptom) observed and reported under the conditions (nature and onset) pre-listed in the protocol and case report form (CRF) collected within 7 days after each injection and considered to be related to the corresponding study vaccine administered. An injection site reaction was an AR at and around the injection site of the study vaccine. Systemic AR were all ARs that were not injection site reactions and included systemic manifestations such as headache, fever, as well as localized or topical manifestations that are not associated with the injection site.
Time frame: Up to 7 days after each vaccination (post-dose on Days 1 and 22)
Stage 1 and Stage 2: Number of Participants With Unsolicited Non-Serious Adverse Events (AEs)
An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An unsolicited AE was an observed AE that did not fulfill the conditions of solicited reactions, that was pre-listed in the CRF in terms of diagnosis and onset window post-vaccination.
Time frame: Up to 21 days after each vaccination (post-dose on Days 1 and 22)
Stage 1 and Stage 2: Number of Participants With Immediate Adverse Events
An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Immediate events were recorded to capture medically relevant unsolicited injection site and systemic AEs which occurred within the first 30 minutes after vaccination.
Time frame: Up to 30 minutes after each vaccination (post-dose on Days 1 and 22)
Stage 1 and Stage 2: Number of Participants With Medically Attended Adverse Events (MAAE), Serious Adverse Events (SAE), and Adverse Events of Special Interest (AESI)
An SAE was defined as any AE that at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was an important medical event. An AESI (serious or non-serious) was 1 of scientific and medical concern specific to the Sponsor's study intervention or program, for which ongoing monitoring and rapid communication by the Investigator to the Sponsor could be appropriate. An MAAE was a new onset or a worsening of a condition that prompted the participant or participant's parent/guardian to seek unplanned medical advice at a physician's office or Emergency Department.
Time frame: From first dose of study vaccine administration (Day 1) up to 387 days
Stage 1 and Stage 2: Percentage of Participants With Virologically-Confirmed SARS-CoV-2 Infection and/or Symptomatic COVID-19
Virologically-confirmed SARS-CoV-2 infection was defined as a positive result for SARS CoV-2 by nucleic acid amplification test (NAAT) on at least 1 respiratory sample. This included positive results by any NAAT that included tests performed outside the trial protocol if confirmed by the adjudication committee. Symptomatic COVID-19 was defined as virologically-confirmed SARS-CoV-2 infection accompanied by protocol-defined COVID-19-like illness. Percentages are rounded off to the tenth decimal place. Here, percentage of participants with virologically-confirmed SARS-CoV-2 infection and/or symptomatic COVID-19 (regardless of adjudication) are reported.
Time frame: From first dose of study vaccine administration (Day 1) up to 387 days
Stage 1 and Stage 2: Number of Participants With SARS-CoV-2 Infection
SARS-CoV-2 infection was defined as a serologically-confirmed SARS-CoV-2 infection or virologically-confirmed SARS-CoV-2 infection.
Time frame: From Day 36 up to Day 387
Stage 1 and Stage 2: Number of Participants With Occurrence of Severe COVID-19
Severe COVID-19 was defined as COVID-19 with any 1 of the following: Any clinical signs of severe illness measured at least on 2 occasions separated by 30 minutes. Supplemental oxygen administration for \> 1 hour. Use of invasive or non-invasive ventilation or extracorporeal membrane oxygenation. Clinical diagnosis of respiratory failure. Significant acute renal, hepatic, or neurologic dysfunction. Shock. Admission to an intensive care unit. Death.
Time frame: From Day 36 up to Day 387
Stage 1 and Stage 2: Number of Participants With Asymptomatic SARS-CoV-2 Infection
Asymptomatic SARS-CoV-2 infection was defined as SARS-CoV-2 infection, with no reported COVID-19-like illness episodes between enrollment and 14 days after the timepoint at which SARS-CoV-2 infection was ascertained.
Time frame: From first dose of study vaccine administration (Day 1) up to 387 days
Stage 1 and Stage 2: Number of Swabs With Positive Nucleic Acid Amplification Test (NAAT)
The viral copies were collected as protocol-defined respiratory swabs during participant's illness episode and reported as positive continuous values. Here, duration between two consecutive positive NAAT results was calculated as: (the date of last swab tested positive) - (the date of first tested positive) + 1.
Time frame: From first dose of study vaccine administration (Day 1) up to 387 days
Stage 1 and Stage 2: Number of Participants With Respective Number of Days Between Two Consecutive Positive Nucleic Acid Amplification Test
Duration between two consecutive positive NAAT results was calculated as: the date of last swab tested positive - the date of first swab tested positive + 1.
