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    Clinical Trial Results:
    COVID-19: A Phase 3, Randomized, Observer-Blinded, Placebo-Controlled Clinical Study Evaluating the Safety and Immunogenicity of Investigational SARS-CoV-2 mRNA Vaccine CVnCoV in Adult Health Care Workers in Mainz (Germany)

    Summary
    EudraCT number
    		 2020-004066-19
    Trial protocol
    		 DE  
    Global end of trial date
    08 Jun 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Dec 2022
    First version publication date
    21 Dec 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CV-NCOV-005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04674189
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    CureVac SE
    Sponsor organisation address
    Schumannstrasse 27, Frankfurt, Germany, 60325
    Public contact
    Clinical Trial Information, CureVac SE, 0049 6976805870, clinicaltrials@curevac.com
    Scientific contact
    Clinical Trial Information, CureVac SE, 0049 6976805870, clinicaltrials@curevac.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 Jun 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jun 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The trial aimed to: - Evaluate the safety (in all participants) and reactogenicity (in a subset of participants) of CVnCoV administered as a 2-dose schedule to adult participants 18 years of age or older. - Assess antibody responses to the receptor-binding domain (RBD) of spike protein of SARS-CoV-2 after 1 and 2 doses of CVnCoV in adult participants 18 years of age or older included in a subset of participants.
    Protection of trial subjects
    This trial was conducted with the highest respect for the individual participants in compliance with the requirements of this clinical trial protocol (and amendments), and also in compliance with the following: - The ethical principles that have their origin in the Declaration of Helsinki. - International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use E6 (R2) Good Clinical Practice: Revised and consolidated guidelines. - All applicable laws and regulations, including, without limitation, data privacy laws, clinical trial disclosure laws, and regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Dec 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 2357
    Worldwide total number of subjects
    2357
    EEA total number of subjects
    2357
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    2215
    From 65 to 84 years
    142
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This trial was performed in Germany between 23 December 2020 and 08 June 2022.

    Pre-assignment
    Screening details
    		 Of the 2357 participants who were randomized, 2351 participants were treated.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CVnCoV: Group 1, Lot 1
    Arm description
    		 Participants in Group 1 were vaccinated with CVnCoV 12 µg Lot 1 as an intramuscular injection by needle in the deltoid area on Day 1 and Day 29.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CVnCoV Vaccine
    Investigational medicinal product code
    CV07050101
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscular injection.

    Arm title
    		 CVnCoV: Group 2, Lot 2
    Arm description
    		 Participants in Group 2 were vaccinated with CVnCoV 12 µg Lot 2 as an intramuscular injection by needle in the deltoid area on Day 1 and Day 29.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CVnCoV Vaccine
    Investigational medicinal product code
    CV07050101
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscular injection.

    Arm title
    		 Placebo
    Arm description
    		 Participants received a placebo as an intramuscular injection by needle in the deltoid area on Day 1 and Day 29.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscular injection.

    Number of subjects in period 1
    		CVnCoV: Group 1, Lot 1 CVnCoV: Group 2, Lot 2 Placebo
    Started
    786
    786
    785
    Safety Analysis Set
    783
    785
    783
    Completed
    617
    637
    372
    Not completed
    169
    149
    413
         Withdrawal by Participant
    83
    71
    142
         Physician Decision
    1
    -
    -
         Adverse event, non-fatal
    -
    -
    1
         Miscellaneous
    27
    23
    207
         Received Alternative Authorized Vaccine
    -
    1
    17
         Lost to follow-up
    55
    53
    44
         Did Not Receive Treatment
    3
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CVnCoV: Group 1, Lot 1
    Reporting group description
    		 Participants in Group 1 were vaccinated with CVnCoV 12 µg Lot 1 as an intramuscular injection by needle in the deltoid area on Day 1 and Day 29.

    Reporting group title
    CVnCoV: Group 2, Lot 2
    Reporting group description
    		 Participants in Group 2 were vaccinated with CVnCoV 12 µg Lot 2 as an intramuscular injection by needle in the deltoid area on Day 1 and Day 29.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received a placebo as an intramuscular injection by needle in the deltoid area on Day 1 and Day 29.

