Study of Recombinant Protein Vaccines With Adjuvant as a Primary Series and as a Booster Dose Against COVID-19 in Adults 18 Years of Age and Older

Study Overview
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Brief Summary
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The primary objectives of the study are: To assess the safety profile of the study vaccines in each study intervention group. To assess the neutralizing antibody profile after primary series vaccination in SARS-CoV-2-naïve adults. To demonstrate that a booster dose of monovalent or bivalent SARS-CoV-2 vaccine given to adults previously vaccinated with an authorized/approved COVID-19 vaccine induces an immune response that is non-inferior to the response induced by a twodose priming series with the monovalent vaccine, and superior to that observed immediately before booster. The secondary objectives of the study are: To assess the neutralizing and binding antibody profiles after primary series vaccination at pre-defined time points during the study. To assess the neutralizing and binding antibody responses of booster vaccination. To describe the occurrences of laboratory-confirmed symptomatic COVID19 after primary series and booster vaccination. To describe the occurrences of serologically-confirmed SARS-CoV-2 infection after primary series vaccination.

Detailed Description
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The duration of each participant's participation in the study will be approximately: Original Phase 2 part: 365 days postinjection 2 (ie, 386 days total). Supplemental Cohorts 1 and 2: 365 days post-booster injection (ie, 366 days total).

Official Title
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Immunogenicity and Safety of SARS-CoV-2 Recombinant Protein Vaccines With AS03 Adjuvant in Adults 18 Years of Age and Older as a Primary Series and Immunogenicity and Safety of a Booster Dose of SARS-CoV-2 Adjuvanted Recombinant Protein Vaccines (Two Monovalent and One Bivalent)

Conditions
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COVID-19

Intervention / Treatment
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* Biological: SARS-CoV-2 recombinant protein vaccine Phase 2 Formulation 1
* Biological: SARS-CoV-2 recombinant protein vaccine Phase 2 Formulation 2
* Biological: SARS-CoV-2 recombinant protein vaccine Phase 2 Formulation 3
* Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine, monovalent (D614)-AS03, Dosage A
* Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine, monovalent (B.1.351)-AS03
* Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine, monovalent (D614)-AS03, Dosage B
* Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine, monovalent (B.1.351)-AS03 Alternative Exploratory Formulation 1
* Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine, monovalent (B.1.351)-AS03 Alternative Exploratory Formulation 2
* Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine, monovalent (B.1.351)-AS03 Alternative Exploratory Formulation 3
* Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine, monovalent (B.1.351)-AS03 Alternative Exploratory Formulation 4
* Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine, bivalent (D614+B.1.351)-AS03


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: -Aged 18 years or older on the day of inclusion. - -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 mut 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 vaccination until at least 12 weeks after the last vaccination (ie, second dose of primary series or booster injection). A participant of childbearing potential must have a negative highly sensitive pregnancy test (urine or serum as required by local regulation) within 4 hours before any dose of study intervention. - -Informed consent form has been signed and dated. Able to attend all scheduled visits and to comply with all study procedures. SARS-CoV-2 rapid serodiagnostic test performed at the time of enrollment to detect presence of SARS-CoV-2 antibodies (Original Phase 2 Cohort). For persons living with human immunodeficiency virus (HIV), stable HIV infection determined by participant currently on antiretrovirals with CD4 count > 200/mm3. Does not intend to receive an authorized/approved COVID-19 vaccine from first vaccination to 3 weeks after the second vaccination despite encouragement by the investigator to receive the authorized vaccine available to them at the time of enrollment. Supplemental cohorts: for participants originally enrolled in the Phase II cohort of the study, informed consent has to be signed and dated for transitioning to Supplemental Cohort 2. Supplemental cohorts, Booster arms: received a complete primary vaccination series with an authorized/conditionally approved mRNA COVID-19 vaccine (mRNA-1273 [Moderna] or BNT162b2 [Pfizer/BioNTech]) or adenovirus-vectored COVID-19 vaccine (ChAdOx1 nCoV-19 [Oxford University/AstraZeneca] or Ad26.CoV2.S [J&J/Janssen]), with the last dose administered a minimum of 4 months prior to inclusion but not longer than 10 months prior to inclusion. 