Time frame: From first dose of study vaccine administration (Day 1) up to 387 days
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Synexus Clinical Research US, Inc. - Orlando- Site Number : 8400020
Orlando, Florida, United States
AES St. Petersburg- Site Number : 8400017
Pinellas Park, Florida, United States
Synexus Clinical Research US, Inc. - Atlanta- Site Number : 8400005
Atlanta, Georgia, United States
Synexus Clinical Research Chicago- Site Number : 8400012
Chicago, Illinois, United States
Synexus Clinical Research Evansville- Site Number : 8400008
Evansville, Indiana, United States
...and 76 more locations
Stage 1 and Stage 2: Number of Participants With Positive NAAT for SARS-CoV-2
Virologically-confirmed SARS-CoV-2 infection was defined as a positive result for SARS-CoV-2 by NAAT on at least 1 respiratory sample. Respiratory samples for NAAT testing were collected in participants with CLI through the study.
Time frame: From first dose of study vaccine administration (Day 1) up to 387 days
Stage 1 and Stage 2: Number of Participants With Centers for Disease Control and Prevention (CDC)-Defined COVID-19
CDC-defined COVID-19 included virologically-confirmed SARS-CoV-2 infection with at least 1 of: fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny nose, nausea or vomiting, diarrhea.
Time frame: From first dose of study vaccine administration (Day 1) up to 387 days
Stage 1 and Stage 2: Number of Participants With Occurrences of Hospitalized COVID-19
Hospitalized COVID-19 was defined as an episode of symptomatic COVID-19 that required inpatient hospitalization.
Time frame: From first dose of study vaccine administration (Day 1) up to 387 days
Stage 1 and Stage 2: Number of Participants With Symptomatic COVID-19 With Severity of Moderate or Worse
Symptomatic COVID-19 was defined as virologically-confirmed SARS-CoV-2 infection accompanied by protocol-defined CLI. Moderate COVID-19 was defined as symptomatic COVID-19 with either shortness of breath that persisted for at least 12 hours or clinical signs of moderate illness measured at least on 2 occasions separated by 30 minutes and no clinical signs indicative of severe COVID-19.
Time frame: From first dose of study vaccine administration (Day 1) up to 387 days
Stage 1 and Stage 2: Geometric Mean Titers of Neutralizing Antibodies Against SARS-CoV-2 D614G Strain at Days 1, 22, and 43
Neutralizing antibodies activity against SARS-CoV-2 D614G strain was measured with the neutralization assay (monogram assay) and the results were expressed as geometric mean titers.
Time frame: Pre-vaccination on Day 1 and post-vaccination on Days 22, and 43
Crossover: Geometric Mean Titers of Neutralizing Antibodies Against SARS-CoV-2 D614G and B.1.351 Strains at Days 1, 43, 142, 163, and 322
Neutralizing antibodies activity against SARS-CoV-2 D614G strain and B.1.351 strain was measured with the neutralization assay (monogram assay) and the results were expressed as geometric mean titers.
Time frame: Pre-vaccination on Day 1 and post-vaccination on Days 43, 142, 163 and 322
Booster: Geometric Mean Titers of Neutralizing Antibodies Against SARS-CoV-2 D614G and B.1.351 Strains at Days 1, 22, and 202
Neutralizing antibodies activity against SARS-CoV-2 D614G strain and B.1.351 strain was measured with the neutralization assay (monogram assay) and the results were expressed as geometric mean titers.
Time frame: Pre-vaccination on Day 1 and post-vaccination on Days 22, and 202
Stage 1 and Stage 2: Number of Responders as Determined by Neutralizing Antibody Titers Against SARS-CoV-2 D614G Strain at Days 22 and 43
Responders are participants who had baseline values below lower limit of quantification (LLOQ) with quantifiable neutralization titer above assay LLOQ at each pre-defined post-vaccination timepoint and participants with baseline values above LLOQ with a 4-fold increase in neutralizing antibody titers at each pre-defined post-vaccination timepoint.
Time frame: Post-vaccination on Days 22 and 43
Crossover: Number of Responders as Determined by Neutralizing Antibody Titers Against SARS-CoV-2 D614G and B.1.351 Strains at Days 43, 142, 163, and 322
Responders are participants who had baseline values below LLOQ with quantifiable neutralization titer above assay LLOQ at each pre-defined post-vaccination timepoint and participants with baseline values above LLOQ with a 4-fold increase in neutralizing antibody titers at each pre-defined post-vaccination timepoint.