    Reporting group values
    		 CVnCoV: Group 1, Lot 1 CVnCoV: Group 2, Lot 2 Placebo Total
    Number of subjects
    		 786 786 785 2357
    Age categorical
    Units: Subjects
    Age continuous
    Data were recorded for the Safety Analysis Set only. This included all participants randomized in the trial who received at least one dose of any lot of CVnCoV or placebo vaccine.
    Units: years
        arithmetic mean (standard deviation)
    		 42.2 ( 14.88 ) 43.4 ( 14.80 ) 42.7 ( 14.52 ) -
    Gender categorical
    Data were recorded for the Safety Analysis Set only. This included all participants randomized in the trial who received at least one dose of any lot of CVnCoV or placebo vaccine.
    Units: Subjects
        Female
    		 527 539 521 1587
        Male
    		 256 246 262 764
        Not Recorded
    		 3 1 2 6
    Ethnicity
    Data were recorded for the Safety Analysis Set only. This included all participants randomized in the trial who received at least one dose of any lot of CVnCoV or placebo vaccine.
    Units: Subjects
        Hispanic or Latino
    		 5 5 4 14
        Not Hispanic or Latino
    		 764 759 758 2281
        Unknown or Not Reported
    		 14 21 21 56
        Not Recorded
    		 3 1 2 6
    Race
    Data were recorded for the Safety Analysis Set only. This included all participants randomized in the trial who received at least one dose of any lot of CVnCoV or placebo vaccine.
    Units: Subjects
        White
    		 755 765 760 2280
        Black or African American
    		 2 1 0 3
        Asian
    		 13 9 14 36
        American Indian or Alaska Native
    		 0 1 0 1
        Native Hawaiian or Other Pacific Islander
    		 2 0 0 2
        Other
    		 4 3 5 12
        Unknown or Not Reported
    		 7 6 4 17
        Not Recorded
    		 3 1 2 6

    End points

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    End points reporting groups
    Reporting group title
    CVnCoV: Group 1, Lot 1
    Reporting group description
    		 Participants in Group 1 were vaccinated with CVnCoV 12 µg Lot 1 as an intramuscular injection by needle in the deltoid area on Day 1 and Day 29.

    Reporting group title
    CVnCoV: Group 2, Lot 2
    Reporting group description
    		 Participants in Group 2 were vaccinated with CVnCoV 12 µg Lot 2 as an intramuscular injection by needle in the deltoid area on Day 1 and Day 29.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received a placebo as an intramuscular injection by needle in the deltoid area on Day 1 and Day 29.

    Subject analysis set title
    CVnCoV: Pooled Lots 1 and 2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants in Group 1 and Group 2. Participants were vaccinated with either CVnCoV 12 µg Lot 1 or CVnCoV 12 µg Lot 2 as an intramuscular injection by needle in the deltoid area on Day 1 and Day 29.

    Primary: Number of Participants Who Experienced a Medically Attended Adverse Event (AE) Occurring in the Following 6 Months After Dose 2

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    End point title
    		 Number of Participants Who Experienced a Medically Attended Adverse Event (AE) Occurring in the Following 6 Months After Dose 2 [1]
    End point description
    Medically attended AEs were defined as AEs with medically attended visits that are not routine visits for physical examination or vaccination, such as visits for hospitalization, an emergency room visit, or an otherwise unscheduled visit to or from medical personnel (medical doctor) for any reason. The Investigator assessed the relationship between trial vaccine and occurrence of each AE. Safety Analysis Set: All participants randomized in the trial who received at least one dose of any lot of CVnCoV or placebo vaccine.
    End point type
    Primary
    End point timeframe
    Up to 6 months after Dose 2 (Days 29 to 211)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 CVnCoV: Group 1, Lot 1 CVnCoV: Group 2, Lot 2 Placebo
    Number of subjects analysed
    783
    785
    783
    Units: participants
        Any medically attended AEs
    95
    133
    58
        Any related medically attended AEs
    34
    32
    13
    No statistical analyses for this end point

    Primary: Number of Participants Who Experienced a Serious Adverse Event (SAE)

