Dose-Confirmation Study to Evaluate the Safety, Reactogenicity, and Immunogenicity of mRNA-1273 COVID-19 Vaccine in Adults Aged 18 Years and Older

An MAAE is an AE that leads to an unscheduled visit to a healthcare practitioner (HCP). A summary of SAEs and all nonserious AEs (Other), regardless of causality, is located in the Reported Adverse Events section.

Time frame: Up to Month 15

Population: Safety Set: All participants who received any study injection in their respective part of the study.

An SAE was defined as any AE that resulted in death, is life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in disability/permanent damage, was a congenital anomaly/birth defect, or was an important medical event. A summary of SAEs and all nonserious AEs (Other), regardless of causality, is located in the Reported Adverse Events section.

Time frame: Up to Month 15

Population: Safety Set: All participants who received any study injection in their respective part of the study.

Solicited ARs, including local and systemic ARs were collected in the eDiary. Local ARs included: pain at injection site, erythema (redness) at injection site, swelling/induration (hardness) at injection site, and localized axillary swelling or tenderness ipsilateral to the injection arm. Systemic ARs included: headache, fatigue, myalgia (muscle aches all over the body), arthralgia (aching in several joints), nausea/vomiting, rash, body temperature (potentially fever), and chills. All solicited ARs (local and systemic) considered causally related to injection. ARs were graded 0-4 as reviewed and confirmed by Investigator; lower score indicates lower severity and a higher score indicates greater severity. Note, not all solicited ARs were considered adverse events (AEs). The Investigator reviewed whether the solicited AR was also to be recorded as an AE. A summary of SAEs and all nonserious AEs (Other), regardless of causality, is located in the Reported Adverse Events section.

Time frame: 7 days post-vaccination

Population: Solicited Safety Set for Parts A, B, and C included all participants who received any study injection in the applicable part of the study and contributed any solicited AR data (that is, had at least 1 post-baseline solicited safety assessment in the applicable part of the study). Number Analyzed = participants who were evaluable at specified timepoints.

An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. A treatment-emergent AE (TEAE) was defined as any event not present before exposure to vaccine or any event already present that worsens in intensity or frequency after exposure. Any abnormal laboratory test result (hematology, clinical chemistry, or prothrombin time \[PT\]/partial thromboplastin time \[PTT\]) or other safety assessment (for example, electrocardiogram, radiological scan, vital sign measurement), including one that worsens from baseline and is considered clinically significant in the medical and scientific judgment of the Investigator. A summary of SAEs and all nonserious AEs (Other) reported up to the end of the study (up to Month 15), regardless of causality, is located in the Reported Adverse Events section.

Time frame: Up to 28 days post-vaccination

Population: Safety Set: All participants who received any study injection in their respective part of the study.

The geometric mean (GM) level of VAC58 spike immunoglobulin G (IgG) antibodies, as measured by ELISA specific to the SARS-CoV-2 spike protein is reported. Antibody values reported as below the lower limit of quantification (LLOQ) were replaced by 0.5\*LLOQ. Values that were greater than the upper limit of quantification (ULOQ) were converted to the ULOQ if actual values were not available. LLOQ was 1 and ULOQ was 2052. The 95% confidence intervals (CIs) were calculated based on the t-distribution of the log-transformed values or the difference in the log-transformed values for GM value, respectively, then back transformed to the original scale for presentation.

Time frame: Days 1 (Baseline), 29, 43, 57, and 209

Population: Per-Protocol (PP) Set included randomized participants who received any study injection, had required baseline (Day 1) data, had ≥1 post-injection assessment for the analysis endpoint, complied with injection schedule, had post-injection results available for ≥1 assay component corresponding to immunogenicity analysis, did not have SARS-CoV-2 infection, and had no major protocol deviations impacting applicable immune response. Number Analyzed = participants evaluable at specified timepoints.

The GM level of VAC65 spike IgG antibodies, as measured by ELISA specific to the SARS-CoV-2 spike protein is reported. Antibody values reported as below the LLOQ were replaced by 0.5\*LLOQ. Values that were greater than the ULOQ are converted to the ULOQ. LLOQ was 1 and ULOQ was 2052. The 95% CIs were calculated based on the t-distribution of the log-transformed values or the difference in the log-transformed values for GM value, respectively, then back transformed to the original scale for presentation. The PP Set included participants with a study injection, required baseline data, had postinjection results at timepoint of primary interest for immunogenicity analysis, no major protocol deviations impacting immune response, and didn't have SARS-CoV-2.

