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Clinical Trial

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

Lindsey R Baden et al. N Engl J Med. .

Abstract

Background: Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle-encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19.

Methods: This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo 28 days apart. 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 SARS-CoV-2.

Results: The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups.

Conclusions: The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (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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Conflict of interest statement

Dr. Baden reports being funded by the NIH to conduct clinical trials in collaboration with Crucell/Janssen and Moderna; Dr. Rouphael, receiving grant support from Pfizer, Merck, Sanofi–Pasteur, Eli Lilly, and Quidel; Dr. Creech, receiving grant support from Merck, consulting fees from Horizon Pharma and GSK, and fees for serving on a data and safety monitoring board from Astellas; Dr. Neuzil, receiving grant support from Pfizer; Dr. Graham, holding pending patent WO/2018/081318 on prefusion coronavirus spike proteins and their use and pending patent 62/972,886 on 2019-nCoV vaccine; Dr. Bennett, being employed by and owning stock and stock options in Moderna; Dr. Pajon, being employed by and owning stock in Moderna; Dr. Knightly, being employed by and owning stock and stock options in Moderna; Drs. Leav, Deng, and Zhou being employees of Moderna; Dr. Han, being employed by and owning stock and stock options in Moderna; Dr. Ivarsson, being employed by and owning share options in Moderna; Dr. Miller, being employed by and owning stock and stock options in Moderna; and Dr. Zaks, being employed by and owning stock options in Moderna. No other potential conflict of interest relevant to this article was reported.

Figures

Figure 1
Figure 1. Randomization and Analysis Populations.
The data cutoff for the primary analysis occurred on November 25, 2020. The full analysis population consisted of participants who underwent randomization and received at least one dose of mRNA-1273 or placebo; the modified intention-to-treat population comprised 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 analysis population included participants in the modified intention-to-treat population who received two doses, with no major protocol deviations. The safety population included all participants who received at least one injection. Among participants who received an incorrect injection, three participants in the mRNA-1273 group received at least one dose of placebo and no dose of mRNA-1273 and were included in the placebo safety population, and three received one dose of placebo and one dose of mRNA-1273 and were included in the mRNA-1273 safety population; in the placebo group all seven received mRNA-1273 and were included in the mRNA-1273 safety population. Participants who received dose 2 outside the window for the per-protocol analysis are those who did not receive the second dose between 7 days before and 14 days after day 29.
Figure 2
Figure 2. Solicited Local and Systemic Adverse Events.
Shown is the percentage of participants who had a solicited local or systemic adverse event within 7 days after injection 1 or injection 2 of either the placebo or the mRNA-1273 vaccine.
Figure 3
Figure 3. Vaccine Efficacy of mRNA-1273 to Prevent Covid-19.
Shown is the cumulative incidence of Covid-19 events in the primary analysis based on adjudicated assessment starting 14 days after the second vaccination in the per-protocol population (Panel A) and after randomization in the modified intention-to-treat population (Panel B) (see the Supplementary Appendix). The dotted line in Panel A indicates day 42 (14 days after vaccination 2), when the per-protocol follow-up began, and arrows in both panels indicate days 1 and 29, when injections were administered. Tick marks indicate censored data. Vaccine efficacy was defined as 1 minus the hazard ratio (mRNA vs. placebo), and the 95% confidence interval was 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, with adjustment for stratification factor. Incidence was defined as the number of events divided by number of participants at risk and was adjusted by person-years. Symptomatic Covid-19 case accrual for placebo and vaccine in the modified intention-to-treat population is displayed (does not include asymptomatic cases of SARS-CoV-2 detected at the day 29 by nasopharyngeal swab).
Figure 4
Figure 4. Vaccine Efficacy of mRNA-1273 to Prevent Covid-19 in Subgroups.
The efficacy of the RNA-1273 vaccine in preventing 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, adjusting for stratification factor if applicable. Race and ethnic group categories shown are White (non-Hispanic) and communities of color (all others, including those whose race and ethnicity were both reported as unknown, were not reported, or were both missing at screening). Data for communities of color were pooled owing to limited numbers of participants in each racial or ethnic group, to ensure that the subpopulations would be large enough for meaningful analyses.
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