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Clinical Trial

Efficacy of the mRNA-1273 SARS-CoV-2 Vaccine at Completion of Blinded Phase

Hana M El Sahly et al. N Engl J Med. .

Abstract

Background: At interim analysis in a phase 3, observer-blinded, placebo-controlled clinical trial, the mRNA-1273 vaccine showed 94.1% efficacy in preventing coronavirus disease 2019 (Covid-19). After emergency use of the vaccine was authorized, the protocol was amended to include an open-label phase. Final analyses of efficacy and safety data from the blinded phase of the trial are reported.

Methods: We enrolled volunteers who were at high risk for Covid-19 or its complications; participants were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo, 28 days apart, at 99 centers across the United States. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The data cutoff date was March 26, 2021.

Results: The trial enrolled 30,415 participants; 15,209 were assigned to receive the mRNA-1273 vaccine, and 15,206 to receive placebo. More than 96% of participants received both injections, 2.3% had evidence of SARS-CoV-2 infection at baseline, and the median follow-up was 5.3 months in the blinded phase. Vaccine efficacy in preventing Covid-19 illness was 93.2% (95% confidence interval [CI], 91.0 to 94.8), with 55 confirmed cases in the mRNA-1273 group (9.6 per 1000 person-years; 95% CI, 7.2 to 12.5) and 744 in the placebo group (136.6 per 1000 person-years; 95% CI, 127.0 to 146.8). The efficacy in preventing severe disease was 98.2% (95% CI, 92.8 to 99.6), with 2 cases in the mRNA-1273 group and 106 in the placebo group, and the efficacy in preventing asymptomatic infection starting 14 days after the second injection was 63.0% (95% CI, 56.6 to 68.5), with 214 cases in the mRNA-1273 group and 498 in the placebo group. Vaccine efficacy was consistent across ethnic and racial groups, age groups, and participants with coexisting conditions. No safety concerns were identified.

Conclusions: The mRNA-1273 vaccine continued to be efficacious in preventing Covid-19 illness and severe disease at more than 5 months, with an acceptable safety profile, and protection against asymptomatic infection was observed. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.).

