A Phase 2b/3, Randomized, Observer-Blinded, Placebo-Controlled, Multicenter Clinical Study Evaluating the Efficacy and Safety of Investigational SARS-CoV-2 mRNA Vaccine CVnCoV in Adults 18 Years of Age and Older

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 of each SAE reported during the trial. Each SAE was graded from Mild (Grade 1) to Severe (Grade 3), where higher grades indicated a worse outcome. Participants were censored at the first day after unblinding or at the day after receiving the authorized/licensed vaccine, whichever was earlier.

Time frame: Day 1 to Day 393

Population: SAS: Included all participants randomized in Phase 2b or 3 who received at least one dose of CVnCoV or placebo. Only participants who experienced SAEs were included.

A fatal SAE was defined as an SAE that resulted in death. Participants were censored at the first day after unblinding or at the day after receiving the authorized/licensed vaccine, whichever was earlier.

Time frame: Day 1 to Day 393

Population: SAS: Included all participants randomized in Phase 2b or 3 who received at least one dose of CVnCoV or placebo.

A case of COVID-19 meeting the definition for primary efficacy analysis was defined as follows: * Virologically-confirmed case of COVID-19 (of any severity) defined as a positive SARS-CoV-2 specific RT-PCR test in a person with clinically symptomatic COVID-19. * Symptom onset ≥ 15 days after second trial vaccination. * First episode of virologically-confirmed COVID-19, i.e. the participant must not have had a history of virologically-confirmed COVID-19 illness at enrollment or have had developed a case of virologically-confirmed COVID-19 before 15 days after the second trial vaccination. * Participant was SARS-CoV-2 naïve at baseline and Day 43 (defined as seronegative to N protein in the blood samples collected at baseline and Day 43). * Primary efficacy cases were confirmed by an Adjudication Committee. Participants were censored at the first day after unblinding or at the day after receiving the authorized/licensed vaccine, whichever was earlier.

Time frame: Day 44 to Day 393

Population: Efficacy Analysis Set (EAS): All participants randomized in Phase 2b or Phase 3 who received both doses of trial vaccine, had not developed a virologically-confirmed case of COVID-19 before trial entry or before 15 days after the second vaccination \& were SARS-CoV-2 naïve at baseline \& Day 43. Participants must have not developed an asymptomatic case of SARS-CoV-2, not stopped the trial, not received an AV for preventing COVID-19 or been unblinded prior to 15 days after the second vaccination.

AESIs included: * AEs with a suspected immune-medicated etiology. * Other AEs relevant to SARS-CoV-2 vaccine development or the target disease. The Investigator assessed the relationship between trial vaccine and occurrence of each AESI. Participants were censored at the first day after unblinding or at the day after receiving the authorized/licensed vaccine, whichever was earlier.

Time frame: Day 1 to Day 393

Population: SAS: Included all participants randomized in Phase 2b or 3 who received at least one dose of CVnCoV or placebo.

Participants were censored at the first day after unblinding or at the day after receiving the authorized/licensed vaccine, whichever was earlier.

Time frame: Day 1 to Day 393

Population: SAS: Included all participants randomized in Phase 2b or 3 who received at least one dose of CVnCoV or placebo.

Medically-attended AEs were defined as AEs with medically-attended visits that were 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. Clinic visits for COVID-19 testing resulting in negative test results were not considered as medically attended visits, if there is no confirmed diagnosis and no prescribed concomitant medication. The Investigator assessed the relationship between trial vaccine and occurrence of each AE. Participants were censored at the first day after unblinding or at the day after receiving the authorized/licensed vaccine, whichever was earlier.

Time frame: Day 1 to Day 211

Population: Safety Analysis Set (SAS): Included all participants randomized in Phase 2b or 3 who received at least one dose of CVnCoV or placebo.

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 SAE. Participants were censored at the first day after unblinding or at the day after receiving the authorized/licensed vaccine, whichever was earlier.

Time frame: Day 1 to Day 393

Population: SAS: Included all participants randomized in Phase 2b or 3 who received at least one dose of CVnCoV or placebo.

Solicited local AEs (injection site pain, redness, swelling, and itching) and solicited systemic AEs (fever, headache, fatigue, chills, myalgia, arthralgia, nausea/vomiting, and diarrhea) were recorded on the day of vaccination and the following 7 days using an eDiary. Duration is calculated as consecutive days with a respective solicited AE regardless of the grade of the AE. AEs ongoing after Day 8 are included. In each case only the longest consecutive duration is displayed. Participants were censored at the first day after unblinding or at the day after receiving the authorized/licensed vaccine, whichever was earlier.

