Long-term safety and effectiveness of mRNA-1273 vaccine in adults: COVE trial open-label and booster phases

Abstract

Primary vaccination with mRNA-1273 (100-µg) was safe and efficacious at preventing coronavirus disease 2019 (COVID-19) in the previously reported, blinded Part A of the phase 3 Coronavirus Efficacy (COVE; NCT04470427) trial in adults (≥18 years) across 99 U.S. sites. The open-label (Parts B and C) primary objectives were evaluation of long-term safety and effectiveness of primary vaccination plus a 50-µg booster dose; immunogenicity was a secondary objective. Of 29,035 open-label participants, 19,609 received boosters (mRNA-1273 [n = 9647]; placebo-mRNA-1273 [n = 9952]; placebo [n = 10] groups). Booster safety was consistent with that reported for primary vaccination. Incidences of COVID-19 and severe COVID-19 were higher during the Omicron BA.1 than Delta variant waves and boosting versus non-boosting was associated with a significant, 47.0% (95% CI : 39.0-53.9%) reduction of Omicron BA.1 incidence (24.6 [23.4 - 25.8] vs 46.4 [40.6 - 52.7]/1000 person-months). In an exploratory Cox regression model adjusted for time-varying covariates, a longer median interval between primary vaccination and boosting (mRNA-1273 [13 months] vs placebo-mRNA-1273 [8 months]) was associated with significantly lower, COVID-19 risk (24.0% [16.0% - 32.0%]) during Omicron BA.1 predominance. Boosting elicited greater immune responses against SARS-CoV-2 than primary vaccination, irrespective of prior SARS-CoV-2 infection. Primary vaccination and boosting with mRNA-1273 demonstrated acceptable safety, effectiveness and immunogenicity against COVID-19, including emergent variants.

Fig. 1. Trial profile of participants in the Parts B and C safety sets.

BDV booster decision visit, FPFV first participant first visit, PDV participant decision visit. ^*Participants (n = 29,035) who started the open-label observational phase include those who had a PDV or unblinding date. ^†In Part B, 12,554 of the 12,649 participants in the placebo-mRNA-1273 group who received a first injection of mRNA-1273 also received a second dose. Of the 15,185 participants in the mRNA-1273 group who received at least one injection of mRNA-1273 in Part A, 139 received one injection of mRNA-1273 in Part B. ^§One participant discontinued after the discontinuation cutoff date. ^¶A greater proportion of participants in the placebo compared with the mRNA-1273 group discontinued the study due to protocol deviations, primarily receipt of an off-study COVID-19 vaccine. ^ǁThe higher number of discontinuations by the withdrawal of consent in the mRNA-1273 group is explained largely by the recruitment of participants to other booster dose clinical studies (~3863 participants to phase 2 [NCT04405076] and phase 2/3 [NCT05249829] studies). ^‡Participants were considered to have completed the study if they completed the final visit on day 759 (month 25), 24 months following the last injection of study vaccination. ^**Included one participant who did not enter the open-label observational phase. ^††Included 10 participants who did not enter the open-label observational phase. Study initiation dates: for Part A blinded FPFV July 27, 2020; for Part B (PDV) December 2020; Part C (BDV) September 23, 2021. Data-cutoff date: Part A March 26, 2021; Part B Booster day 1 visit or database lock date, April 7, 2023, whichever is earlier; database lock date: Part C April 7, 2023.

Fig. 2. COVID-19 events based on adjudication committee assessments starting 14 days after booster, across subgroups (Part C per-protocol set).

CI confidence interval, COVID-19 coronavirus disease 2019, IR incidence rate, N number of participants at risk. Incidence rates among subgroups following administration of mRNA-1273 as a 50-µg booster dose are presented. Error bars represent 95% confidence intervals. Incidence is defined as the number of participants with an event starting 14 days after booster by the number of participants at risk at 14 days after booster and adjusted by person-months (total time at risk) in each treatment group. 1 month = 30.4375 days. White is defined as White and non-Hispanic, and communities of color include all the others whose race or ethnicity is unknown, unreported, or missing. Participants at risk for severe COVID-19 included those aged ≥65 years and <65 years with at least one of the risk factors (chronic lung disease, significant cardiac disease, severe obesity, diabetes, liver disease, or HIV infection).