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Figures

Figure 1
Figure 1. Randomization and Analysis Populations.
Eight participants, including six with major protocol deviations and two who erroneously underwent randomization twice, were excluded from the original randomization population (30,423 participants) and from all analysis sets. The full analysis population comprised all participants who had undergone randomization and received at least one injection; the modified intention-to-treat population included participants in the full analysis population who had no immunologic or virologic evidence of previous Covid-19 (i.e., had both a negative nasopharyngeal swab specimen and a negative anti-nucleocapsid antibody test result) at day 1 before the first injection; and the per-protocol population consisted of all participants in the modified intent-to-treat population who received planned injections according to the schedule and had no major protocol deviations that affected key trial data. The safety population included all participants who had undergone randomization and received at least one injection; this population was used for all safety analyses except the analysis for solicited adverse events. For safety analyses, participants were evaluated according to the injection received. Three participants assigned to the mRNA-1273 group received two doses of placebo and were included in the placebo safety population, and seven participants assigned to the placebo group received one or two doses of mRNA-1273 and were included in the mRNA-1273 safety population. The data cutoff date was March 26, 2021.
Figure 2
Figure 2. Efficacy of the mRNA-1273 Vaccine in Preventing Covid-19.
In Panels A and C, the dashed vertical line denotes the adjudicated assessment beginning at day 42 (14 days after the second injection of vaccine or placebo). Tick marks in all three panels indicate censored data. Vaccine efficacy was defined as 1 minus the hazard ratio (mRNA-1273 vs. placebo), and 95% confidence intervals were estimated with the use of a stratified Cox proportional-hazards model with Efron’s method of tie handling and with treatment group as a covariate, adjusted for stratification factor. The data cutoff date was March 26, 2021.
Figure 3
Figure 3. Vaccine Efficacy for Primary and Secondary End Points.
Vaccine efficacy was defined as 1 minus the hazard ratio (mRNA-1273 vs. placebo), and 95% confidence intervals were estimated using a stratified Cox proportional-hazards model with Efron’s method of tie handling and with the treatment group as a covariate, adjusted for stratification factor. The P value for the vaccine efficacy against Covid-19 (upper right corner) is P<0.001. The dashed vertical line represents a vaccine efficacy of 30%, based on the null hypothesis that the primary efficacy of the mRNA-1273 vaccine is 30% or less. In the Covid-19 rows, censoring rules for efficacy analyses (Covid-19 cases based on eligible symptoms and positive reverse-transcriptase–polymerase-chain-reaction [RT-PCR] assay within 14 days before the second injection) were applied, except for deaths from Covid-19. If a participant had a positive RT-PCR assay at the visit before the second dose (day 29) without eligible symptoms within the previous 14 days, or a positive anti-nucleocapsid antibody test at a scheduled visit before Covid-19 was diagnosed, the participant’s data were censored at the date of the positive RT-PCR assay or anti-nucleocapsid antibody test. Covid-19 diagnoses were based on adjudication committee assessments. The data for Covid-19 regardless of previous SARS-CoV-2 status were based on the number of participants in the full analysis population (15,166 participants in the placebo group and 15,180 participants in the mRNA-1273 group). Data for the asymptomatic subgroup include data from the participant-decision visit. Asymptomatic was defined as the absence of symptoms (according to either the primary efficacy end point of Covid-19 or the secondary definition of Covid-19 [the Centers for Disease Control and Prevention definition, requiring only one symptom]) and of infection as detected by RT-PCR assay (at scheduled visits) or seroconversion (anti-nucleocapsid antibody test). In the primary approach, documented asymptomatic infection was counted beginning 14 days after the second injection, which required seroconversion at month 2 (day 57 through the participant-decision visit). Asymptomatic seroconversion excludes infections confirmed by RT-PCR assay only and includes infections confirmed by seroconversion and those confirmed by both RT-PCR and seroconversion (Table S28). Vaccine efficacy and 95% confidence intervals for asymptomatic SARS-CoV-2 infection were estimated with Fine and Gray’s subdistribution hazard model, with disease cases as competing events and with treatment group as a covariate, adjusted for stratification factor. Results for additional end points are summarized in Table S27. The data cutoff date was March 26, 2021. NE indicates that the lower bound of the 95% confidence interval could not be estimated.
Figure 4
Figure 4. Efficacy of the mRNA-1273 Vaccine in Preventing Covid-19 in Subgroups.
Analysis of the vaccine efficacy of mRNA-1273 in the prevention of Covid-19 in various subgroups in the per-protocol population was based on adjudicated assessments starting 14 days after the second injection. Vaccine efficacy, defined as 1 minus the hazard ratio (mRNA-1273 vs. placebo), and 95% confidence intervals were estimated with the use of a stratified Cox proportional-hazards model with Efron’s method of tie-handling and with the treatment group as a covariate, adjusted for stratification factor if applicable. The total number of events for race includes 38 placebo recipients and 3 mRNA-1273 recipients who were in “Multiple,” “Other,” or not reported or unknown categories, and the total number for ethnicity includes 4 placebo recipients and no mRNA-1273 recipients who were in not reported or unknown categories (not shown). Race and ethnic group were reported by the participant. The body-mass index (BMI) is the weight in kilograms divided by the square of the height in meters. Additional subgroup data are provided in Table S29. The data cutoff date was March 26, 2021. HIV denotes human immunodeficiency virus.
Figure 5
Figure 5. Incidence of Covid-19 According to Time Periods in the Per-Protocol Population.
The incidence rate based on adjudicated Covid-19 cases was defined as the number of participants with an event during the period divided by the number of participants at risk at the beginning of each period and adjusted by person-years (total time at risk) in each treatment group. The dashed vertical line represents a vaccine efficacy of 30% based on the null hypothesis that the primary efficacy of the mRNA-1273 vaccine is 30% or less. The number of person-years was calculated from randomization to the date of onset of Covid-19, the end of each time period, the last date of participation in the trial, or the efficacy data cutoff date, whichever date was the earliest. For the analysis of time intervals starting from 14 days after the first injection, starting from the second injection, and starting 14 days after the second injection, assessed every 2 months, person-years for each time period were defined starting from the beginning of each time interval and truncating at the end of the interval (if there was an ending time). Vaccine efficacy was defined as 1 minus the hazard ratio (mRNA-1273 vs. placebo). The 95% confidence interval for the ratio was calculated with the exact method, conditional on the total number of cases and adjusted for person-years for the time period. The data cutoff date was March 26, 2021.
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