Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine

This phase 3 randomized, stratified, observer-blinded, placebo-controlled trial enrolled adults in medically stable condition at 99 U.S. sites. Participants received the first trial injection between July 27 and October 23, 2020. The trial is being conducted in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Good Clinical Practice guidelines, and applicable government regulations. The central institutional review board approved the protocol and the consent forms. All participants provided written informed consent before enrollment. Safety is reviewed by a protocol safety review team weekly and by an independent data and safety monitoring board on a continual basis. The trial Investigational New Drug sponsor, Moderna, was responsible for the overall trial design (with input from the Biomedical Advanced Research and Development Authority, the NIAID, the Covid-19 Prevention Network, and the trial cochairs), site selection and monitoring, and data analysis. Investigators are responsible for data collection. A medical writer funded by Moderna assisted in drafting the manuscript for submission. The authors vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol. The trial is ongoing, and the investigators remain unaware of participant-level data. Designated team members within Moderna have unblinded access to the data, to facilitate interface with the regulatory agencies and the data and safety monitoring board; all other trial staff and participants remain unaware of the treatment assignments.

Eligible participants were persons 18 years of age or older with no known history of SARS-CoV-2 infection and with locations or circumstances that put them at an appreciable risk of SARS-CoV-2 infection, a high risk of severe Covid-19, or both. Inclusion and exclusion criteria are provided in the protocol (available with the full text of this article at NEJM.org). To enhance the diversity of the trial population in accordance with Food and Drug Administration Draft Guidance, site-selection and enrollment processes were adjusted to increase the number of persons from racial and ethnic minorities in the trial, in addition to the persons at risk for SARS-CoV-2 infection in the local population. The upper limit for stratification of enrolled participants considered to be “at risk for severe illness” at screening was increased from 40% to 50%.¹⁷

Participants were randomly assigned in a 1:1 ratio, through the use of a centralized interactive response technology system, to receive vaccine or placebo. Assignment was stratified, on the basis of age and Covid-19 complications risk criteria, into the following risk groups: persons 65 years of age or older, persons younger than 65 years of age who were at heightened risk (at risk) for severe Covid-19, and persons younger than 65 years of age without heightened risk (not at risk). Participants younger than 65 years of age were categorized as having risk for severe Covid-19 if they had at least one of the following risk factors, based on the Centers for Disease Control and Prevention (CDC) criteria available at the time of trial design: chronic lung disease (e.g., emphysema, chronic bronchitis, idiopathic pulmonary fibrosis, cystic fibrosis, or moderate-to-severe asthma); cardiac disease (e.g., heart failure, congenital coronary artery disease, cardiomyopathies, or pulmonary hypertension); severe obesity (body mass index [the weight in kilograms divided by the square of the height in meters] ≥40); diabetes (type 1, type 2, or gestational); liver disease; or infection with the human immunodeficiency virus.¹⁸

Vaccine dose preparation and administration were performed by pharmacists and vaccine administrators who were aware of treatment assignments but had no other role in the conduct of the trial. Once the injection was completed, only trial staff who were unaware of treatment assignments performed assessments and interacted with the participants. Access to the randomization code was strictly controlled at the pharmacy. The data and safety monitoring board reviewed efficacy data at the group level and unblinded safety data at the participant level.

The mRNA-1273 vaccine, provided as a sterile liquid at a concentration of 0.2 mg per milliliter, was administered by injection into the deltoid muscle according to a two-dose regimen. Injections were given 28 days apart, in the same arm, in a volume of 0.5 ml containing 100 μg of mRNA-1273 or saline placebo.¹ Vaccine mRNA-1273 was stored at 2° to 8°C (35.6° to 46.4°F) at clinical sites before preparation and vaccination. No dilution was required. Doses could be held in syringes for up to 8 hours at room temperature before administration.

Safety assessments included monitoring of solicited local and systemic adverse events for 7 days after each injection; unsolicited adverse reactions for 28 days after each injection; adverse events leading to discontinuation from a dose, from participation in the trial, or both; and medically attended adverse events and serious adverse events from day 1 through day 759. Adverse event grading criteria and toxicity tables are described in the protocol. Cases of Covid-19 and severe Covid-19 were continuously monitored by the data and safety monitoring board from randomization onward.

