A Randomized Trial Comparing Omicron-Containing Boosters with the Original Covid-19 Vaccine mRNA-1273

Background Omicron-containing bivalent boosters are available worldwide. Results of a large, randomized, active-controlled study are presented. Methods This phase 3, randomized, observer-blind, active-controlled trial in the United Kingdom evaluated the immunogenicity and safety of 50-µg doses of omicron-BA.1-monovalent mRNA-1273.529 and bivalent mRNA-1273.214 booster vaccines compared with 50-µg mRNA-1273 administered as boosters in individuals ≥16 years. Participants had previously received 2 doses of any authorized/approved Covid-19 vaccine with or without an mRNA vaccine booster. Safety and immunogenicity were primary objectives; immunogenicity was assessed in all participants, with analysis conducted based on prior infection status. Incidence of Covid-19 post-boost was a secondary (mRNA-1273.214) or exploratory (mRNA-1273.529) objective. Results In part 1 of the study, 719 participants received mRNA-1273.529 (n=362) or mRNA-1273 (n=357); in part 2, 2813 received mRNA-1273.214 (n=1418) or mRNA-1273 (n=1395). Median durations (months [interquartile range]) between the most recent Covid-19 vaccine and study boosters were similar in the mRNA-1273.529 (4.0 [3.6-4.7]) and mRNA-1273 (4.1 [3.5-4.7]) (part 1), and mRNA-1273.214 (5.5 [4.8-6.2] and mRNA-1273 (5.4 [4.8-6.2]) groups (part 2). Both mRNA-1273.529 and mRNA-1273.214 elicited superior neutralizing antibody responses against omicron BA.1 with geometric mean ratios (99% CIs) of 1.68 (1.45-1.95) and 1.53 (1.41-1.67) compared to mRNA-1273 at day 29 post-boost. Although the study was not powered to assess relative vaccine efficacy, the incidence rates/1000 person years (95% CI) of Covid-19 trended lower with mRNA-1273.529 (670.5 [528.3-839.3]) than mRNA-1273 (769.3 [615.4-950.1]) and mRNA-1273.214 (633.0 [538.1-739.7]) than mRNA-1273 (711.6 [607.5-828.5]). Sequence analysis in part 2 showed that this was driven by lower incidence of Covid-19 in the mRNA-1273.214 cohort with BA.2 and BA.4 sublineages but not BA.5 sublineages. All study boosters were well-tolerated. Conclusion The bivalent omicron BA.1-containing booster elicited superior neutralizing antibody responses against omicron BA.1 with acceptable safety results consistent with the BA.1 monovalent vaccine. Incidence rates for Covid-19 were numerically lower in participants who received mRNA-1273.214 compared to the original booster vaccine mRNA-1273, driven by the BA.2 and BA.4 sublineages. ### Competing Interest Statement PM reports being a speaker/advisor and/or research grants from GSK, Sanofi, Novavax, Moderna, MSD, Janssen, Medicago, and AstraZenica; PK reports being a speaker/advisor/travel grants and/or research grants from GSK, Pfizer, Pharmacosmos, Astellas, Vifor, Astra Zeneca, Bayer, Unicyte, Evotec, Fresenius, and Otsuka; PD reports research grants for COVID-19 research studies from Moderna, Astra Zeneca, Janssen, and Atea; MBoffito reports being a advisor/speaker for GSK, Atea, ViiV, MSD, Janssen, Gilead, Cipla, Mylan, Roche and has received research grants from ViiV, MSD, Janssen, Gilead, Novavax, Valneva, and Moderna; FB reports receiving speaker fees and a research grant to institution from Gilead Sciences Ltd; CD reports receiving Grants from Wellcome Trust and MRC; DC reports receiving research grants to institution from Gilead Sciences Ltd, ViiV Healthcare, Moderna, Janssen, GSK, and Novavax; ASR received research grants (to my Organisation) from Pfizer, Novavax, Valneva, Moderna, and Janssen; PH reports being a speaker/advisor and/or research grants from Pfizer, Novavax, Valneva, Moderna, and Janssen. CG, CB, RN, MBula, RC, RS, EM, TD, DS, PL and EG report no conflicts. ITL, SC, BG, CP, DR, SM, EW, AS, WD, XC, LT, HZ, JM, and RD are employees of Moderna, Inc. and hold stock/stock options in the company. JET and FJD are Moderna consultants. ### Clinical Trial UK; EudraCT, 2022-000063-51 ### Funding Statement This study was funded by Moderna, Inc., Cambridge, Massachusetts, USA. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Derby Research Ethics Committee gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes As the trial is ongoing, access to patient-level data and supporting clinical documents by qualified external researchers may be available upon request and subject to review once the trial is complete.