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    End point title
    		 Number of Participants Who Experienced a Serious Adverse Event (SAE) [2]
    End point description
    An SAE was defined as 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 disability/incapacity. - Was a congenital anomaly/birth defect in the offspring of the participant. - Was an important medical event. The Investigator assessed the relationship between trial vaccine and occurrence of each AE. Safety Analysis Set: All participants randomized in the trial who received at least one dose of any lot of CVnCoV or placebo vaccine.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 393
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 CVnCoV: Group 1, Lot 1 CVnCoV: Group 2, Lot 2 Placebo
    Number of subjects analysed
    783
    785
    783
    Units: participants
        Any SAEs
    8
    10
    6
        Any related SAEs
    1
    1
    0
    No statistical analyses for this end point

    Primary: Intensity of SAEs Per the Investigator's Assessment

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    End point title
    		 Intensity of SAEs Per the Investigator's Assessment [3]
    End point description
    An SAE was defined as 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 disability/incapacity. - Was a congenital anomaly/birth defect in the offspring of the participant. - Was an important medical event. The Investigator made an assessment of intensity for each AE reported during the trial and assigned it to one of the following categories: - Mild: an event that was easily tolerated by the participant, causing minimal discomfort and not interfering with everyday activities. - Moderate: an event that caused sufficient discomfort to interfere with normal everyday activities. - Severe: an event that prevented normal everyday activities. Safety Analysis Set: All participants randomized in the trial who received at least one dose of any lot of CVnCoV or placebo vaccine.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 393
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 CVnCoV: Group 1, Lot 1 CVnCoV: Group 2, Lot 2 Placebo
    Number of subjects analysed
    783
    785
    783
    Units: participants
        Any mild SAEs
    0
    0
    0
        Any moderate SAEs
    2
    5
    1
        Any severe SAEs
    6
    5
    5
    No statistical analyses for this end point

    Primary: Number of Participants Who Experienced an Adverse Event of Special Interest (AESI) Occurring in the Following 1 Year After Dose 2

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    End point title
    		 Number of Participants Who Experienced an Adverse Event of Special Interest (AESI) Occurring in the Following 1 Year After Dose 2 [4]
    End point description
    The following events were considered and collected as AESI throughout the trial: - AEs with a suspected immune-mediated etiology. - Other AEs relevant to SARS-CoV-2 vaccine development or the target disease. - COVID-19. The Investigator assessed the relationship between trial vaccine and occurrence of each AE. Safety Analysis Set: All participants randomized in the trial who received at least one dose of any lot of CVnCoV or placebo vaccine.
    End point type
    Primary
    End point timeframe
    Up to 1 year after Dose 2 (Days 29 to 393)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 CVnCoV: Group 1, Lot 1 CVnCoV: Group 2, Lot 2 Placebo
    Number of subjects analysed
    783
    785
    783
    Units: participants
        Any AESIs
    14
    14
    5
        Any related AESIs
    7
    5
    0
    No statistical analyses for this end point

    Primary: Number of Participants Who Experienced Death Due to SAE

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    End point title
    		 Number of Participants Who Experienced Death Due to SAE [5]
    End point description
    An SAE was defined as 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 disability/incapacity. - Was a congenital anomaly/birth defect in the offspring of the participant. - Was an important medical event. Safety Analysis Set: All participants randomized in the trial who received at least one dose of any lot of CVnCoV or placebo vaccine.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 393
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 CVnCoV: Group 1, Lot 1 CVnCoV: Group 2, Lot 2 Placebo
    Number of subjects analysed
    783
    785
    783
    Units: participants
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Participants Who Experienced an AE Leading to Vaccine Withdrawal Occurring in the Following 1 Year After Dose 2

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    End point title
    		 Number of Participants Who Experienced an AE Leading to Vaccine Withdrawal Occurring in the Following 1 Year After Dose 2 [6]
    End point description
    Safety Analysis Set: All participants randomized in the trial who received at least one dose of any lot of CVnCoV or placebo vaccine.
    End point type
    Primary
    End point timeframe
    Up to 1 year after Dose 2 (Days 29 to 393)
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 CVnCoV: Group 1, Lot 1 CVnCoV: Group 2, Lot 2 Placebo
    Number of subjects analysed
    783
    785
    783
    Units: participants
    7
    5
    2
    No statistical analyses for this end point