The primary end point was the efficacy of the mRNA-1273 vaccine in preventing a first occurrence of symptomatic Covid-19 with onset at least 14 days after the second injection in the per-protocol population, among participants who were seronegative at baseline. End points were judged by an independent adjudication committee that was unaware of group assignment. Covid-19 cases were defined as occurring in participants who had at least two of the following symptoms: fever (temperature ≥38°C), chills, myalgia, headache, sore throat, or new olfactory or taste disorder, or as occurring in those who had at least one respiratory sign or symptom (including cough, shortness of breath, or clinical or radiographic evidence of pneumonia) and at least one nasopharyngeal swab, nasal swab, or saliva sample (or respiratory sample, if the participant was hospitalized) that was positive for SARS-CoV-2 by reverse-transcriptase–polymerase-chain-reaction (RT-PCR) test. Participants were assessed for the presence of SARS-CoV-2–binding antibodies specific to the SARS-CoV-2 nucleocapsid protein (Roche Elecsys, Roche Diagnostics International) and had a nasopharyngeal swab for SARS-CoV-2 RT-PCR testing (Viracor, Eurofins Clinical Diagnostics) before each injection. SARS-CoV-2–infected volunteers were followed daily, to assess symptom severity, for 14 days or until symptoms resolved, whichever was longer. A nasopharyngeal swab for RT-PCR testing and a blood sample for identifying serologic evidence of SARS-CoV-2 infection were collected from participants with symptoms of Covid-19.

The consistency of vaccine efficacy at the primary end point was evaluated across various subgroups, including age groups (18 to <65 years of age and ≥65 years), age and health risk for severe disease (18 to <65 years and not at risk; 18 to <65 years and at risk; and ≥65 years), sex (female or male), race and ethnic group, and risk for severe Covid-19 illness. If the number of participants in a subgroup was too small, it was combined with other subgroups for the subgroup analyses.

A secondary end point was the efficacy of mRNA-1273 in the prevention of severe Covid-19 as defined by one of the following criteria: respiratory rate of 30 or more breaths per minute; heart rate at or exceeding 125 beats per minute; oxygen saturation at 93% or less while the participant was breathing ambient air at sea level or a ratio of the partial pressure of oxygen to the fraction of inspired oxygen below 300 mm Hg; respiratory failure; acute respiratory distress syndrome; evidence of shock (systolic blood pressure <90 mm Hg, diastolic blood pressure <60 mm Hg, or a need for vasopressors); clinically significant acute renal, hepatic, or neurologic dysfunction; admission to an intensive care unit; or death. Additional secondary end points included the efficacy of the vaccine at preventing Covid-19 after a single dose or at preventing Covid-19 according to a secondary (CDC), less restrictive case definition: having any symptom of Covid-19 and a positive SARS-CoV-2 test by RT-PCR (see Table S1 in the Supplementary Appendix, available at NEJM.org).

For analysis of the primary end point, the trial was designed for the null hypothesis that the efficacy of the mRNA-1273 vaccine is 30% or less. A total of 151 cases of Covid-19 would provide 90% power to detect a 60% reduction in the hazard rate (i.e., 60% vaccine efficacy), with two planned interim analyses at approximately 35% and 70% of the target total number of cases (151) and with a one-sided O’Brien–Fleming boundary for efficacy and an overall one-sided error rate of 0.025. The efficacy of the mRNA-1273 vaccine could be demonstrated at either the interim or the primary analysis, performed when the target total number of cases had been observed. The Lan–DeMets alpha-spending function was used for calculating efficacy boundaries at each analysis. At the first interim analysis on November 15, 2020, vaccine efficacy had been demonstrated in accordance with the prespecified statistical criteria. The vaccine efficacy estimate, based on a total of 95 adjudicated cases (63% of the target total), was 94.5%, with a one-sided P value of less than 0.001 to reject the null hypothesis that vaccine efficacy would be 30% or less. The data and safety monitoring board recommendation to the oversight group and the trial sponsor was that the efficacy findings should be shared with the participants and the community (full details are available in the protocol and statistical analysis plan).

Vaccine efficacy was assessed in the full analysis population (randomized participants who received at least one dose of mRNA-1273 or placebo), the modified intention-to-treat population (participants in the full analysis population who had no immunologic or virologic evidence of Covid-19 on day 1, before the first dose), and the per-protocol population (participants in the modified intention-to-treat population who received two doses, with no major protocol deviations). The primary efficacy end point in the interim and primary analyses was assessed in the per-protocol population. Participants were evaluated in the treatment groups to which they were assigned. Vaccine efficacy was defined as the percentage reduction in the hazard ratio for the primary end point (mRNA-1273 vs. placebo). A stratified Cox proportional hazards model was used to assess the vaccine efficacy of mRNA-1273 as compared with placebo in terms of the percentage hazard reduction. (Details regarding the analysis of vaccine efficacy are provided in the Methods section of the Supplementary Appendix.)