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 trial procedures based on Investigator or designee'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. Receipt of solid-organ or bone marrow transplants in the past 180 days. Receipt of anti-cancer chemotherapy in the last 90 days. Receipt of immunoglobulins, blood, or blood-derived products in the past 3 months. 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 trial 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. Applicable to Original Phase II Cohort, Supplemental Cohort 1 and Cohort 2 Comparator Group: Prior administration of a coronavirus vaccine (SARS-CoV-2, SARS-CoV, Middle East Respiratory Syndrome [MERS-CoV]). Participation at the time of study enrollment (or in the 30 days preceding the first study vaccination) or planned participation during the present study trial period in another clinical study investigating a vaccine, drug, medical device, or medical procedure. Exclusion criterion for the Supplemental Cohort 1 and Cohort 2 comparator group: positive rapid diagnostic test for SARS-CoV-2 antibodies at time of enrollment. Exclusion criterion for participants in Supplemental Cohort 2 who were primed as participant in the Original Phase II Cohort of the present study: Receipt of authorized/conditionally approved COVID-19 vaccine after enrollment in Original Phase 2 Cohort. Exclusion criterion for all Booster groups: Documented virologically-confirmed SARS-CoV-2 infection (by NAAT) after first dose of primary immunization.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: To address the emergence of variant strains, Sanofi Pasteur is developing monovalent and bivalent vaccines for use as universal late booster vaccines which will be studied in additional Phase 3 study cohorts that are added to the initial Phase 2 protocol cohorts. Supplemental Cohorts 1 and 2 will evaluate booster vaccine candidates.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 2 Cohort -SARS-CoV-2 vaccine Formulation 1<br>2 injections of SARS-CoV-2 vaccine Formulation 1 at Day 1 and Day 22 | Biological: SARS-CoV-2 recombinant protein vaccine Phase 2 Formulation 1<br>* Pharmaceutical form: Emulsion for injection Route of administration: Intramuscular injection<br>|
| Experimental: Phase 2 Cohort - SARS-CoV-2 vaccine Formulation 2<br>2 injections of SARS-CoV-2 vaccine Formulation 2 at Day 1 and Day 22 | Biological: SARS-CoV-2 recombinant protein vaccine Phase 2 Formulation 2<br>* Pharmaceutical form: Emulsion for injection Route of administration: Intramuscular injection<br>|
| Experimental: Phase 2 Cohort - SARS-CoV-2 vaccine Formulation 3<br>2 injections of SARS-CoV-2 vaccine Formulation 3 Day 1 and Day 22 | Biological: SARS-CoV-2 recombinant protein vaccine Phase 2 Formulation 3<br>* Pharmaceutical form: Emulsion for injection Route of administration: Intramuscular injection<br>|
| Experimental: Supplemental Cohort 1 - Booster Monovalent (D614)-AS03 SARS-CoV-2 vaccine<br>Participants who were previously vaccinated 4 to < 10 months prior with an authorized mRNA or adenovirus-vector COVID-19 vaccine will receive 1 booster injection of monovalent (D614)-AS03 SARS-CoV-2 vaccine | Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine, monovalent (D614)-AS03, Dosage A<br>* Pharmaceutical form: Emulsion for injection Route of administration: Intramuscular injection<br>|
| Experimental: Supplemental Cohort 2 - Booster Monovalent (B.1.351)-AS03 SARS-CoV-2 vaccine<br>Participants who were vaccinated 4 to < 10 months prior with an authorized mRNA or adenovirus-vector COVID-19 vaccine or SARS-Cov-2 vaccine will receive 1 booster injection of monovalent (B.1.351)-AS03 SARS-CoV-2 vaccine | Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine, monovalent (B.1.351)-AS03<br>* Pharmaceutical form: Emulsion for injection Route of administration: Intramuscular injection<br>|
| Experimental: Supplemental Cohort 2 - Booster Bivalent (D614 + B.1.351)-AS03 SARS-CoV-2 vaccine<br>Participants who were vaccinated 4 to < 10 months prior with an authorized mRNA or adenovirus-vector COVID-19 vaccine will receive 1 booster injection of bivalent (D614+B.1.351)-AS03 SARS-CoV-2 vaccine | Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine, bivalent (D614+B.1.351)-AS03<br>* Pharmaceutical form: Emulsion for injection Route of administration: Intramuscular injection<br>|
| Experimental: Supplemental Cohort 2 - Booster Monovalent (D614)-AS03 SARS-CoV-2 vaccine<br>Participants who were vaccinated 4 to < 10 months prior with SARS-Cov-2 vaccine will receive 1 booster injection of monovalent (D614)-AS03 SARS-CoV-2 vaccine | Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine, monovalent (D614)-AS03, Dosage A<br>* Pharmaceutical form: Emulsion for injection Route of administration: Intramuscular injection<br>|