Time frame: Up to 7 days after vaccination (Days 1 to 7 and Days 29 to 36)

Population: The SASsol: Included all phase 2b participants of the SAS with at least one diary collection indicating the occurrence or lack of occurrence of solicited AEs. Only participants who experienced solicited AEs were included.

Solicited local AEs (injection site pain, redness, swelling, and itching) and solicited systemic AEs (fever, headache, fatigue, chills, myalgia, arthralgia, nausea/vomiting, and diarrhea) were recorded on the day of vaccination and the following 7 days using an eDiary. The Investigator made an assessment of intensity of each solicited AE reported during the trial. Each solicited AE was graded from Mild (Grade 1) to Severe (Grade 3), where higher grades indicated a worse outcome. Participants were censored at the first day after unblinding or at the day after receiving the authorized/licensed vaccine, whichever was earlier.

Time frame: Up to 7 days after vaccination (Days 1 to 7 and Days 29 to 36)

Population: The SASsol: Included all phase 2b participants of the SAS with at least one diary collection indicating the occurrence or lack of occurrence of solicited AEs. Only participants who experienced solicited AEs were included.

eDiaries were used for collection of unsolicited AEs on each vaccination day and the following 28 days. In addition, participants received a prompt (by e.g., a phone call or text message) to verify whether the participants had any health concerns since the last visit. The Investigator made an assessment of intensity of each unsolicited AE reported during the trial. Each unsolicited AE was graded from Mild (Grade 1) to Severe (Grade 3), where higher grades indicated a worse outcome. Participants were censored at the first day after unblinding or at the day after receiving the authorized/licensed vaccine, whichever was earlier.

Time frame: Up to 28 days after vaccination (Days 1 to 29 and Days 29 to 57)

Population: SAS 2: Included all Phase 2b participants of the SAS.

Solicited local AEs (injection site pain, redness, swelling, and itching) and solicited systemic AEs (fever, headache, fatigue, chills, myalgia, arthralgia, nausea/vomiting, and diarrhea) were recorded on the day of vaccination and the following 7 days using an eDiary. Participants were censored at the first day after unblinding or at the day after receiving the authorized/licensed vaccine, whichever was earlier.

Time frame: Up to 7 days after vaccination (Days 1 to 7 and Days 29 to 36)

Population: The SASsol: Included all phase 2b participants of the SAS with at least one diary collection indicating the occurrence or lack of occurrence of solicited AEs.

eDiaries were used for collection of unsolicited AEs on each vaccination day and the following 28 days. In addition, participants received a prompt (by e.g., a phone call or text message) to verify whether the participants had any health concerns since the last visit. The Investigator assessed the relationship between trial vaccine and each occurrence of each AE. Participants were censored at the first day after unblinding or at the day after receiving the authorized/licensed vaccine, whichever was earlier.

Time frame: Up to 28 days after vaccination (Days 1 to 29 and Days 29 to 57)

Population: SAS 2: Included all Phase 2b participants of the SAS.

Score #2 was defined as no disease (not infected or asymptomatic infection) = 0; disease without hospitalization = 1; disease with hospitalization = 2; death = 3. Participants were censored at the first day after unblinding or at the day after receiving the authorized/licensed vaccine, whichever was earlier.

Time frame: Day 44 to Day 393

Population: EAS: All participants randomized in Phase 2b or Phase 3 who received both doses of trial vaccine, had not developed a virologically-confirmed case of COVID-19 before trial entry or before 15 days after the second vaccination, \& were SARS-CoV-2 naïve at baseline and Day 43. Participants must have not developed an asymptomatic case of SARS-CoV-2, not stopped the trial, not received an AV for preventing COVID-19 or not been unblinded prior to 15 days after the second vaccination.

Score #1 was defined as no disease (not infected or asymptomatic infection) = 0; mild or moderate disease = 1; severe disease = 2. Participants were censored at the first day after unblinding or at the day after receiving the authorized/licensed vaccine, whichever was earlier.

Time frame: Day 44 to Day 393

Population: EAS: All participants randomized in Phase 2b or Phase 3 who received both doses of trial vaccine, had not developed a virologically-confirmed case of COVID-19 before trial entry or before 15 days after the second vaccination, \& were SARS-CoV-2 naïve at baseline and Day 43. Participants must have not developed an asymptomatic case of SARS-CoV-2, not stopped the trial, not received an AV for preventing COVID-19 or not been unblinded prior to 15 days after the second vaccination.

