Study of mRNA Vaccine Formulation Against COVID-19 in Healthy 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 describe the safety profile of all participants in each age group and each study intervention group up to 12 months post-last dose. To describe the neutralizing antibody profile at Day 1, Day 22, and Day 36 of each study intervention group. The secondary objectives of the study are: To describe binding antibody profile from Day 1 to Day 387 of each study intervention group. To describe the neutralizing antibody profile from Day 91 to Day 387 of each study intervention group. To describe the occurrence of virologically-confirmed coronavirus disease-2019 (COVID-19)-like illness and serologically-confirmed SARS-CoV-2 infection. To evaluate the correlation/association between antibody responses to SARS-CoV-2 messenger RNA (mRNA) vaccine and the risk of virologically-confirmed COVID-19-like illness and/or serologically-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection.

Detailed Description
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The duration of each participant's participation in the study was approximately 365 days post-last injection: approximately 386 days duration for participants receiving 2 injections and approximately 365 days duration total for participants receiving a single injection.

Official Title
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Immunogenicity and Safety of the First-in-Human SARS-CoV-2 mRNA Vaccine Formulation in Healthy Adults 18 Years of Age and Older

Conditions
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COVID-19

Intervention / Treatment
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* Biological: SARS-CoV-2 mRNA vaccine formulation 1
* Biological: SARS-CoV-2 mRNA vaccine formulation 2
* Biological: SARS-CoV-2 mRNA vaccine formulation 3
* Biological: Placebo (0.9% normal saline)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Aged >= 18 years on the day of inclusion. A female participant was eligible to participate if she was not pregnant or breastfeeding and one of the following conditions applies: Was of non-childbearing potential. To be considered of non-childbearing potential, a female must be pre-menarche or post-menopausal for at least 1 year, or surgically sterile. OR Was of childbearing potential and agreed 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. A participant of childbearing potential must had a negative highly sensitive pregnancy test (urine or serum as required by local regulation) within 8 hours before the study intervention. Informed Consent Form had been signed and dated. Participant not eligible to receive, based on local guidance, or if eligible does not intend to receive an authorized/approved COVID-19 vaccine from first vaccination until completion of the key timepoint of Day 43 of follow-up of this study. Exclusion criteria: History of COVID-19 disease or prior SARS-CoV-2 infection confirmed serologically. Known or suspected congenital or acquired immunodeficiency; or receipt of immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy, within the preceding 6 months; or long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks within the past 3 months). Chronic illness or condition considered to potentially increase the risk for severe COVID illness or that, in the opinion of the Investigator, is at a stage where it might interfere with study conduct or completion. Known liver disease or fatty liver. Positive test for chronic active Hepatitis B surface antigen, Hepatitis B core antibody, Hepatitis C antibody, or human immunodeficiency virus (HIV) antibody from blood work collected at screening visit. Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, contraindicating intramuscular vaccination based on Investigator's judgment. Receipt of immunoglobulins, blood or blood-derived products in the past 3 months. Prior administration of a coronavirus vaccine (SARS-CoV-2, SARS-CoV, Middle East Respiratory Syndrome coronavirus [MERS-CoV]). Receipt of any vaccine in the 30 days preceding the first study vaccination or planned receipt of any vaccine in the 30 days following the last study vaccination except for influenza vaccination, which might be received at least 2 weeks before and a minimum of 2 weeks after study vaccines. Receipt of any therapy known to have in-vitro antiviral activity against SARS-CoV-2 within 72 hours prior to the first blood draw or planned use of such therapy 72 hours prior to study immunogenicity blood draws at Day 22 and Day 36. Residence in a nursing home or long-term care facility. Health care workers providing direct patient care for COVID-19 participants. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