Time frame: Days 1 (Baseline) and 29

Population: PP Set. Number Analyzed=participants evaluable at specified timepoint. Immunogenicity samples from the Part B: Placebo then 100 ug mRNA arm were not tested and no data were generated as results were not thought to provide additional information. After Part B samples were obtained, it was determined that the extensive results for immunogenicity profiles of 2 doses of 100 ug mRNA-1273 that were obtained during Part A of this study and in Study P301 demonstrated enough immune response data.

The GM level of SARS-CoV-2 protein antibody against B.1.351, as measured by MSD MULTIPLEX is reported. Antibody values reported as below the LLOQ were replaced by 0.5\*LLOQ. Values that were greater than the ULOQ are converted to the ULOQ. LLOQ was 18 and ULOQ was 4200000. The 95% CIs were calculated based on the t-distribution of the log-transformed values or the difference in the log-transformed values for GM value, respectively, then back transformed to the original scale for presentation.

Time frame: Days 1 (Baseline), 8, 15, and 29

Population: PP Set included participants who received any study injection, had required baseline (Day 1) data, had ≥1 post-injection assessment for the analysis endpoint, complied with injection schedule, had post-injection results available for ≥1 assay component corresponding to immunogenicity analysis, did not have SARS-CoV-2 infection, and had no major protocol deviations impacting applicable immune response. Number Analyzed = participants who were evaluable at specified timepoints.

Based on MN titers and MN50 titers of serum nAb against SARS-CoV-2 as measured by live virus MN assays, percentage of participants with seroconversion from baseline are reported with 2-sided 95% CI using the Clopper-Pearson method at each post-baseline timepoint. Seroconversion at a participant level was defined as a change of nAb titer from below the limit of detection (LOD) or LLOQ to equal to or above LOD or LLOQ (respectively), or a 4-times or higher titer ratio in participants with pre-existing nAb titers. Antibody values reported as below the LLOQ were replaced by 0.5\*LLOQ. Values that were greater than the ULOQ were converted to the ULOQ. For MN, LLOQ was 40 and ULOQ was 1280. For MN50, LLOQ was 91.10 and ULOQ was 2031.87.

Time frame: Days 29, 43, and 57

Population: PP Set included randomized participants who received any study injection, had required baseline (Day 1) data, had ≥1 post-injection assessment for the analysis endpoint, complied with injection schedule, had post-injection results available for ≥1 assay component corresponding to immunogenicity analysis, did not have SARS-CoV-2 infection, and had no major protocol deviations impacting applicable immune response. Number Analyzed = participants who were evaluable at specified timepoints.

The GM titer (microneutralization \[MN\] and MN50) of serum nAb against SARS-CoV-2 as measured by live virus MN assays is reported. Antibody values reported as below the LLOQ were replaced by 0.5\*LLOQ. Values that were greater than the ULOQ were converted to the ULOQ. For MN, LLOQ was 40 and ULOQ was 1280 at Days 1 (Baseline), 29, 43, and 57. For MN50, LLOQ was 91.10 and ULOQ was 2031.87 at Days 1 (Baseline), 29, 43, and 57. For MN, LLOQ was 160 and ULOQ was 1280 at Day 209. For MN50, LLOQ was 318.46 and ULOQ was 1917.83 at Day 209. The 95% CI was calculated based on the t-distribution of the log-transformed values or the difference in the log-transformed values for GM titer, then back transformed to the original scale for presentation.

Time frame: Days 1 (Baseline), 29, 43, 57, and 209

Population: PP Set included randomized participants who received any study injection, had required baseline (Day 1) data, had ≥1 post-injection assessment for the analysis endpoint, complied with injection schedule, had post-injection results available for ≥1 assay component corresponding to immunogenicity analysis, did not have SARS-CoV-2 infection, and had no major protocol deviations impacting applicable immune response. Number Analyzed = participants who were evaluable at specified timepoints.

Based on ID50 and ID80 titers of nAb against SARS-CoV-2 pseudotyped viruses as measured by pseudovirus nAb assay, % of participants with seroconversion from baseline reported with 2-sided 95% CI using Clopper-Pearson method at each postbaseline timepoint. Seroconversion at participant level defined as change of nAb titer from below LOD or LLOQ to equal to or above LOD or LLOQ (respectively) or 4-times or higher titer ratio in participants with preexisting nAb titers. Antibody values \<LLOQ replaced by 0.5\*LLOQ. Values \>ULOQ converted to ULOQ. LLOQ: 18.5 and ULOQ: 45118 for IC50. LLOQ: 14.3 and ULOQ: 10232 for ID80. 95% CI calculated based on t-distribution of log-transformed values for GMT, then back transformed to original scale for presentation. PP Set: participants with a study injection, required baseline data, had postinjection results at timepoint of primary interest for immunogenicity analysis, no major protocol deviations impacting immune response, and didn't have SARS-CoV-2.

