Study of Monovalent and Bivalent Recombinant Protein Vaccines Against COVID-19 in Adults 18 Years of Age and Older

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Parallel-group, Phase III, Multi-stage, Modified Double-blind, Multi-armed Study to Assess the Efficacy, Safety, and Immunogenicity of Two SARS-CoV-2 Adjuvanted Recombinant Protein Vaccines (Monovalent and Bivalent) for Prevention Against COVID-19 in Adults 18 Years of Age and Older as a Primary Series and Open-label Extension to Assess Immunogenicity, Safety, Efficacy of a Monovalent Booster Dose of SARS-CoV2 Adjuvanted Recombinant Protein Vaccine

Conditions
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COVID-19

Intervention / Treatment
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* Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine (monovalent D614) (primary series)
* Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine (bivalent D614 + B.1.351) (primary series)
* Biological: Placebo
* Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine (monovalent B.1.351) (booster dose) >= 4 months after last vaccination
* Biological: SARS-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


Participation Criteria
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Eligibility Criteria
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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.

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: 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.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage 1: SARS-CoV-2 vaccine<br>2 injections of monovalent SARS-CoV-2 vaccine at Day 1 and Day 22 | Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine (monovalent D614) (primary series)<br>* Pharmaceutical form: emulsion for injection. Route of administration: intramuscular injection<br>Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine (monovalent B.1.351) (booster dose) >= 4 months after last vaccination<br>* Pharmaceutical form: emulsion for injection. Route of administration: intramuscular injection.<br>|
| Placebo Comparator: Stage 1: Placebo<br>2 injections of placebo at Day 1 and Day 22 | Biological: Placebo<br>* Pharmaceutical form: liquid. Route of administration: intramuscular administration.<br>Biological: SARS-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<br>* Pharmaceutical form: emulsion for injection. Route of administration: intramuscular injection.<br>|
| Experimental: Stage 2: SARS-CoV-2 vaccine<br>2 injections of bivalent SARS-CoV-2 vaccine at Day 1 and Day 22 | Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine (bivalent D614 + B.1.351) (primary series)<br>* Pharmaceutical form: emulsion for injection. Route of administration: intramuscular injection.<br>Biological: SARS-CoV-2 adjuvanted recombinant protein vaccine (monovalent B.1.351) (booster dose) >= 4 months after last vaccination<br>* Pharmaceutical form: emulsion for injection. Route of administration: intramuscular injection.<br>|
| Placebo Comparator: Stage 2: Placebo<br>2 injections of placebo at Day 1 and Day 22 | Biological: Placebo<br>* Pharmaceutical form: liquid. Route of administration: intramuscular administration.<br>Biological: SARS-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<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 |
| --- | --- | --- |
| Occurrences of symptomatic COVID-19 | Symptomatic COVID-19 is defined as virologically-confirmed SARS-CoV-2 infection accompanied by protocol-defined COVID-19-like illness. | From ≥ 14 days after the second injection to Day 387 | 
| Presence of solicited injection site or systemic reactions (collected in the reactogenicity subset) | Injection site reactions: injection site pain, erythema and swelling. Systemic reactions: fever, headache, malaise, myalgia, arthralgia and chills. | Within 7 days after vaccination | 
| Presence of non-serious unsolicited adverse events (collected in the reactogenicity subset) | Adverse events other than solicited reactions. | Within 21 days after vaccination | 
| Presence of immediate adverse events | Immediate adverse events include unsolicited injection site and systemic adverse events occurring within 30 minutes after injection. | Within 30 minutes after vaccination | 
| Presence of medically attended adverse events | Medically attended adverse events will be assessed throughout the study. | From Day 1 to Day 387 | 
| Presence of serious adverse events | Serious adverse events will be assessed throughout the study. | From Day 1 to Day 387 | 
| Presence of adverse events of special interest | Adverse events of special interest will be assessed throughout the study. | From Day 1 to Day 387 | 
| Presence of virologically-confirmed SARS-CoV-2 infections and/or symptomatic COVID-19 | Percentage of participants with positive result for SARSCoV-2 infection by Nucleic Acid Amplification Test (NAAT) on at least one respiratory sample accompanied or not by protocol-defined clinical COVID-19 symptoms. | From Day 1 to Day 387 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrences of SARS-CoV-2 infection | SARS-CoV-2 infection is defined as a serologically-confirmed SARS-CoV-2 infection or virologically-confirmed SARS-CoV-2 infection. | From ≥ 14 days after the second injection to Day 387 | 
| Occurrence of severe COVID-19 |  | From ≥ 14 days after the second injection to Day 387 | 
| Occurrences of asymptomatic SARS-CoV-2 infection | Asymptomatic SARS-CoV-2 infection is 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 is ascertained. | From Day 1 to Day 387 | 
| Number of days with positive NAAT |  | From Day 1 to Day 387 | 
| Viral copies/mL in respiratory samples |  | From Day 1 to Day 387 | 
| Occurrences of positive NAAT in respiratory samples at each follow-up timepoint during symptomatic COVID-19 |  | From Day 1 to Day 387 | 
| Occurrences of CDC-defined COVID-19 | Virologically-confirmed SARS-CoV-2 infection with at least one of CDC-defined clinical symptoms. | From Day 1 to Day 387 | 
| Occurrences of hospitalized COVID-19 | Hospitalized COVID-19 is defined as an episode of symptomatic COVID-19 that requires inpatient hospitalization. | From Day 1 to Day 387 | 
| Occurrences of symptomatic COVID-19 with severity of moderate COVID-19 or worse. | Composite endpoint of at least one of moderate or severe COVID-19. | From Day 1 to Day 387 | 
| Neutralizing antibody titer |  | Day 1, Day 22, Day 43, Day 78, Day 134, Day 202, Day 292, and Day 387 | 
| Responders, as determined by neutralizing antibody titers | Responders are defined as participants who had baseline values below lower limit of quantification (LLOQ) with quantifiable neutralization titer above assay LLOQ at each pre-defined post-vaccination time point and participants with baseline values above LLOQ with a 4-fold increase in neutralizing antibody | Day 1, Day 22, Day 43, 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 43, 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 43, Day 78, Day 134, Day 202, Day 292, and Day 387 | 
| Severity of symptoms associated with symptomatic COVID-19 episode |  | From Day 1 to Day 387 | 
| Occurrences of COVID-19 in each severity rating | COVID-19 severity score based on the ordinal scale of clinical assessment (7-point ordinal scale) | From Day 1 to Day 387 | 
| Death associated with COVID-19 |  | From Day 1 to day 387 |