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: This was a sequential group prevention study consisting of a sentinel cohort followed by the Full Enrollment Cohort. There were 3 dose levels (up to 25 participants 18-49 years of age for each dose level) in the Sentinel Cohort, which were done in an open-label fashion with stepwise safety evaluation for each dose level and each vaccination. All sentinel participants received 2 vaccinations, 21 days apart. For the Full Enrollment Cohort (FEC), which was done in a double-blind design participants were stratified into 2 groups based on age at enrollment: the younger adult age group (140 planned participants 18-49 years of age) and the older adult age group (168 planned participants greater than or equal to [>=] 50 years of age). The FEC Cohort 1 (Groups 1 to 3) received a single injection of study intervention while participants in Cohort 2 (Groups 4 to 6) received 2 vaccinations (to be given 21 days apart).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sentinel Cohort: SARS-CoV-2 Vaccine Ultra Low dose<br>Participants received two intramuscular (IM) injections of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Vaccine ultra-low dose on Day 1 and at Day 22, respectively. | Biological: SARS-CoV-2 mRNA vaccine formulation 1<br>* Pharmaceutical form: Sterile suspension Route of administration: Intramuscular injection<br>|
| Experimental: Sentinel Cohort: SARS-CoV-2 Vaccine Low dose<br>Participants received two IM injections of SARS-CoV-2 Vaccine low dose on Day 1 and at Day 22, respectively. | Biological: SARS-CoV-2 mRNA vaccine formulation 2<br>* Pharmaceutical form: Sterile suspension Route of administration: Intramuscular injection<br>|
| Experimental: Sentinel Cohort: SARS-CoV-2 Vaccine Medium dose<br>Participants received two IM injections of SARS-CoV-2 Vaccine medium dose on Day 1 and at Day 22, respectively. | Biological: SARS-CoV-2 mRNA vaccine formulation 3<br>* Pharmaceutical form: Sterile suspension Route of administration: Intramuscular injection<br>|
| Experimental: FEC Cohort 1: SARS-CoV-2 Vaccine Ultra Low dose<br>Participants received a single IM injection of SARS-CoV-2 Vaccine ultra-low dose on Day 1. | Biological: SARS-CoV-2 mRNA vaccine formulation 1<br>* Pharmaceutical form: Sterile suspension Route of administration: Intramuscular injection<br>|
| Experimental: FEC Cohort 1: SARS-CoV-2 Vaccine Low dose<br>Participants received a single IM injection of SARS-CoV-2 Vaccine low dose on Day 1. | Biological: SARS-CoV-2 mRNA vaccine formulation 2<br>* Pharmaceutical form: Sterile suspension Route of administration: Intramuscular injection<br>|
| Placebo Comparator: FEC Cohort 1: Placebo<br>Participants received a single IM injection of placebo matched to SARS-CoV-2 Vaccine on Day 1. | Biological: Placebo (0.9% normal saline)<br>* Pharmaceutical form: Liquid Route of administration: Intramuscular injection<br>|
| Experimental: FEC Cohort 2: SARS-CoV-2 Vaccine Ultra Low dose<br>Participants received two IM injections of SARS-CoV-2 Vaccine ultra-low dose on Day 1 and at Day 22, respectively. | Biological: SARS-CoV-2 mRNA vaccine formulation 1<br>* Pharmaceutical form: Sterile suspension Route of administration: Intramuscular injection<br>|
| Experimental: FEC Cohort 2: SARS-CoV-2 Vaccine Low dose<br>Participants received two IM injections of SARS-CoV-2 Vaccine low dose on Day 1 and at Day 22, respectively. | Biological: SARS-CoV-2 mRNA vaccine formulation 2<br>* Pharmaceutical form: Sterile suspension Route of administration: Intramuscular injection<br>|
| Placebo Comparator: FEC Cohort 2: Placebo<br>Participants received two IM injections of placebo matched to SARS-CoV-2 Vaccine on Day 1 and at Day 22, respectively. | Biological: Placebo (0.9% normal saline)<br>* Pharmaceutical form: Liquid Route of administration: Intramuscular injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Reporting Immediate Unsolicited Adverse Events (AEs) | AE: any untoward medical occurrence in clinical investigation participant administered medicinal product & which did not have any causal relationship with the treatment. Unsolicited AE: observed AE that did not fulfill conditions prelisted in case report form (CRF) in terms of diagnosis &/or onset window post-vaccination. All participants were observed for 30 minutes after vaccination, & any unsolicited AEs occurred during that time were recorded as immediate unsolicited AEs in CRF. Reported AEs were presented as pre-specified in protocol. In the data table, '0' in number analyzed field denotes that no participants were available for assessment for specified Group as no one in that group received vaccination 2. | Within 30 minutes post any and each vaccination (Vaccination 1 [i.e., at Day 1] and 2 [i.e., at Day 22]) | 