A case of COVID-19 was defined as follows: * Virologically-confirmed case of COVID-19 (of any severity) defined as a positive SARS-CoV-2 specific RT-PCR test in a person with clinically symptomatic COVID-19. * Symptom onset ≥ 15 days after second trial vaccination. * First episode of virologically-confirmed COVID-19, i.e. the participant must not have had a history of virologically-confirmed COVID-19 illness at enrollment or have had developed a case of virologically-confirmed COVID-19 before 15 days after the second trial vaccination. * Participant was SARS-CoV-2 naïve at baseline and Day 43 (defined as seronegative to N protein in the blood samples collected at baseline and Day 43). Participants were censored at the first day after unblinding or at the day after receiving the authorized/licensed vaccine, whichever was earlier.

Time frame: Day 44 to Day 393

Population: The EAS including only participants who were aged ≥ 61.

The characterization of SARS-CoV-2 variants were implemented by viral whole genome sequencing of nasopharyngeal swab samples of participants followed by comparison with previously sequenced and typified genomes. The following phylogenetic clustering was applied: 1. Wild type virus: WT/D614G, lineages A.1/B.1 without the variant of concerns (VOCs) (i.e., without B.1.1.7 \[Alpha\], B.1.351 \[Beta\], B.1.429 \[Epsilon\]). 2. UK VOC: B.1.1.7 (Alpha). A case of COVID-19 was defined as follows: * Virologically-confirmed case of COVID-19 defined as a positive SARS-CoV-2 specific RT-PCR test in a person with clinically symptomatic COVID-19. * Symptom onset ≥ 15 days after second vaccination. * First episode of virologically-confirmed COVID-19. * Participant was SARS-CoV-2 naïve at baseline and Day 43. Participants were censored at the first day after unblinding or at the day after receiving the authorized/licensed vaccine, whichever was earlier.

Time frame: Day 44 to Day 393

Population: EAS: All participants randomized in Phase 2b or Phase 3 who received both doses of trial vaccine, had not developed a virologically-confirmed case of COVID-19 before trial entry or before 15 days after the second vaccination, \& were SARS-CoV-2 naïve at baseline and Day 43. Participants must have not developed an asymptomatic case of SARS-CoV-2, not stopped the trial, not received an AV for preventing COVID-19 or not been unblinded prior to 15 days after the second vaccination.

Moderate cases defined by any 1 of the following: * Shortness of breath/difficulty breathing * Respiratory rate ≥20 to \<30 breaths per min * Abnormal SpO2 but still \>93% on room air at sea level * Clinical/radiographic evidence of lower respiratory tract disease * Radiologic evidence of DVT Severe cases defined by any 1 of the following: * Clinical signs at rest indicative of severe systemic illness (respiratory rate ≥ 30breaths per minute, heart rate ≥125 per minute, SpO2 ≤93% on room air at sea level or PaO2/FIO2 \<300 mm Hg) * Respiratory failure (defined as needing high flow-oxygen, noninvasive ventilation, mechanical ventilation or ECMO) * Evidence of shock (SBP \<90mm Hg, DBP \<60 mmHg or requiring vasopressors) * Significant renal, hepatic, or neurologic dysfunction * Admission to ICU * Death Participants were censored at the first day after unblinding or at the day after receiving the authorized/licensed vaccine, whichever was earlier.

Time frame: Day 44 to Day 393

Population: EAS: All participants randomized in Phase 2b or Phase 3 who received both doses of trial vaccine, had not developed a virologically-confirmed case of COVID-19 before trial entry or before 15 days after the second vaccination, \& were SARS-CoV-2 naïve at baseline and Day 43. Participants must have not developed an asymptomatic case of SARS-CoV-2, not stopped the trial, not received an AV for preventing COVID-19 or not been unblinded prior to 15 days after the second vaccination.

Severe COVID-19 cases were defined by any one of the following: * Clinical signs at rest indicative of severe systemic illness (respiratory rate ≥ 30 breaths per minute, heart rate ≥ 125 per minute, SpO2 ≤ 93% on room air at sea level or PaO2/FIO2 \< 300 mm Hg). * Respiratory failure (defined as needing high flow-oxygen, noninvasive ventilation, mechanical ventilation or ECMO). * Evidence of shock (SBP \< 90mm Hg, DBP \< 60 mmHg, or requiring vasopressors). * Significant renal, hepatic, or neurologic dysfunction * Admission to intensive care unit (ICU). * Death. Participants were censored at the first day after unblinding or at the day after receiving the authorized/licensed vaccine, whichever was earlier.

