Efficacy, immunogenicity, and safety of a next-generation mRNA-1283 COVID-19 vaccine compared with the mRNA-1273 vaccine (NextCOVE): results from a phase 3, randomised, observer-blind, active-controlled trial.

Background: mRNA-1283 is an investigational, next-generation COVID-19 vaccine that encodes only the immunodominant regions of the SARS-CoV-2 spike protein-the receptor-binding domain (RBD) and the N-terminal domain rather than the full-length spike used in currently authorised mRNA vaccines. We evaluated the relative vaccine efficacy (rVE), immunogenicity, and safety of mRNA-1283 compared to the first-generation vaccine (mRNA-1273).

Methods: This randomised, observer-masked, active-controlled, phase 3 trial (NextCOVE) was conducted in individuals (aged ≥12 years) with no evidence of SARS-CoV-2 infection within 90 days of screening in the USA, the UK, and Canada. Participants were randomly assigned in a 1:1 ratio to receive one 10 μg dose of the bivalent formulation of mRNA-1283 (original plus omicron BA.4/BA.5) or 50 μg of the bivalent mRNA-1273, encoding the same variants. Randomisation was stratified by age (12-17 years, 18-64 years, and ≥65 years). Primary objectives comparing mRNA-1283 with mRNA-1273 were non-inferior rVE to prevent a first event of COVID-19 from 14 days after study injection to the end of follow-up (assessed in the per-protocol set for efficacy, with non-inferiority declared when the lower bound of the α-adjusted two-sided CI for rVE was greater than -10%), non-inferior immunogenicity at day 29 (assessed in the per-protocol immunogenicity subset, with non-inferiority declared when the lower bounds of the CIs for the geometric mean concentration ratios [GMRs] of neutralising antibodies against SARS-CoV-2 D614G and omicron BA.4/BA.5 were >0·667 and the lower bounds of the 95% CI seroresponse rate differences for the two variants were greater than -10%), and safety (assessed in the safety set, which included all participants who received a vaccination). The trial is registered at ClinicalTrials.gov (NCT05815498) and is complete.

Findings: Between March 28 and Aug 23, 2023, we screened 13 054 individuals for eligibility and randomly allocated 11 454 participants (5728 to mRNA-1283 and 5726 to mRNA-1273). 1177 confirmed COVID-19 events occurred up to Jan 31, 2024 (560 [9·9%] of 5679 in mRNA1283.222 and 617 [10·8%] of 5687 in mRNA-1273.222). The median age of participants at enrolment was 56 years (IQR 38-66). Of the 11 417 participants who received a vaccine, 6200 (54·3%) were female and 5217 (45·7%) were male; 9381 (82·2%) were White; and 1510 (13·2%) were Hispanic or Latino. Of the total cohort, 992 (8·7%) participants were aged 12-17 years, 7151 (62·6%) were aged 18-64 years, and 3274 (28·7%) were 65 years and older; in addition, 6857 participants (60·1%) were 50 years and older. The rVE point estimate was 9·3% (99·4% CI -6·6 to 22·8; p=0·0005). The GMR was 1·3 (95% CI 1·2 to 1·5) for BA.4/BA.5 and 1·2 (1·1 to 1·4) for D614G. The day-29 seroresponse rate difference was 14·4% (95% CI 9·3 to 19·4) for BA.4/BA.5 and 10·7% (6·0 to 15·4) for D614G. Local and systemic adverse reactions were similar between mRNA-1283 and mRNA-1273; mRNA-1283 was associated with fewer injection-site pain reactions than mRNA-1273 (3905 [68·5%] of 5701 vs 4419 [77·5%] of 5705, respectively). The frequency of unsolicited adverse events, serious adverse events, and medically attended adverse events were similar between groups during the first 28 days after injection. One event of sudden death occurred in a participant with underlying cardiovascular disease in the mRNA-1273 group; it was reported as related to vaccination due to its temporal association.

Interpretation: mRNA-1283 was well-tolerated. The rVE and immunogenicity non-inferiority criteria were met, with higher antibody responses for mRNA-1283 versus mRNA-1273. The potential clinical benefit of mRNA-1283 versus mRNA-1273 needs to be confirmed in post-marketing evaluation.

Funding: Moderna.