Time frame: Days 29 and 181

Population: PP Set. Number Analyzed=participants evaluable at specified timepoint. Immunogenicity samples from the Part B: Placebo then 100 ug mRNA arm were not tested and no data were generated as results were not thought to provide additional information. After Part B samples were obtained, it was determined that the extensive results for immunogenicity profiles of 2 doses of 100 ug mRNA-1273 that were obtained during Part A of this study and in Study P301 demonstrated enough immune response data.

The GM titer (50% inhibitory dose \[ID50\], 80% inhibitory dose \[ID80\]) of nAb against SARS-CoV-2 pseudotyped viruses as measured by pseudovirus nAb assay is reported. Antibody values reported as below the LLOQ were replaced by 0.5\*LLOQ. Values that were greater than the ULOQ were converted to the ULOQ if actual values were not available. LLOQ was 18.5 and ULOQ was 45118 for IC50. LLOQ was 14.3 and ULOQ was 10232 for ID80. The 95% CI was calculated based on the t-distribution of the log-transformed values for GM titer, then back transformed to the original scale for presentation. The PP Set included participants with a study injection, required baseline data, had postinjection results at timepoint of primary interest for immunogenicity analysis, no major protocol deviations impacting immune response, and didn't have SARS-CoV-2.

Time frame: Days 1 (Baseline), 29, and 181

Population: PP Set. Number Analyzed=participants evaluable at specified timepoint. Immunogenicity samples from the Part B: Placebo then 100 ug mRNA arm were not tested and no data were generated as results were not thought to provide additional information. After Part B samples were obtained, it was determined that the extensive results for immunogenicity profiles of 2 doses of 100 ug mRNA-1273 that were obtained during Part A of this study and in Study P301 demonstrated enough immune response data.

Based on ID50 titers and ID80 titers of nAb against SARS-CoV-2 pseudotyped viruses (original strain and beta variant \[B.1.351\]) as measured by pseudovirus nAb assay, percentage of participants with seroconversion from baseline are reported with 2-sided 95% CI using Clopper-Pearson method at each post-baseline timepoint. Seroconversion at participant level defined as a change of nAb titer from below LOD or LLOQ ≥LOD or LLOQ (respectively), or a 4-times or higher titer ratio in participants with pre-existing nAb titers. Antibody values reported as below LLOQ were replaced by 0.5\*LLOQ. Values \>ULOQ were converted to ULOQ. NAb ID50 Titers: LLOQ was 18.5 and ULOQ was 45118. NAb ID80 Titers: LLOQ was 14.3 and ULOQ was 10232. NAb ID50 Titers against B.1.351: LLOQ was 19.5 and ULOQ was 385.7. NAb ID80 Titers against B.1.351: LLOQ was 12.5 and ULOQ was 102.2. 95% CI calculated based on t-distribution of log-transformed values for GMT, then back transformed to original scale for presentation.

Time frame: Days 8, 15, 29, and 181

Population: PP Set included participants who received any study injection, had required baseline (Day 1) data, had ≥1 post-injection assessment for the analysis endpoint, complied with injection schedule, had post-injection results available for ≥1 assay component corresponding to immunogenicity analysis, did not have SARS-CoV-2 infection, and had no major protocol deviations impacting applicable immune response. Number Analyzed = participants who were evaluable at specified timepoints.

The GM titer (ID50, ID80) of nAb against SARS-CoV-2 pseudotyped viruses (original strain and beta variant \[B.1.351\]) as measured by pseudovirus nAb assay is reported. Antibody values reported as below the LLOQ were replaced by 0.5\*LLOQ. Values that were greater than the ULOQ were converted to the ULOQ if actual values were not available. For NAb ID50 Titers, LLOQ was 18.5 and ULOQ was 45118. For NAb ID80 Titers, LLOQ was 14.3 and ULOQ was 10232. For NAb ID50 Titers against B.1.351, LLOQ was 19.5 and ULOQ was 385.7. For NAb ID80 Titers against B.1.351, LLOQ was 12.5 and ULOQ was 102.2. The 95% CI was calculated based on the t-distribution of the log-transformed values for GM titer, then back transformed to the original scale for presentation.

Time frame: Days 1 (Baseline), 8, 15, 29, and 181

Population: PP Set included participants who received any study injection, had required baseline (Day 1) data, had ≥1 post-injection assessment for the analysis endpoint, complied with injection schedule, had post-injection results available for ≥1 assay component corresponding to immunogenicity analysis, did not have SARS-CoV-2 infection, and had no major protocol deviations impacting applicable immune response. Number Analyzed = participants who were evaluable at specified timepoints.