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

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 .)

Initial Analysis of Viral Dynamics and Circulating Viral Variants During the mRNA-1273 Phase 3 COVE Trial

“…This is an analysis of the previously reported COVE study, a phase 3 randomized, observerblinded, placebo-controlled trial that enrolled adults in medically-stable condition at 99 US sites (clintrials.gov NCT04470427). 1,2 Eligible participants included adults 18 years or older with no known history of SARS-CoV-2 infection, whose circumstances put them at appreciable risk for SARS-CoV-2 infection and/or high risk of severe Covid-19. Participants were randomized 1:1 to receive mRNA-1273 vaccine (100 µg) or placebo and stratified by age and Covid-19 complications risk criteria (≥18 and <65 years and not at risk, ≥18 and <65 years and at risk, and ≥65 years).…”

“…The trial design, efficacy assessments and study treatment have been previously described and are provided in the supplementary protocol online. 1,2 Briefly, the primary endpoint of the study was the vaccine efficacy of mRNA-1273 at preventing a first occurrence of symptomatic Covid-19 with onset ≥14 days post-second injection, Covid-19 cases defined as having ≥2 of systemic symptoms (fever ≥ 38ºC, chills, myalgia, headache, sore throat, new olfactory and taste disorder[s]), or experienced ≥1 respiratory sign or symptom (cough, shortness of breath, or clinical or radiological evidence of pneumonia), and confirmed by positive RT-PCR for SARS-CoV-2 using NP swab, nasal or saliva sample. The secondary endpoint, severe Covid-19, was defined as confirmed Covid-19 per the primary endpoint case definition, plus one of the clinical signs indicative of severe systemic illness (respiratory rate ≥30 per minute, heart rate ≥125 beats per minute, SpO2 ≤93% on room air at sea level or PaO2/FIO2 <300 mm Hg, OR respiratory failure or Acute Respiratory Distress Syndrome [ARDS, defined as needing high-flow oxygen, non-invasive or mechanical ventilation, or ECMO], evidence of shock [systolic blood pressure <90 mmHg, diastolic BP < 60 mmHg or requiring vasopressors], OR significant acute renal, hepatic or neurologic dysfunction, OR admission to an intensive care unit or death).…”

“…Viral load was assessed in the cohort of participants with adjudicated Covid-19 cases (at an illness visit) in the per-protocol (PP) population during the blinded and placebo-controlled phase of the COVE study. 1,2 The analysis population comprised adjudicated Covid-19 cases in the PP Set with no evidence of infection through day 57, (i.e. those with negative binding antibody [bAb] against nucleocapsid protein [NP, ROCHE Elecsys]) and RT-PCR at baseline and day 29, and negative bAb against NP at day 57.…”

“…The differential in cases between groups is due to the demonstrated >93% efficacy of this vaccine. 1,2 Of the 799 adjudicated cases, 701 (48 in the mRNA-1273 and 653 in the placebo groups) had no evidence of infection through day 57 and were included in the analysis of viral load. Baseline demographics and characteristics were generally balanced for placebo and mRNA-1273 groups (Table S1).…”

“…The mRNA-1273 vaccine, a lipid nanoparticle-encapsulated messenger RNA vaccine encoding a prefusion-stabilized spike (S) protein of the prototype Wuhan-Hu-1 virus isolate, demonstrated high efficacy in preventing symptomatic and asymptomatic severe acute respiratory syndrome (SARS-CoV-2) infections at the primary analysis (December 2020) of the ongoing Coronavirus Efficacy (COVE) phase 3 trial. 1,2 Following Emergency Use Authorization [EUA] issuance of mRNA-1273 in the United States (US), the trial protocol was amended from the observer-blind part of the study to an ongoing open-label part. A recent update of the results reported after completion of the blinded portion of the study (March 2021) with 5.3 months of follow-up time, showed a vaccine efficacy (VE) rate of 93.2% and safety profile similar to those observed at the primary efficacy analysis after 64 days.…”