| Active Comparator: Supplemental Comparator for Cohort 1 and 2 Boosters - Monovalent (D614)-AS03 SARS-CoV-2 vaccine<br>2 injections of monovalent (D614)-AS03 SARS-CoV-2 vaccine at Day 1 and Day 22 in previously unvaccinated, naïve participants | Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine, monovalent (D614)-AS03, Dosage B<br>* Pharmaceutical form: Emulsion for injection Route of administration: Intramuscular injection<br>|
| Experimental: Cohort 2 - Booster Exploratory 1<br>Participants who were vaccinated 4 to < 10 months prior with an authorized mRNA COVID-19 vaccine will receive 1 booster injection of monovalent (B.1.351)-AS03 SARS-CoV-2 vaccine | Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine, monovalent (B.1.351)-AS03 Alternative Exploratory Formulation 1<br>* Pharmaceutical form: Emulsion for injection Route of administration: Intramuscular injection<br>|
| Experimental: Cohort 2 - Booster Exploratory 2<br>Participants who were vaccinated 4 to < 10 months prior with an authorized mRNA COVID-19 vaccine will receive 1 booster injection of monovalent (B.1.351)-AS03 SARS-CoV-2 vaccine | Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine, monovalent (B.1.351)-AS03 Alternative Exploratory Formulation 2<br>* Pharmaceutical form: Emulsion for injection Route of administration: Intramuscular injection<br>|
| Experimental: Cohort 2 - Booster Exploratory 3<br>Participants who were vaccinated 4 to < 10 months prior with an authorized mRNA COVID-19 vaccine will receive 1 booster injection of monovalent (B.1.351)-AS03 SARS-CoV-2 vaccine | Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine, monovalent (B.1.351)-AS03 Alternative Exploratory Formulation 3<br>* Pharmaceutical form: Emulsion for injection Route of administration: Intramuscular injection<br>|
| Experimental: Cohort 2 - Booster Exploratory 4<br>Participants who were vaccinated 4 to < 10 months prior with an authorized mRNA COVID-19 vaccine will receive 1 booster injection of monovalent (B.1.351)-AS03 SARS-CoV-2 vaccine | Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine, monovalent (B.1.351)-AS03 Alternative Exploratory Formulation 4<br>* Pharmaceutical form: Emulsion for injection Route of administration: Intramuscular injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Presence of immediate adverse events | Immediate adverse events include unsolicited adverse events occurring within 30 minutes after injection. | Within 30 minutes after vaccination | 
| Presence of solicited injection site or systemic reactions | Injection site reactions: injection site pain, erythema and swelling. Systemic reactions: fever, headache, malaise and myalgia. | Within 7 days after vaccination | 
| Presence of unsolicited adverse events | Adverse events other than solicited reactions. | Within 21 days after vaccination | 
| Presence of serious adverse events | Serious adverse events are reported throughout the study. | From Day 1 to Day 387 | 
| Presence of adverse events of special interest | Adverse events of special interest are reported throughout the study. | From Day 1 to Day 387 | 
| Presence of medically-attended adverse events | Medically-attended adverse events are new onset or a worsening of a condition that prompts the participant or participant's parent/guardian to seek unplanned medical advice at a physician's office or Emergency Department. | From Day 1 to Day 387 | 
| Neutralizing antibody titer at Day 1 | Neutralizing antibody titers are expressed as geometric mean titers. | Day 1 | 
| Neutralizing antibody titer at Day 36 | Neutralizing antibody titers are expressed as geometric mean titers. | Day 36 | 
| Neutralizing antibody titer fold-rise post-vaccination | Neutralizing antibody titer fold-rise post-vaccination. | From Day 1 to Day 36 | 
| 2-fold rise and 4-fold-rise in neutralization antibody titer | Fold-rise in antibody neutralization titer post-vaccination relative to Day 1. | From Day 1 to Day 36 | 
| Responders, as determined by neutralizing antibody titers at Day 36 | Responders, defined as participants who had baseline values below lower limit of quantification (LLOQ) with detectable neutralization titer above assay LLOQ at each pre-defined time point and participants with baseline values above LLOQ with a 4-fold increase in neutralizing antibody titer at Day 36 | From Day 1 to Day 36 | 
| Neutralizing antibody titer at Day 1 (pre-booster injection) | Neutralizing antibody titers are expressed as geometric mean titers. | Day 1 (pre-booster injection) | 
| Neutralizing antibody titer at Day 15 (post-booster injection) | Neutralizing antibody titers are expressed as geometric mean titers. | Day 15 (post-booster injection) | 
| Neutralizing antibody titer at Day 36 (Cohorts 1 and 2 Comparator Group) | Neutralizing antibody titers are expressed as geometric mean titers. | Day 36 | 