Time frame: Post-vaccination on Days 43, 142, 163 and 322
Booster: Number of Responders as Determined by Neutralizing Antibody Titers Against SARS-CoV-2 D614G and B.1.351 Strains at Days 22 and 202
Responders are participants who had baseline values below LLOQ with quantifiable neutralization titer above assay LLOQ at each pre-defined post-vaccination timepoint and participants with baseline values above LLOQ with a 4-fold increase in neutralizing antibody titers at each pre-defined post-vaccination timepoint.
Time frame: Post-vaccination on Days 22, and 202
Stage 1: Number of Participants With >=2-Fold and >=4-Fold Rise in Neutralizing Antibody Titers Against SARS-CoV-2 D614G Strain at Days 22 and 43
Neutralizing antibodies activity against SARS-CoV-2 D614G strain was measured with serum neutralization assay (monogram assay). Participants with neutralization antibody titers \>=2-fold and \>=4-fold increase from baseline (pre-vaccination) are reported.
Time frame: Pre-vaccination on Day 1 and post-vaccination on Days 22 and 43
Crossover: Number of Participants With >=2-Fold and >=4-Fold Rise in Neutralizing Antibody Titers Against SARS-CoV-2 D614G and B.1.351 Strains at Days 43, 142, 163, and 322
Neutralizing antibodies activity against SARS-CoV-2 D614G strain and B.1.351 strain was measured with serum neutralization assay (monogram assay). Participants with neutralization antibody titers \>=2-fold and \>=4-fold increase from baseline (pre-vaccination) are reported.
Time frame: Pre-vaccination on Day 1 and post-vaccination on Days 43, 142, 163, and 322
Booster: Number of Participants With >=2-Fold and >=4-Fold Rise in Neutralizing Antibody Titers Against SARS-CoV-2 D614G and B.1.351 Strains at Days 22 and 202
Neutralizing antibodies activity against SARS-CoV-2 D614G strain and B.1.351 strain was measured with serum neutralization assay (monogram assay). Participants with neutralization antibody titers \>=2-fold and \>=4-fold increase from baseline (pre-vaccination) are reported.
Time frame: Pre-vaccination on Day 1 and post-vaccination on Days 22, and 202
Number of Participants With Symptomatic COVID-19 Episodes
Symptomatic COVID-19 is defined as virologically-confirmed SARS-CoV-2 infection accompanied by protocol-defined CLI. Grade 1: A type of AE that was usually transient and required only minimal treatment or therapeutic intervention and did not generally interfere with usual activities of daily living. Grade 2: A type of AE that was usually alleviated with additional therapeutic intervention and interfered with usual activities of daily living, causing discomfort but posed no significant or permanent risk of harm to the research participant. Grade 3: A type of AE that interrupted usual activities of daily living, or significantly affects clinical status, or required intensive therapeutic intervention.
Time frame: Stages 1 and 2: From first dose of study vaccine administration (Day 1) up to Day 387. Crossover and Booster: From first dose of study vaccine administration (Day 1) up to Day 487
Number of Participants With COVID-19 Severity Using a 7-Point Ordinal Scale
The COVID-19 severity scale was based on the 7-point ordinal scale of clinical assessments: 1: death; 2: hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation; 3: hospitalized, on non-invasive ventilation or high flow oxygen devices; 4: hospitalized, that required supplemental oxygen; 5: hospitalized, that did not require supplemental oxygen- discharged but required ongoing medical care (COVID-19 related or otherwise); 6: hospitalized, that did not require supplemental oxygen discharged without ongoing medical care; 7: not hospitalized.
Time frame: Stages 1 and 2: From first dose of study vaccine administration (Day 1) up to Day 387. Crossover and Booster: From first dose of study vaccine administration (Day 1) up to Day 487
Number of Deaths Associated With COVID-19
Death associated with COVID-19 was defined as death in a participant with COVID-19 who died within 28 days of the first positive specimen date or who died more than 28 days after the first specimen date and COVID-19 was mentioned as an immediate or underlying cause of death on the death certificate.
Time frame: Stages 1 and 2: From first dose of study vaccine administration (Day 1) up to Day 387. Crossover and Booster: From first dose of study vaccine administration (Day 1) up to Day 487