Safety was assessed in all participants in the solicited safety population (i.e., those who received at least one injection and reported a solicited adverse event). Descriptive summary data (numbers and percentages) for participants with any solicited adverse events, unsolicited adverse events, unsolicited severe adverse events, serious adverse events, medically attended adverse events, and adverse events leading to discontinuation of the injections or withdrawal from the trial are provided by group. Two-sided 95% exact confidence intervals (Clopper–Pearson method) are provided for the percentages of participants with solicited adverse events. Unsolicited adverse events are presented according to the Medical Dictionary for Regulatory Activities (MedDRA), version 23.0, preferred terms and system organ class categories.

To meet the regulatory agencies’ requirement of a median follow-up duration of at least 2 months after completion of the two-dose regimen, a second analysis was performed, with an efficacy data cutoff date of November 21, 2020. This second analysis is considered the primary analysis of efficacy, with a total of 196 adjudicated Covid-19 cases in the per-protocol population, which exceeds the target total number of cases (151) specified in the protocol. This was an increase from the 95 cases observed at the first interim analysis data cutoff on November 11, 2020. Results from the primary analysis are presented in this report. Subsequent analyses are considered supplementary.

Between July 27, 2020, and October 23, 2020, a total of 30,420 participants underwent randomization, and the 15,210 participants in each group were assigned to receive two doses of either placebo or mRNA-1273 (100 μg) (Figure 1). More than 96% of participants received the second dose (Fig. S1). Common reasons for not receiving the second dose were withdrawal of consent (153 participants) and the detection of SARS-CoV-2 by PCR before the administration of the second dose on day 29 (114 participants: 69 in the placebo group and 45 in the mRNA-1273 group). The primary efficacy and safety analyses were performed in the per-protocol and safety populations, respectively. Of the participants who received a first injection, 14,073 of those in the placebo group and 14,134 in the mRNA-1273 group were included in the primary efficacy analysis; 525 participants in the placebo group and 416 in the mRNA-1273 group were excluded from the per-protocol population, including those who had not received a second dose by the day 29 data cutoff (Figure 1). As of November 25, 2020, the participants had a median follow-up duration of 63 days (range, 0 to 97) after the second dose, with 62% of participants having more than 56 days of follow-up.

Baseline demographic characteristics were balanced between the placebo group and the mRNA-1273 vaccine group (Table 1 and Table S2). The mean age of the participants was 51.4 years, 47.3% of the participants were female, 24.8% were 65 years of age or older, and 16.7% were younger than 65 years of age and had predisposing medical conditions that put them at risk for severe Covid-19. The majority of participants were White (79.2%), and the racial and ethnic proportions were generally representative of U.S. demographics, including 10.2% Black or African American and 20.5% Hispanic or Latino. Evidence of SARS-CoV-2 infection at baseline was present in 2.3% of participants in the mRNA-1273 group and in 2.2% in the placebo group, as detected by serologic assay or RT-PCR testing.

Solicited adverse events at the injection site occurred more frequently in the mRNA-1273 group than in the placebo group after both the first dose (84.2%, vs. 19.8%) and the second dose (88.6%, vs. 18.8%) (Figure 2 and Tables S3 and S4). In the mRNA-1273 group, injection-site events were mainly grade 1 or 2 in severity and lasted a mean of 2.6 and 3.2 days after the first and second doses, respectively (Table S5). The most common injection-site event was pain after injection. Delayed injection-site reactions (those with onset on or after day 8) were noted in 244 participants (0.8%) after the first dose and in 68 participants (0.2%) after the second dose. Reactions were characterized by erythema, induration, and tenderness, and they resolved over the following 4 to 5 days. Solicited systemic adverse events occurred more often in the mRNA-1273 group than in the placebo group after both the first dose (54.9%, vs. 42.2%) and the second dose (79.4%, vs. 36.5%). The severity of the solicited systemic events increased after the second dose in the mRNA-1273 group, with an increase in proportions of grade 2 events (from 16.5% after the first dose to 38.1% after the second dose) and grade 3 events (from 2.9% to 15.8%). Solicited systemic adverse events in the mRNA-1273 group lasted a mean of 2.9 days and 3.1 days after the first and second doses, respectively (Table S5). Both solicited injection-site and systemic adverse events were more common among younger participants (18 to <65 years of age) than among older participants (≥65 years of age). Solicited adverse events were less common in participants who were positive for SARS-CoV-2 infection at baseline than in those who were negative at baseline (Tables S6 and S7).