| Number of Participants With Solicited Injection Site Reactions | Solicited reaction (SR): expected adverse reaction (sign or symptom) observed & reported under conditions (nature & onset) prelisted (i.e., solicited) in CRF and considered as related to product administered. Solicited injection site reactions included pain, erythema, & swelling. Reported AEs for each arm were presented as pre-specified in study protocol. In the data table, '0' in number analyzed field denotes that no participants were available for assessment for specified Group as no one in that group received vaccination 2. | Within 7 days after any and each vaccination (Vaccination 1 [i.e., at Day 1] and 2 [i.e., at Day 22]) | 
| Number of Participants With Solicited Systemic Reactions | SR was an expected adverse reaction (sign or symptom) observed & reported under conditions (nature & onset) prelisted (i.e., solicited) in CRF & considered as related to product administered. Solicited systemic reactions included fever, headache, malaise, myalgia, arthralgia & chills. Reported AEs for each arm were presented as pre-specified in study protocol. In the data table, '0' in number analyzed field denotes that no participants were available for assessment for specified Group as no one in that group received vaccination 2. | Within 7 days after any and each vaccination (Vaccination 1 [i.e., at Day 1] and 2 [i.e., at Day 22]) | 
| Number of Participants With Unsolicited Adverse Events | An AE was any untoward medical occurrence in a clinical investigation participant administered a medicinal product and which did not have any casual relationship with the treatment. An unsolicited AE was an observed AE that did not fulfill the conditions prelisted in the CRF in terms of diagnosis and/or onset window post-vaccination. Reported AEs for each arm were presented as pre-specified in the study protocol. In the data table, '0' in number analyzed field denotes that no participants were available for assessment for specified Group as no one in that group received vaccination 2. | Within 21 days after any and each vaccination (Vaccination 1 [i.e., at Day 1] and 2 [i.e., at Day 22]) | 
| Number of Participants Reporting Serious Adverse Events (SAEs), Adverse Event of Special Interest (AESIs) and Medically Attended Adverse Events (MAAEs) | SAEs: any untoward medical occurrence 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. AESIs: event for which ongoing monitoring & rapid communication by investigator to the sponsor was done. MAAE was a new onset or worsening of a condition that prompted participant or participant's parent/legally acceptable representative to seek unplanned medical advice at physician's office or emergency department. Reported AEs for each arm were presented as pre-specified in study protocol. | From Day 1 until 12 months post last vaccination (i.e., up to Day 366 for Cohort 1 groups and up to Day 387 for Cohort 2 groups) | 
| Number of Participants With Laboratory Test Results Based on US Food and Drug Administration (FDA) Toxicity Grading Guidance | Laboratory tests: hemoglobin (male & female), above & below normal white blood cell, lymphocytes, neutrophils & eosinophils, platelet count, creatinine & blood urea nitrogen, hyponatremia & hypernatremia, hyperkalemia & hypokalemia, hyperglycemia (non-fasting), hypoproteinemia, alkaline phosphate, alanine aminotransferase, aspartate aminotransferase, bilirubin (with any increase in liver function test [LFT], bilirubin (normal LFT), prothrombin & partial thromboplastin time (seconds), Urine: protein, glucose & blood. US FDA Toxicity Grading Scale for Healthy Adults & Adolescent Volunteers was used for grading; Grade 1=mild, Grade 2=moderate & Grade 3=severe. In the data table, 'number analyzed'=participants with available data for each specified category & '0'=none of participants were available for assessment for specified Group. | From Day 1 up to up to 8 days post last vaccination (i.e., up to Day 9 for Cohort 1 groups; up to Day 30 for Cohort 2 groups) | 
| Geometric Mean Titers (GMTs) of Neutralizing Antibodies Against SARS-CoV-2 Recombinant Protein Vaccine at Day 1 | GMTs of SARS-CoV-2 neutralizing antibodies (D614G variant) was measured using a neutralization assay. Titers were expressed in terms of 1/dilution. Data for this OM was planned to be collected and analyzed for combined population (FEC+ Sentinel Cohort) in which same dose-level groups in Sentinel Cohort and FEC were pooled for analysis. | Day 1 (pre-vaccination) | 