    Primary: Number of Participants Who Experienced an AE Leading to Trial Discontinuation Occurring in the Following 1 Year After Dose 2

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    End point title
    		 Number of Participants Who Experienced an AE Leading to Trial Discontinuation Occurring in the Following 1 Year After Dose 2 [7]
    End point description
    Safety Analysis Set: All participants randomized in the trial who received at least one dose of any lot of CVnCoV or placebo vaccine.
    End point type
    Primary
    End point timeframe
    Up to 1 year after Dose 2 (Days 29 to 393)
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 CVnCoV: Group 1, Lot 1 CVnCoV: Group 2, Lot 2 Placebo
    Number of subjects analysed
    783
    785
    783
    Units: participants
    1
    0
    1
    No statistical analyses for this end point

    Primary: Number of Participants Who Experienced an Unsolicited AE Occurring on the Day of Vaccination and the Following 28 Days After Any Dose

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    End point title
    		 Number of Participants Who Experienced an Unsolicited AE Occurring on the Day of Vaccination and the Following 28 Days After Any Dose [8]
    End point description
    eDiaries were used for the collection of unsolicited AEs on each vaccination day and the following 28 days. The Investigator assessed the relationship between trial vaccine and occurrence of each AE. Safety Analysis Subset: The first 1289 participants enrolled who belong to the Safety Analysis Set.
    End point type
    Primary
    End point timeframe
    Day 1 to 28 days after Dose 2 (Day 57)
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 CVnCoV: Group 1, Lot 1 CVnCoV: Group 2, Lot 2 Placebo
    Number of subjects analysed
    430
    429
    430
    Units: participants
        Any unsolicited AEs
    245
    270
    187
        Any related unsolicited AEs
    183
    186
    88
    No statistical analyses for this end point

    Primary: Intensity of Unsolicited AEs Per the Investigator's Assessment Occurring on the Day of Vaccination and the Following 28 Days After Any Dose

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    End point title
    		 Intensity of Unsolicited AEs Per the Investigator's Assessment Occurring on the Day of Vaccination and the Following 28 Days After Any Dose [9]
    End point description
    eDiaries were used for the collection of unsolicited AEs on each vaccination day and the following 28 days. The Investigator made an assessment of intensity for each AE reported during the trial and assigned it to one of the following categories: - Mild: an event that was easily tolerated by the participant, causing minimal discomfort and not interfering with everyday activities. - Moderate: an event that caused sufficient discomfort to interfere with normal everyday activities. - Severe: an event that prevented normal everyday activities. Safety Analysis Subset: The first 1289 participants enrolled who belong to the Safety Analysis Set.
    End point type
    Primary
    End point timeframe
    Day 1 to 28 days after Dose 2 (Day 57)
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 CVnCoV: Group 1, Lot 1 CVnCoV: Group 2, Lot 2 Placebo
    Number of subjects analysed
    430
    429
    430
    Units: participants
        Any mild unsolicited AEs
    133
    149
    114
        Any moderate unsolicited AEs
    73
    71
    42
        Any severe unsolicited AEs
    14
    28
    10
        Any unsolicited AEs without intensity assessment
    25
    22
    21
    No statistical analyses for this end point

    Primary: Occurrence of Seroconversion for SARS-CoV-2 RBD of Spike Protein Antibodies (IgG) on Day 29 and Day 43