The frequency of unsolicited adverse events, unsolicited severe adverse events, and serious adverse events reported during the 28 days after injection was generally similar among participants in the two groups (Tables S8 through S11). Three deaths occurred in the placebo group (one from intraabdominal perforation, one from cardiopulmonary arrest, and one from severe systemic inflammatory syndrome in a participant with chronic lymphocytic leukemia and diffuse bullous rash) and two in the vaccine group (one from cardiopulmonary arrest and one by suicide). The frequency of grade 3 adverse events in the placebo group (1.3%) was similar to that in the vaccine group (1.5%), as were the frequencies of medically attended adverse events (9.7% vs. 9.0%) and serious adverse events (0.6% in both groups). Hypersensitivity reactions were reported in 1.5% and 1.1% of participants in the vaccine and placebo groups, respectively (Table S12). Bell’s palsy occurred in the vaccine group (3 participants [<0.1%]) and the placebo group (1 participant [<0.1%]) during the observation period of the trial (more than 28 days after injection). Overall, 0.5% of participants in the placebo group and 0.3% in the mRNA-1273 group had adverse events that resulted in their not receiving the second dose, and less than 0.1% of participants in both groups discontinued participation in the trial because of adverse events after any dose (Table S8). No evidence of vaccine-associated enhanced respiratory disease was noted, and fewer cases of severe Covid-19 or any Covid-19 were observed among participants who received mRNA-1273 than among those who received placebo (Tables S13 and S14). Adverse events that were deemed by the trial team to be related to the vaccine or placebo were reported among 4.5% of participants in the placebo group and 8.2% in the mRNA-1273 group. The most common treatment-related adverse events (those reported in at least 1% of participants) in the placebo group and the mRNA-1273 group were fatigue (1.2% and 1.5%) and headache (0.9% and 1.4%). In the overall population, the incidence of treatment-related severe adverse events was higher in the mRNA-1273 group (71 participants [0.5%]) than in the placebo group (28 participants [0.2%]) (Tables S8 and S15). The relative incidence of these adverse events according to vaccine group was not affected by age.

After day 1 and through November 25, 2020, a total of 269 Covid-19 cases were identified, with an incidence of 79.7 cases per 1000 person-years (95% confidence interval [CI], 70.5 to 89.9) among participants in the placebo group with no evidence of previous SARS-CoV-2 infection. For the primary analysis, 196 cases of Covid-19 were diagnosed: 11 cases in the vaccine group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0) and 185 cases in the placebo group (56.5 per 1000 person-years; 95% CI, 48.7 to 65.3), indicating 94.1% efficacy of the mRNA-1273 vaccine (95% CI, 89.3 to 96.8%; P<0.001) for the prevention of symptomatic SARS-CoV-2 infection as compared with placebo (Figure 3A). Findings were similar across key secondary analyses (Table S16), including assessment starting 14 days after dose 1 (225 cases with placebo, vs. 11 with mRNA-1273, indicating a vaccine efficacy of 95.2% [95% CI, 91.2 to 97.4]), and assessment including participants who were SARS-CoV-2 seropositive at baseline in the per-protocol analysis (187 cases with placebo, vs. 12 with mRNA-1273; one volunteer assigned to receive mRNA-1273 was inadvertently given placebo], indicating a vaccine efficacy of 93.6% [95% CI, 88.6 to 96.5]). Between days 1 and 42, seven cases of Covid-19 were identified in the mRNA-1273 group, as compared with 65 cases in the placebo group (Figure 3B).

A key secondary end point evaluated the efficacy of mRNA-1273 at preventing severe Covid-19. Thirty participants in the trial had severe Covid-19; all 30 were in the placebo group (indicating vaccine efficacy of 100% [95% CI, could not be estimated to 1.0]), and one death among these participants was attributed to Covid-19 (Table S16). The vaccine efficacy to prevent Covid-19 was consistent across subgroups stratified by demographic and baseline characteristics (Figure 4): age groups (18 to <65 years of age and ≥65 years), presence of risk for severe Covid-19, sex, and race and ethnic group (non-Hispanic White and communities of color). Among participants who were positive for SARS-CoV-2, by serologic or virologic testing, at baseline (337 in the placebo group and 343 in the mRNA-1273 group), one case of Covid-19 was diagnosed by RT-PCR testing in a placebo recipient and no cases were diagnosed in mRNA-1273 recipients (Table S17). Among participants who were negative for SARS-CoV-2 at baseline (by RT-PCR or antibody testing), in addition to symptomatic Covid-19 cases 39 (0.3%) in the placebo group and 15 (0.1%) in the mRNA-1273 group had nasopharyngeal swabs that were positive for SARS-CoV-2 by RT-PCR at the second dose visit (surveillance swab) but had no evidence of Covid-19 symptoms (Table S18).