| Geometric Mean Titers (GMTs) of Neutralizing Antibodies Against SARS-CoV-2 Recombinant Protein Vaccine at Day 22 | GMTs of SARS-CoV-2 neutralizing antibodies (D614G variant) was measured using a neutralization assay. Titers were expressed in terms of 1/dilution. | Day 22 (post-vaccination) | 
| Geometric Mean Titers (GMTs) of Neutralizing Antibodies Against SARS-CoV-2 Recombinant Protein Vaccine at Day 36 | GMTs of SARS-CoV-2 neutralizing antibodies (D614G variant) was measured using a neutralization assay. Titers were expressed in terms of 1/dilution. | Day 36 (post-vaccination) | 
| Geometric Mean Fold-rise (GMFR) of Serum Neutralization Antibody Titers at Day 22 | SARS-CoV-2 neutralizing antibodies (D614G variant) was measured using a neutralization assay. Fold-rise was calculated as the ratio of titer values of neutralizing antibodies post-vaccination (Day 22) and pre-vaccination (on Day 1) i.e., Day 22/Day 1. | Day 1 (pre-vaccination) and Day 22 (post-vaccination) | 
| Geometric Mean Fold-rise of Serum Neutralization Antibody Titers at Day 36 | SARS-CoV-2 neutralizing antibodies (D614G variant) was measured using a neutralization assay. Fold-rise was calculated as the ratio of titer values of neutralizing antibodies post-vaccination (Day 36) and pre-vaccination (on Day 1) i.e., Day 36/Day 1. | Day 1 (pre-vaccination) and Day 36 (post-vaccination) | 
| Percentage of Participants With >=2-fold and >=4-fold Rise in Serum Neutralization Antibody Titers at Day 22 | SARS-CoV-2 neutralizing antibodies (D614G variant) was measured using a neutralization assay. The fold rise (2-fold and 4-fold) was calculated as the ratio of titer values of neutralizing antibodies post-vaccination (on Day 22) and pre-vaccination (on Day 1) i.e., Day 22/Day 1. | Day 1 (pre-vaccination) and Day 22 (post-vaccination) | 
| Percentage of Participants With >=2-Fold and >=4-Fold Rise in Serum Neutralization Antibody Titer at Day 36 | SARS-CoV-2 neutralizing antibodies (D614G variant) was measured using a neutralization assay. The fold rise (2-fold and 4-fold) was calculated as the ratio of titer values of neutralizing antibodies post-vaccination (on Day 36) and pre-vaccination (on Day 1) i.e., Day 36/Day 1. | Day 1 (pre-vaccination) and Day 36 (post-vaccination) | 
| Percentage of Participants Achieving Seroconversion Against SARS-CoV-2 Virus Antigens at Day 22 | Seroconversion was defined as participants with a Baseline (Day 1) titer values below lower limit of quantification (LLOQ) with a detectable neutralization antibody titer above assay LLOQ post injection (at Day 22). LLOQ of the neutralization assay was a titer of 10. | Day 22 (post-vaccination) | 
| Percentage of Participants Achieving Seroconversion Against SARS-CoV-2 Virus Antigens at Day 36 | Seroconversion was defined as participants with a Baseline (Day 1) titer values below LLOQ with a detectable neutralization antibody titer above assay LLOQ post injection (at Day 36). LLOQ of the neutralization assay was a titer of 10. | Day 36 (post-vaccination) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Concentration (GMC) of Anti-S Binding Antibody at Day 1, 22, 36, 91, 112, 181, and 202 | GMC of Anti-S binding antibodies were assessed using enzyme-linked immunosorbent assay (ELISA) and were measured in ELISA unit/mL (ELU/mL). Data for this OM was planned to be collected and analyzed for combined population (FEC + Sentinel Cohort) in which same dose-level groups in Sentinel Cohort and FEC were pooled for analysis. | Day 1 (pre-vaccination); Day 22 (post-vaccination), Day 36 (post-vaccination), Day 91 (only for Cohort 1), Day 112 (only for Cohort 2), Day 181 (only for Cohort 1), and Day 202 (only for Cohort 2) | 
| Geometric Mean Fold-rise (GMFR) of Binding Antibody Concentration at Day 22, 36, 91, 112, 181, and 202 | Binding antibody titers were evaluated by ELISA. Fold-rise was calculated as the ratio of geometric mean concentrations of antibodies post-vaccination at specified timepoints and pre-vaccination (on Day 1) i.e., Day 22/Day 1, Day 36/Day 1, Day 91/Day 1, Day 112/Day 1, Day 181/Day 1, and Day 202/Day 1. Data for this OM was planned to be collected and analyzed for combined population (FEC + Sentinel Cohort) in which same dose-level groups in Sentinel Cohort and FEC were pooled for analysis. | Day 1 (pre-vaccination); Day 22 (post-vaccination), Day 36 (post-vaccination), Day 91 (only for Cohort 1), Day 112 (only for Cohort 2), Day 181 (only for Cohort 1), and Day 202 (only for Cohort 2) | 