Time frame: Day 44 to Day 393

Population: EAS: All participants randomized in Phase 2b or Phase 3 who received both doses of trial vaccine, had not developed a virologically-confirmed case of COVID-19 before trial entry or before 15 days after the second vaccination, \& were SARS-CoV-2 naïve at baseline and Day 43. Participants must have not developed an asymptomatic case of SARS-CoV-2, not stopped the trial, not received an AV for preventing COVID-19 or not been unblinded prior to 15 days after the second vaccination.

Titers of IgG antibodies directed against the SARS-CoV-2 RBD of Spike Protein antigen were measured by ELISA. Percentage with 95% CI of participants for whom a seroconversion was observed is presented by group. In participants who tested seronegative to the N protein for SARS-CoV-2 at baseline, seroconversion was defined as a fold increase above 1 in antibody titer against SARS-CoV-2 RBD of S protein. Only participants seronegative at baseline with evaluable samples at each visit are included. Participants who tested positive for SARS-CoV-2 via PCR or N-protein antibodies had their data included up to the point of positive test result or symptom onset. Participants who received a licensed/authorized vaccine were censored at the day after receiving the licensed/authorized vaccine.

Time frame: Baseline and Days 29, 43, 120 and 211

Population: PPI Set: Included all Phase 2b participants seronegative at baseline from the Immunogenicity Subset who received both doses as randomized \& within the specified windows, had no important protocol deviations that impacted immunogenicity outcomes, did not receive medical treatments that interfered with the proposed immunogenicity measurements and had at least one blood sample collected at baseline and starting at 14 days post-second vaccination available for analysis.

Titers of viral neutralizing antibodies were determined by an activity assay. Percentage with 95% CI of participants for whom a seroconversion was observed is presented by group. In participants who tested seronegative to the N protein for SARS-CoV-2 at baseline, seroconversion was defined as a fold increase above 1 in antibody titer against SARS-CoV-2 neutralizing antibody titer. Only participants seronegative at baseline with evaluable samples at each visit are included. Participants who have tested positive for SARS-CoV-2 via PCR or N-protein antibodies have their data included up to the point of positive test result or symptom onset. Participants who received a licensed/authorized vaccine were censored at the day after receiving the licensed/authorized vaccine.

Time frame: Baseline and Days 29, 43, 120 and 211

Population: PPI Set: Included all Phase 2b participants from the Immunogenicity Subset who received both doses as randomized and within the specified windows, had no important protocol deviations that impacted immunogenicity outcomes, did not receive medical treatments that interfered with the proposed immunogenicity measurements and had at least one blood sample collected at baseline and starting at 14 days post-second vaccination available for analysis.

Titers of IgG antibodies directed against the SARS-CoV-2 RBD of Spike Protein antigen were measured by enzyme- linked immunosorbent assay (ELISA) and expressed as geometric mean of titers (GMT) with 95% confidence interval (CI), by group. Individual values below the lower limit of quantification (LLOQ) were set to half of the LLOQ. Only participants seronegative at baseline with evaluable samples at each visit are included. Participants who tested positive for SARS-CoV-2 via PCR or N-protein antibodies had their data included up to the point of positive test result or symptom onset. Participants who received a licensed/authorized vaccine were censored at the day after receiving the licensed/authorized vaccine.

Time frame: Days 1 (baseline), 29, 43, 120 and 211

Population: Per Protocol Immunogenicity (PPI) Set: Included all Phase 2b participants from the Immunogenicity Subset who received both doses as randomized and within the specified windows, had no important protocol deviations that impacted immunogenicity outcomes, did not receive medical treatments that interfered with the proposed immunogenicity measurements and had at least one blood sample collected at baseline and starting at 14 days post-second vaccination available for analysis.

Titers of viral neutralizing antibodies were determined by an activity assay and expressed as GMT with 95% CI, by group. Individual values below the LLOQ were set to half of the LLOQ. Only participants seronegative at baseline with evaluable samples at each visit are included. Participants who have tested positive for SARS-CoV-2 via PCR or N-protein antibodies have their data included up to the point of positive test result or symptom onset. Participants who received a licensed/authorized vaccine were censored at the day after receiving the licensed/authorized vaccine.

Time frame: Days 1 (baseline), 29, 43, 120 and 211

Population: PPI Set: Included all Phase 2b participants from the Immunogenicity Subset who received both doses as randomized and within the specified windows, had no important protocol deviations that impacted immunogenicity outcomes, did not receive medical treatments that interfered with the proposed immunogenicity measurements and had at least one blood sample collected at baseline and starting at 14 days post-second vaccination available for analysis.