| Responders, as determined by neutralizing antibody titers at Day 36 (Cohorts 1 and 2 Comparator Group) | Responders are defined as participants with a 4-fold-or greater rise in serum neutralization titer [pre/post] at Day 36 relative to Day 1 | From Day 1 to Day 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neutralizing antibody titer at all pre-defined time points |  | Day 1, Day 22, Day 36, Day 78, Day 134, Day 202, Day 292 and Day 387 | 
| Neutralizing antibody titer fold-rise post-vaccination at all pre-defined time points | Fold-rise in antibody neutralization titer post-vaccination relative to Day 1. | Day 1, Day 22, Day 36, Day 78, Day 134, Day 202, Day 292 and Day 387 | 
| Responders, as determined by neutralizing antibody titers at each pre-defined time point | Responders, defined as participants who had baseline values below LLOQ with detectable neutralization titer above assay LLOQ at each pre-defined time point and participants with baseline values above LLOQ with a 4-fold increase in neutralizing antibody titer at each pre-defined timepoint. | Day 1, Day 22, Day 36, Day 78, Day 134, Day 202, Day 292 and Day 387 | 
| 2-fold rise and 4-fold-rise in neutralization antibody titer at all pre-defined time points | Fold-rise in antibody neutralization titer post-vaccination relative to Day 1. | Day 1, Day 22, Day 36, Day 78, Day 134, Day 202, Day 292 and Day 387 | 
| Binding antibody fold-rise | Fold-rise in concentration relative to Day 1. | Day 1, Day 22, Day 36, Day 78, Day 134, Day 202, Day 292 and Day 387 | 
| Binding antibody concentrations |  | Day 1, Day 22, Day 36, Day 78, Day 134, Day 202, Day 292 and Day 387 | 
| 2-fold-rise and 4-fold rise in binding antibody concentration | Fold-rise in concentration relative to Day 1. | Day 1, Day 22, Day 36, Day 78, Day 134, Day 202, Day 292 and Day 387 | 
| Responders, as determined by binding antibody concentrations | Responders are defined as participants who had baseline values below LLOQ with detectable anti concentration above assay LLOQ at each pre-defined time point and participants with baseline values above LLOQ with a 4-fold increase in anti-S antibody concentration at each pre-defined time point. | Day 1, Day 22, Day 36, Day 78, Day 134, Day 202, Day 292 and Day 387 | 
| Occurrences of laboratory-confirmed symptomatic COVID-19 | Symptomatic COVID-19 is defined as laboratory-confirmed SARS-CoV-2 infection accompanied by protocol-defined COVID-19-like illness. Laboratory-confirmed SARS-CoV-2 infection is defined as a positive result for SARS CoV-2 by nucleic acid amplification test (NAAT), done by the central laboratory or locally, on at least one respiratory sample. | From Day 1 to Day 387 | 
| Occurrences of symptomatic COVID-19 episodes associated with hospitalization | Symptomatic COVID-19 is defined as laboratory-confirmed SARS-CoV-2 infection accompanied by protocol-defined COVID-19-like illness. | From Day 1 to Day 387 | 
| Occurrences of severe symptomatic COVID-19 | Symptomatic COVID-19 is defined as laboratory-confirmed SARS-CoV-2 infection accompanied by protocol-defined COVID-19-like illness with pre-defined criteria of severity. | From Day 1 to Day 387 | 
| Occurrences of death associated with symptomatic COVID-19 | Symptomatic COVID-19 is defined as laboratory-confirmed SARS-CoV-2 infection accompanied by protocol-defined COVID-19-like illness. | From Day 1 to Day 387 | 
| Occurrences of serologically-confirmed SARS-CoV-2 infection | Serologically-confirmed SARS-CoV-2 infection is defined as a positive result in a serum sample for antibodies against SARS-CoV-2. | From Day 1 to Day 387 | 
| Neutralizing antibody titer at all pre-defined time points post-booster and booster comparator injection |  | Day 1 and Day 15 (post-booster injection) and Day 36 | 
| Neutralizing antibody titer fold-rise post-vaccination at all pre-defined time points post-booster and booster comparator injection | Neutralizing antibody titer fold-rise post-vaccination. | Day 1 and Day 15 (post-booster injection) and Day 36 | 
| 2-fold rise and 4-fold-rise in neutralization antibody titer at all pre-defined time points post-booster and booster comparator injection | Neutralizing antibody titer fold-rise post-vaccination. | Day 1 and Day 15 -post-booster injection) and Day 36 | 
| Seroresponse rate post-booster and booster comparator injection | Seroresponse rate is defined as the percentage or participants with 4-fold-or greater rise in serum neutralization titer [pre/post] at post-vaccination relative to pre-vaccination. | Day 1 and Day 15 (post-booster injection) and Day 36 | 
| Binding antibody concentrations post-booster injection |  | Day 1, Day 15, Day 29, Day 91, Day 181, and Day 366 (post-booster injection) | 
| Binding antibody fold-rise post-booster injection | Fold-rise in concentration relative to Day 1. | Day 1, Day 15, Day 29, Day 91, Day 181, and Day 366 (post-booster injection) | 
| 2-fold-rise and 4-fold rise in binding antibody concentration post-booster injection | Fold-rise in concentration relative to Day 1. | Day 1, Day 15, Day 29, Day 91, Day 181, and Day 366 (post-booster injection) |