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    End point title
    		 Occurrence of Seroconversion for SARS-CoV-2 RBD of Spike Protein Antibodies (IgG) on Day 29 and Day 43 [10]
    End point description
    Titers of IgG antibodies directed against the SARS-CoV-2 RBD of Spike Protein antigen were measured by enzyme-linked immunosorbent assay (ELISA). Percentage with 95% confidence interval (CI) of participants for whom a seroconversion was observed is presented by group. Seroconversion was defined as a fold increase above 1 in SARS-CoV-2 Spike Protein RBD IgG antibody levels in participants seronegative at Baseline. Participants who tested positive for COVID-19 had their data included up to the point of a positive test result. Participants who received a licensed/authorized vaccine were censored at the day after receiving the licensed/authorized vaccine. Per Protocol Immunogenicity Set: 250 participants who received both doses as randomized and within the windows defined in the protocol, had no major protocol deviations expected to impact the immunogenicity outcomes, and had not received medical treatments that may interfere with any of the immunogenicity measurements.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1), Day 29 and Day 43
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 CVnCoV: Group 1, Lot 1 CVnCoV: Group 2, Lot 2 Placebo CVnCoV: Pooled Lots 1 and 2
    Number of subjects analysed
    99 [11]
    98 [12]
    48 [13]
    197 [14]
    Units: percentage of participants
    number (confidence interval 95%)
        Day 29
    8.1 (3.6 to 15.3)
    18.4 (11.3 to 27.5)
    0.0 (0.0 to 7.4)
    13.2 (8.8 to 18.7)
        Day 43
    95.5 (88.8 to 98.7)
    94.2 (87.0 to 98.1)
    0.0 (0.0 to 8.6)
    94.8 (90.4 to 97.6)
    Notes
    [11] - Day 43 N = 88.
    [12] - Day 43 N = 86.
    [13] - Day 43 N = 41.
    [14] - Day 43 N = 174.
    No statistical analyses for this end point

    Primary: SARS-CoV-2 RBD of Spike Protein Antibody (IgG) Levels on Days 1, 29 and 43

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    End point title
    		 SARS-CoV-2 RBD of Spike Protein Antibody (IgG) Levels on Days 1, 29 and 43 [15]
    End point description
    Titers of IgG antibodies directed against the SARS-CoV-2 RBD of Spike Protein antigen were measured by ELISA and expressed as geometric mean of titers (GMT) with 95% CI, by group. Individual values below the lower limit of quantification (LLOQ) were set to half of the LLOQ. Participants who tested positive for COVID-19 had their data included up to the point of a positive test result. Participants who received a licensed/authorized vaccine were censored at the day after receiving the licensed/authorized vaccine. Per Protocol Immunogenicity Set: 250 participants who received both doses as randomized and within the windows defined in the protocol, had no major protocol deviations expected to impact the immunogenicity outcomes, and had not received medical treatments that may interfere with any of the immunogenicity measurements.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1), Day 29 and Day 43
    Notes
    [15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 CVnCoV: Group 1, Lot 1 CVnCoV: Group 2, Lot 2 Placebo CVnCoV: Pooled Lots 1 and 2
    Number of subjects analysed
    99 [16]
    98 [17]
    48 [18]
    197 [19]
    Units: GMT
    geometric mean (confidence interval 95%)
        Day 1
    50.000 (50.000 to 50.000)
    50.000 (50.000 to 50.000)
    50.000 (50.000 to 50.000)
    50.000 (50.000 to 50.000)
        Day 29
    55.145 (51.403 to 59.160)
    62.236 (56.437 to 68.631)
    50.000 (50.000 to 50.000)
    58.566 (55.144 to 62.199)
        Day 43
    1285.722 (1003.885 to 1646.683)
    1151.416 (869.345 to 1525.008)
    50.000 (50.000 to 50.000)
    1217.489 (1011.594 to 1465.289)
    Notes
    [16] - Day 43 N = 88.
    [17] - Day 43 N = 86.
    [18] - Day 43 N = 41.
    [19] - Day 43 N = 174.
    No statistical analyses for this end point

    Secondary: Occurrence of Seroconversion for SARS-CoV-2 Neutralizing Antibodies on Day 29 and Day 43

