COVID-19
Conditions
Brief summary
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.
Detailed description
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.
Interventions
BIOLOGICALSARS-CoV-2 adjuvanted recombinant protein vaccine (monovalent D614) (primary series)
Pharmaceutical form: emulsion for injection. Route of administration: intramuscular injection
BIOLOGICALSARS-CoV-2 adjuvanted recombinant protein vaccine (bivalent D614 + B.1.351) (primary series)
Pharmaceutical form: emulsion for injection. Route of administration: intramuscular injection.
BIOLOGICALPlacebo
Pharmaceutical form: liquid. Route of administration: intramuscular administration.
BIOLOGICALSARS-CoV-2 adjuvanted recombinant protein vaccine (monovalent B.1.351) (booster dose) >= 4 months after last vaccination
Pharmaceutical form: emulsion for injection. Route of administration: intramuscular injection.
BIOLOGICALSARS-CoV-2 adjuvanted recombinant protein vaccine(monovalent D614)(primary series)& SARS-CoV-2 adjuvanted recombinant protein vaccine(monovalent B.1.351)(booster dose)>=4 months after last vaccination
Pharmaceutical form: emulsion for injection. Route of administration: intramuscular injection.
Sponsors
Sanofi Pasteur, a Sanofi Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
For initial, double-blind, primary series design of study: participants, outcome assessors, Investigators, laboratory personnel, and sponsor trial staff are blinded to intervention group; and those preparing the study interventions are unblinded to vaccine assignment group. For crossover / booster design of study (Stage 1 and Stage 2): unblinded
Intervention model description
The study is designed to demonstrate clinical efficacy of each of the two SARS-CoV-2 adjuvanted recombinant protein vaccines (monovalent and bivalent). In Stage 1, the monovalent vaccine will be evaluated against a placebo control. In Stage 2, the bivalent vaccine will be assessed against a placebo control.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Aged 18 years or older on the day of inclusion. * For persons living with human immunodeficiency virus (HIV), stable HIV infection determined by participant currently on antiretrovirals with CD4 count \> 200/mm3. * SARS-CoV-2 rapid serodiagnostic test performed at the time of enrollment to detect presence of SARS-CoV-2 antibodies. * Does not intend to receive an authorized/approved COVID-19 vaccine despite encouragement by the Investigator to receive the authorized vaccine available to them at the time of enrollment. * Informed consent form has been signed and dated * Able to attend all visits and to comply with all study procedures * Covered by health insurance, only if required by local, regional or national regulations * A female participant is eligible to participate if she is not pregnant or breastfeeding and one of the following conditions applies: * is of non-childbearing potential. To be considered of non-childbearing potential, a female must be post-menopausal for at least 1 year or surgically sterile, or * is of childbearing potential and agrees to use an effective contraceptive method or abstinence from at least 4 weeks prior to the first study intervention administration until at least 12 weeks after the second study intervention administration. A participant of childbearing potential must have a negative highly sensitive pregnancy test (urine or serum as required by local regulation) within 25 hours before any dose of study intervention.
Exclusion criteria
* Known systemic hypersensitivity to any of the vaccine components, or history of a life-threatening reaction to a vaccine containing any of the same substances. * Dementia or any other cognitive condition at a stage that could interfere with following the study procedures based on Investigator?s judgment. * Self-reported thrombocytopenia, contraindicating intramuscular (IM) vaccination based on Investigator?s judgment * Bleeding disorder, or receipt of anticoagulants in the past 21 days preceding inclusion, contraindicating IM vaccination based on Investigator?s judgment. * Unstable acute or chronic illness that in the opinion of the Investigator or designee poses additional risk as a result of participation or that could interfere with the study procedures. * Moderate or severe acute illness/infection (according to investigator judgment) on the day of vaccination or febrile illness (temperature ? 38.0 C \[? 100.4 F\]). A prospective participant should not be included in the study until the condition has resolved or the febrile event has subsided. * Receipt of any vaccine in the 30 days preceding or on the day of the first study vaccination or planned receipt of any vaccine between the first study vaccination and in the 30 days following the second study vaccination except for influenza vaccination, which may be received at any time in relation to study intervention. * Prior administration of a coronavirus vaccine (SARS-CoV-2, SARS-CoV, Middle East Respiratory Syndrome). * Receipt of solid-organ or bone marrow transplants in the past 180 days. * Receipt of anti-cancer chemotherapy in the last 90 days. * Deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily. * Identified as an Investigator or employee of the Investigator or study center with direct involvement in the proposed study, or identified as an immediate family member (ie, parent, spouse, natural or adopted child) of the Investigator or employee with direct involvement in the proposed study. * Participation at the time of study enrollment (or in the 30 days preceding the first study vaccination) or planned participation during the present study period in another clinical study investigating a vaccine, drug, medical device, or medical procedure.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Stage 1 and Stage 2: Number of Participants With Onset of Symptomatic Coronavirus Disease 2019 (COVID-19) Episode | From Day 36 up to Day 387 | Symptomatic COVID-19 was defined as virologically-confirmed SARS-CoV-2 infection accompanied by protocol-defined COVID-19-like illness (CLI). |
| Stage 1 and Stage 2: Number of Participants With Solicited Injection Site and Systemic Reactions | Up to 7 days after each vaccination (post-dose on Days 1 and 22) | 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. |
| Stage 1 and Stage 2: Number of Participants With Unsolicited Non-Serious Adverse Events (AEs) | Up to 21 days after each vaccination (post-dose on Days 1 and 22) | 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. |