| Percentage of Participants With >=2- and >=4- Fold Rise in Anti-S Binding Antibody Concentration at Day 22, 36, 91, 112, 181, and 202 | Binding antibody titers were evaluated by ELISA. Fold-rise (2-fold and 4-fold) was calculated as the ratio of geometric mean concentrations of antibodies post-vaccination at specified timepoints and pre-vaccination (on Day 1) i.e., Day 22/Day 1, Day 36/Day 1, Day 91/Day 1, Day 112/Day 1, Day 181/Day 1, and Day 202/Day 1. Data for this OM was planned to be collected and analyzed for combined population (FEC + Sentinel Cohort) in which same dose-level groups in Sentinel Cohort and FEC were pooled for analysis. | Day 1 (pre-vaccination); Day 22 (post-vaccination), Day 36 (post-vaccination), Day 91 (only for Cohort 1), Day 112 (only for Cohort 2), Day 181 (only for Cohort 1), and Day 202 (only for Cohort 2) | 
| Geometric Mean Titers of Neutralizing Antibody Titer Against SARS-CoV-2 Recombinant Protein Vaccine Formulations at Day 91, 112, 181, and 202 | GMTs of SARS-CoV-2 neutralizing antibodies (D614G variant) was measured using a neutralization assay. Titers were expressed in terms of 1/dilution. Data for this OM was planned to be collected and analyzed for combined population (FEC + Sentinel Cohort) in which same dose-level groups in Sentinel Cohort and FEC were pooled for analysis. | Cohort 1: Day 91, Day 181 and Cohort 2: Day 112, and Day 202 (post-vaccination) | 
| Geometric Mean Fold-rise of Serum Neutralization Antibody Titer at Day 91, 112, 181, and 202 | SARS-CoV-2 neutralizing antibodies (D614G variant) was measured using a neutralization assay. Fold-rise was calculated as the ratio of titer values of antibodies post-vaccination at specified timepoints and pre-vaccination (on Day 1) i.e., for Cohort 1: Day 91/Day 1, Day 181/Day 1; Cohort 2: Day 112/Day 1, and Day 202/Day 1. Data for this OM was planned to be collected and analyzed for combined population (FEC + Sentinel Cohort) in which same dose-level groups in Sentinel Cohort and FEC were pooled for analysis. | Day 1 (pre-vaccination), Cohort 1: Day 91, Day 181 and Cohort 2: Day 112, and Day 202 (post-vaccination) | 
| Percentage of Participants With 2-Fold and 4-Fold Rise in Serum Neutralization Antibody Titer at Day 91, 112, 181, and 202 | SARS-CoV-2 neutralizing antibodies (D614G variant) was measured using a neutralization assay. Fold-rise (2-fold and 4-fold) was calculated as the ratio of geometric mean concentrations of antibodies post-vaccination at specified timepoints and pre-vaccination (on Day 1) i.e., Day 91/Day 1, Day 112/Day 1, Day 181/Day 1, and Day 202/Day 1. Data for this OM was planned to be collected and analyzed for combined population (FEC + Sentinel Cohort) in which same dose-level groups in Sentinel Cohort and FEC were pooled for analysis. | Day 1 (pre-vaccination), Cohort 1: Day 91, Day 181 and Cohort 2: Day 112, and Day 202 (post-vaccination) | 
| Percentage of Participants Achieving Seroconversion Against SARS-CoV-2 Virus Antigens | Seroconversion was defined as participants with a Baseline (Day 1) titer values below lower limit of quantification (LLOQ) with a detectable neutralization antibody titer above assay LLOQ post injection. LLOQ of the neutralization assay was a titer of 10. Data for this OM was planned to be collected and analyzed for combined population (FEC + Sentinel Cohort) in which same dose-level groups in Sentinel Cohort and FEC were pooled for analysis. | Cohort 1: Day 91, Day 181 and Cohort 2: Day 112, and Day 202 (post-vaccination) | 
| Number of Participants With Virologically-confirmed Coronavirus Disease (COVID-19)-Like Illness | Virologically-confirmed COVID-19-like illness was defined by specified clinical symptoms and signs and confirmed by positive result for SARS-CoV-2 by nucleic acid amplification test (NAAT) on a respiratory sample in association with a COVID-19-like illness. | Cohort 1: up to Day 366 (post-vaccination) and Cohort 2: up to Day 387 (post-vaccination) | 
| Number of Participants With Serologically-confirmed SARS-CoV-2 Infection | Serologically-confirmed SARS-CoV-2 infection as defined by SARS-CoV-2 Nucleoprotein specific antibody detection immunoassay was reported in this outcome measure. | Cohort 1: up to Day 366 (post-vaccination) and Cohort 2: up to Day 387 (post-vaccination) | 
| Correlates of Risk/Protection Based on Antibody Responses to SARS-CoV-2 | Correlate of risk / protection based on antibody responses to SARS-CoV-2 was evaluated using virus neutralization or ELISA, considering virologically-confirmed COVID-19-like illness and/or serologically-confirmed SARS-CoV-2 infection. | Cohort 1: up to Day 366 (post-vaccination) and Cohort 2: up to Day 387 (post-vaccination) |