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    End point title
    		 Occurrence of Seroconversion for SARS-CoV-2 Neutralizing Antibodies on Day 29 and Day 43
    End point description
    Neutralizing activity of induced antibodies was determined by an activity assay. Percentage with 95% CI of participants for whom a seroconversion was observed is presented by group. Seroconversion was defined as a fold increase above 1 in SARS-CoV-2 neutralizing antibody levels in participants seronegative at Baseline. Participants who tested positive for COVID-19 had their data included up to the point of a positive test result. Participants who received a licensed/authorized vaccine were censored at the day after receiving the licensed/authorized vaccine. Per Protocol Immunogenicity Set: 250 participants who received both doses as randomized and within the windows defined in the protocol, had no major protocol deviations expected to impact the immunogenicity outcomes, and had not received medical treatments that may interfere with any of the immunogenicity measurements.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 29 and Day 43
    End point values
    		 CVnCoV: Group 1, Lot 1 CVnCoV: Group 2, Lot 2 Placebo CVnCoV: Pooled Lots 1 and 2
    Number of subjects analysed
    99 [20]
    98 [21]
    48 [22]
    197 [23]
    Units: percentage of participants
    number (confidence interval 95%)
        Day 29
    2.0 (0.2 to 7.1)
    2.0 (0.2 to 7.2)
    0.0 (0.0 to 7.4)
    2.0 (0.6 to 5.1)
        Day 43
    76.1 (65.9 to 84.6)
    75.6 (65.1 to 84.2)
    0.0 (0.0 to 8.6)
    75.9 (68.8 to 82.0)
    Notes
    [20] - Day 43 N = 88.
    [21] - Day 43 N = 86.
    [22] - Day 43 N = 41.
    [23] - Day 43 N = 174.
    No statistical analyses for this end point

    Secondary: SARS-CoV-2 Neutralizing Antibody Levels on Days 1, 29 and 43

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    End point title
    		 SARS-CoV-2 Neutralizing Antibody Levels on Days 1, 29 and 43
    End point description
    Neutralizing activity of induced antibodies was determined by an activity assay. GMT with 95% CI of SARS-CoV-2 neutralizing antibody levels is presented by group. Individual values below the LLOQ were set to half of the LLOQ. Participants who tested positive for COVID-19 had their data included up to the point of a positive test result. Participants who received a licensed/authorized vaccine were censored at the day after receiving the licensed/authorized vaccine. Per Protocol Immunogenicity Set: 250 participants who received both doses as randomized and within the windows defined in the protocol, had no major protocol deviations expected to impact the immunogenicity outcomes, and had not received medical treatments that may interfere with any of the immunogenicity measurements.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 29 and Day 43
    End point values
    		 CVnCoV: Group 1, Lot 1 CVnCoV: Group 2, Lot 2 Placebo CVnCoV: Pooled Lots 1 and 2
    Number of subjects analysed
    99 [24]
    98 [25]
    48 [26]
    197 [27]
    Units: GMT
    geometric mean (confidence interval 95%)
        Day 1
    5.000 (5.000 to 5.000)
    5.000 (5.000 to 5.000)
    5.000 (5.000 to 5.000)
    5.000 (5.000 to 5.000)
        Day 29
    5.160 (4.906 to 5.427)
    5.071 (4.972 to 5.172)
    5.000 (5.000 to 5.000)
    5.116 (4.980 to 5.256)
        Day 43
    28.846 (21.716 to 38.318)
    23.976 (18.394 to 31.252)
    5.000 (5.000 to 5.000)
    26.327 (21.707 to 31.929)
    Notes
    [24] - Day 43 N = 88.
    [25] - Day 43 N = 86.
    [26] - Day 43 N = 41.
    [27] - Day 43 N = 174.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 to Day 393
    Adverse event reporting additional description
    Safety Analysis Set: All participants randomized in the trial who received at least one dose of any lot of CVnCoV or placebo vaccine.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    CVnCoV: Group 1, Lot 1
    Reporting group description
    		 Participants in Group 1 were vaccinated with CVnCoV 12 µg Lot 1 as an intramuscular injection by needle in the deltoid area on Day 1 and Day 29.

    Reporting group title
    CVnCoV: Group 2, Lot 2
    Reporting group description
    		 Participants in Group 2 were vaccinated with CVnCoV 12 µg Lot 2 as an intramuscular injection by needle in the deltoid area on Day 1 and Day 29.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received a placebo as an intramuscular injection by needle in the deltoid area on Day 1 and Day 29.