| Stage 1 and Stage 2: Number of Participants With Immediate Adverse Events | Up to 30 minutes after each vaccination (post-dose on Days 1 and 22) | 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. |
| 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) | From first dose of study vaccine administration (Day 1) up to 387 days | 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. |
| Stage 1 and Stage 2: Percentage of Participants With Virologically-Confirmed SARS-CoV-2 Infection and/or Symptomatic COVID-19 | From first dose of study vaccine administration (Day 1) up to 387 days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Stage 1 and Stage 2: Number of Participants With SARS-CoV-2 Infection | From Day 36 up to Day 387 | SARS-CoV-2 infection was defined as a serologically-confirmed SARS-CoV-2 infection or virologically-confirmed SARS-CoV-2 infection. |
| Stage 1 and Stage 2: Number of Participants With Occurrence of Severe COVID-19 | From Day 36 up to Day 387 | 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. |
| Stage 1 and Stage 2: Number of Participants With Asymptomatic SARS-CoV-2 Infection | From first dose of study vaccine administration (Day 1) up to 387 days | 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. |
| Stage 1 and Stage 2: Number of Swabs With Positive Nucleic Acid Amplification Test (NAAT) | From first dose of study vaccine administration (Day 1) up to 387 days | 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. |
| Stage 1 and Stage 2: Number of Participants With Respective Number of Days Between Two Consecutive Positive Nucleic Acid Amplification Test | From first dose of study vaccine administration (Day 1) up to 387 days | 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. |
| Stage 1 and Stage 2: Number of Participants With Positive NAAT for SARS-CoV-2 | From first dose of study vaccine administration (Day 1) up to 387 days | 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. |
| Stage 1 and Stage 2: Number of Participants With Centers for Disease Control and Prevention (CDC)-Defined COVID-19 | From first dose of study vaccine administration (Day 1) up to 387 days | 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. |
| Stage 1 and Stage 2: Number of Participants With Occurrences of Hospitalized COVID-19 | From first dose of study vaccine administration (Day 1) up to 387 days | Hospitalized COVID-19 was defined as an episode of symptomatic COVID-19 that required inpatient hospitalization. |
| Stage 1 and Stage 2: Number of Participants With Symptomatic COVID-19 With Severity of Moderate or Worse | From first dose of study vaccine administration (Day 1) up to 387 days | 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. |
| Stage 1 and Stage 2: Geometric Mean Titers of Neutralizing Antibodies Against SARS-CoV-2 D614G Strain at Days 1, 22, and 43 | Pre-vaccination on Day 1 and post-vaccination on Days 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. |
| 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 | Pre-vaccination on Day 1 and post-vaccination on Days 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. |
| Booster: Geometric Mean Titers of Neutralizing Antibodies Against SARS-CoV-2 D614G and B.1.351 Strains at Days 1, 22, and 202 | Pre-vaccination on Day 1 and post-vaccination on Days 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. |
| 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 | Post-vaccination on 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. |
| 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 | Post-vaccination on 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. |
| 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 | Post-vaccination on 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. |
| 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 | Pre-vaccination on Day 1 and post-vaccination on 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. |
| 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 | Pre-vaccination on Day 1 and post-vaccination on 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. |
| 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 | Pre-vaccination on Day 1 and post-vaccination on 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. |
| Number of Participants With Symptomatic COVID-19 Episodes | 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 | 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. |
| Number of Participants With COVID-19 Severity Using a 7-Point Ordinal Scale | 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 | 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. |
| Number of Deaths Associated With COVID-19 | 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 | 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. |
Countries
Colombia, Ghana, Honduras, India, Japan, Kenya, Mexico, Nepal, Uganda, Ukraine, United States
Participant flow
Recruitment details
The study was conducted at 87 centers in 11 countries from 26 May 2021 to 31 August 2024.
Pre-assignment details
10139 participants were enrolled in Stage 1 and 13531 in Stage 2. A total of 23670 unique participants were enrolled in the study. Participants from the Original Cohort (Stage 1 and Stage 2) were included in the booster cohort because these assessed separate objectives. The study was terminated as per Sponsor decision.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 36.9 year STANDARD_DEVIATION 13.4 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 404 Participants |
| Race/Ethnicity, Customized Asian | 2562 Participants |
| Race/Ethnicity, Customized Black or African American | 2854 Participants |
| Race/Ethnicity, Customized Multiple | 5 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 9 Participants |
| Race/Ethnicity, Customized Not Reported | 181 Participants |
| Race/Ethnicity, Customized Unknown | 492 Participants |
| Race/Ethnicity, Customized White | 114 Participants |
| Sex: Female, Male Female | 2174 Participants |
| Sex: Female, Male Male | 2836 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 9 / 5,049 | 26 / 5,064 | 29 / 6,733 | 40 / 6,714 | 6 / 6,529 | 21 / 14,237 |
| other Total, other adverse events | 1,321 / 5,049 | 845 / 5,064 | 1,610 / 6,733 | 1,200 / 6,714 | 133 / 6,529 | 261 / 14,237 |
| serious Total, serious adverse events | 100 / 5,049 | 135 / 5,064 | 149 / 6,733 | 160 / 6,714 | 53 / 6,529 | 125 / 14,237 |
Outcome results
None listed