    Serious adverse events
    		 CVnCoV: Group 1, Lot 1 CVnCoV: Group 2, Lot 2 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 783 (1.02%)
    10 / 785 (1.27%)
    6 / 783 (0.77%)
         number of deaths (all causes)
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 783 (0.00%)
    0 / 785 (0.00%)
    2 / 783 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    1 / 783 (0.13%)
    1 / 785 (0.13%)
    0 / 783 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ganglioglioma
         subjects affected / exposed
    0 / 783 (0.00%)
    0 / 785 (0.00%)
    1 / 783 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 785 (0.00%)
    0 / 783 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Invasive lobular breast carcinoma
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 785 (0.00%)
    0 / 783 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 785 (0.00%)
    0 / 783 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ligament rupture
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 785 (0.00%)
    0 / 783 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    0 / 783 (0.00%)
    0 / 785 (0.00%)
    1 / 783 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 785 (0.13%)
    0 / 783 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 785 (0.00%)
    0 / 783 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 785 (0.13%)
    0 / 783 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 785 (0.00%)
    0 / 783 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 785 (0.13%)
    0 / 783 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 785 (0.13%)
    0 / 783 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    0 / 783 (0.00%)
    0 / 785 (0.00%)
    1 / 783 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 785 (0.13%)
    0 / 783 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 785 (0.00%)
    1 / 783 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 785 (0.00%)
    0 / 783 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 785 (0.13%)
    0 / 783 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachypnoea
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 785 (0.00%)
    0 / 783 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 783 (0.00%)
    0 / 785 (0.00%)
    1 / 783 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 785 (0.13%)
    0 / 783 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 783 (0.00%)
    2 / 785 (0.25%)
    0 / 783 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical spinal stenosis
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 785 (0.13%)
    0 / 783 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 785 (0.00%)
    0 / 783 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 785 (0.13%)
    0 / 783 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestine gangrene
         subjects affected / exposed
    0 / 783 (0.00%)
    0 / 785 (0.00%)
    1 / 783 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 CVnCoV: Group 1, Lot 1 CVnCoV: Group 2, Lot 2 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    542 / 783 (69.22%)
    547 / 785 (69.68%)
    475 / 783 (60.66%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    428 / 783 (54.66%)
    430 / 785 (54.78%)
    293 / 783 (37.42%)
         occurrences all number
    924
    952
    615
    Dizziness
         subjects affected / exposed
    37 / 783 (4.73%)
    46 / 785 (5.86%)
    34 / 783 (4.34%)
         occurrences all number
    42
    54
    43
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    425 / 783 (54.28%)
    427 / 785 (54.39%)
    278 / 783 (35.50%)
         occurrences all number
    835
    852
    530
    Injection site pain
         subjects affected / exposed
    387 / 783 (49.43%)
    390 / 785 (49.68%)
    160 / 783 (20.43%)
         occurrences all number
    693
    698
    205
    Chills
         subjects affected / exposed
    276 / 783 (35.25%)
    275 / 785 (35.03%)
    81 / 783 (10.34%)
         occurrences all number
    419
    457
    95
    Pyrexia
         subjects affected / exposed
    218 / 783 (27.84%)
    221 / 785 (28.15%)
    61 / 783 (7.79%)
         occurrences all number
    309
    330
    64
    Pain
         subjects affected / exposed
    46 / 783 (5.87%)
    62 / 785 (7.90%)
    47 / 783 (6.00%)
         occurrences all number
    53
    68
    52
    Injection site pruritus
         subjects affected / exposed
    27 / 783 (3.45%)
    43 / 785 (5.48%)
    18 / 783 (2.30%)
         occurrences all number
    31
    53
    22
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    140 / 783 (17.88%)
    132 / 785 (16.82%)
    65 / 783 (8.30%)
         occurrences all number
    197
    195
    82
    Diarrhoea
         subjects affected / exposed
    104 / 783 (13.28%)
    113 / 785 (14.39%)
    66 / 783 (8.43%)
         occurrences all number
    146
    144
    78
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    106 / 783 (13.54%)
    107 / 785 (13.63%)
    99 / 783 (12.64%)
         occurrences all number
    134
    135
    133
    Nasal congestion
         subjects affected / exposed
    98 / 783 (12.52%)
    106 / 785 (13.50%)
    95 / 783 (12.13%)
         occurrences all number
    128
    145
    121
    Cough
         subjects affected / exposed
    70 / 783 (8.94%)
    85 / 785 (10.83%)
    62 / 783 (7.92%)
         occurrences all number
    89
    106
    84
    Rhinorrhoea
         subjects affected / exposed
    32 / 783 (4.09%)
    39 / 785 (4.97%)
    41 / 783 (5.24%)
         occurrences all number
    38
    44
    47
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    344 / 783 (43.93%)
    341 / 785 (43.44%)
    136 / 783 (17.37%)
         occurrences all number
    569
    565
    183
    Arthralgia
         subjects affected / exposed
    250 / 783 (31.93%)
    245 / 785 (31.21%)
    75 / 783 (9.58%)
         occurrences all number
    376
    378
    98
    Infections and infestations
    COVID-19
         subjects affected / exposed
    106 / 783 (13.54%)
    99 / 785 (12.61%)
    123 / 783 (15.71%)
         occurrences all number
    111
    103
    131

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Mar 2021
    The protocol was updated to include: - Clarifications to protocol text "students in clinical years". - Clarifications that participants who reported to have COVID-19 symptoms were only followed-up if the Investigator considered the symptoms to potentially indicate a COVID-19 case. - Clarifications that participants who tested positive for SARS-CoV-2 outside of the trial context were considered for active surveillance for COVID-19. - Unblinding was allowed in the case a participant became eligible to receive an authorized/licensed vaccine. - Inclusion of information on authorized vaccine availability. - History of potential immune-mediated disease was separated from history of angioedema or anaphylactic reaction. - Instructions to state that viral ribonucleic acid (RNA) of SARS-CoV-2 should be sequenced at a Sponsor-designated laboratory to identify spike protein variants in participants with positive reverse transcriptase-polymerase chain reaction (RT-PCR) tests. - Guidance that participants may receive the second trial vaccine dose if they developed COVID-19 between Dose 1 and 2. - Inclusion of instructions that COVID-19 illness and its complications/sequelae were to be reported as an AESI. - Exclusion of the genitourinary system examination from the complete physical examination. Inclusion of O2 saturation measurement at the discretion of the Investigator. - Minor editorial and document formatting revisions.
    23 Jul 2021
    The protocol was updated to include: - The summary of CVnCoV final efficacy analysis of the HERALD trial. - The unblinding of all blinded participants and subsequent change on the schedules of activities to guarantee safety follow-up of all the participants exposed to CVnCoV. - Text that ensures access to information on the HERALD final analysis results for all the participants.
    11 Aug 2021
    The protocol was updated to include: - Clarification that the Trial Physician was responsible for providing trial results to participants. - Participants receiving authorized SARS-CoV-2 vaccines were not to be included in the antibody response. - Minor editorial and document formatting revisions.
    22 Dec 2021
    The protocol was updated to include: - New medical responsible person. - Added e-mail address for post-trial safety reporting. - Trial was to remain blinded until approval of trial protocol version 3.0. - Assessment of cell mediated immune response was cancelled. - Comparison of efficacy by pooling of results with trial COVID19-5-P-002 was cancelled. - Limitation of immunogenicity analyses to 100 CVnCoV participants per lot and 50 placebo participants and to the following time points: Baseline, Day 29 and Day 43. - Assessment of seroconversion to the N-protein of SARS-CoV-2 at Day 393 was cancelled. - Assessment of efficacy of CVnCoV in the prevention or reduction of asymptomatic infections was cancelled. - Measurement of antibody responses for all COVID-19 cases that occur in the trial was cancelled. - For positive RT-PCR tests, viral RNA of the SARS-CoV-2 sequencing to identify spike protein variants were no longer required. - Efficacy cases were no longer to be confirmed by adjudication. - AE recording was only to be done for criteria defined. - Withdrawal procedure for placebo participants added. - Option for remote source data verification included.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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