Background Booster vaccines providing protection against emergent SARS-CoV-2 variants are needed. In an international phase 3 study, we evaluated booster vaccines containing prototype (D614) and/or Beta (B.1.351) variant recombinant spike proteins and AS03 adjuvant (CoV2 preS dTM-AS03). Methods Adults, primed 4-10 months earlier with mRNA (BNT162b2, mRNA-1273]), adenovirus-vectored (Ad26.CoV2.S, ChAdOx1nCoV-19) or adjuvanted protein (CoV2 preS dTM-AS03 [D614]) vaccines and stratified by age (18-55 and ≥56 years), were boosted with monovalent (MV) D614 (5≥g, n=1285), MV (B.1351) (5μg, n=707) or bivalent (BiV) (2.5≥g D614 plus 2.5≥g B.1.351, n=625) CoV2 preS dTM-AS03. SARS-CoV-2-naïve adults (controls, n=479) received a primary series (two injections, 21 days apart) of CoV2 preS dTM-AS03 containing 10μg D614. Antibodies to D614G, B.1.351 and Omicron BA.2 and BA.1 variants were evaluated using validated pseudovirus (lentivirus) neutralization (PsVN) assay. D614G or B.1.351 PsVN titers 14 days (D15) post-booster were compared with pre-booster (D1) titers in BNT162b2-primed participants (18-55 years old) and controls (D36), for each booster formulation (co-primary objectives). Safety was evaluated throughout the trial. Results of a planned interim analysis are presented. Results Among BNT162b2-primed adults (18-55 years old), PsVN titers against D614G or B.1.351 were significantly higher post-booster than anti-D614G titers post-primary vaccination in controls, for all booster formulations, with an anti-D614G GMT ratio (98.3% CI) of 2.16 (1.69; 2.75) for MV(D614), an anti-B.1.351 ratio of 1.96 (1.54; 2.50) for MV (B.1.351) and anti-D614G and anti-B.1.351 ratios of 2.34 (1.84; 2.96) and 1.39 (1.09; 1.77), respectively, for BiV. All booster formulations elicited cross-neutralizing antibodies against Omicron BA.2 across vaccine priming subgroups and against Omicron BA.1 (evaluated in BNT162b2-primed participants). Similar patterns in antibody responses were observed for participants aged ≥56 years. No safety concerns were identified. Conclusion CoV2 preS dTM-AS03 boosters demonstrated acceptable safety and elicited robust neutralizing antibodies against multiple variants, regardless of priming vaccine. ClinicalTrials.gov: NCT04762680

GdB, JW, AP, MSR, HA, MIB, RC, RF, BF, JG, M-HG, SG, OH, RM, JP, NR, RMC and SSa are Sanofi employees; MIB, RMC hold stock options. SSa was a Sanofi employee at the time of study conduct. SSr, RMC, GdB, CAD and SSa, are inventors on a pending patent application filed by Sanofi and GSK for the development of the CoV-2 dTM vaccine. MAC, LS and MK are employed by GSK and hold restricted shares in the GSK group of companies. FTDS was employed by GSK, and held restricted shares in the GSK group of companies, at the time of the study. DMRM declares that her institution received funding from Sanofi. FM-T has received honoraria from GSK group of companies, Pfizer Inc, Sanofi, MSD, Seqirus, Biofabri, and Janssen for taking part in advisory boards and expert meetings and for acting as a speaker in congresses outside the scope of the submitted work. FM-T has also acted as principal investigator in randomized controlled trials of the above-mentioned companies as well as Ablynx, Gilead, Regeneron, Roche, Abbott, Novavax, and MedImmune, with honoraria paid to his institution. AF receives research funding, paid to his employers, from Sanofi both for work related to this study and other unrelated vaccine trials and from GSK for other unrelated studies. He receives research funding from other vaccine manufacturers relating to trials and studies and undertakes paid consultancy related to a number of developmental antimicrobial drugs and vaccines. xxx declare no conflict of interest.

NCT04762680

Sanofi and federal funds from the Biomedical Advanced Research and Development Authority (BARDA), part of the office of the Administration for Strategic Preparedness and Response at the U.S. Department of Health and Human Services under Contract # HHSO100201600005I, and in collaboration with the U.S. Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense under Contract # W15QKN-16-9-1002.

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 study was undertaken in compliance with the International Conference on Harmonization guidelines for Good Clinical Practice and the principles of the Declaration of Helsinki. The protocol and amendments were approved by Independent Ethics Committees (country ethics committees for Honduras [Comite Etica Independiente Zugueme], France [Comite De Protection Des Personnes Ile De France III Hopital Tarnier-Cochin, France], Spain [Comite De Eticade Investigacion Con Medicamentos Parc Tauli, Spain] and the UK [HRA and Health and Care Research Wales, UK], a central ethics committee for the USA [Advarra] and local ethics committees for the USA [WCG IRB, Columbia Research Human Research Protection Office, Langone Health Office of Science and Research Institutional Review Board and the Yale Human Research Protection Program] and for Australia [Bellberry, Sydney Children's Hospitals Network Human Research Ethics Committee and Sydney Children's Hospital Network (SCHN) Research Governance]) as per local regulations. Written informed consent was obtained from all participants before any study procedures were performed.

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

Qualified researchers can request access to patient-level data and related study documents, including the clinical study report, study protocol with any amendments, blank case report forms, statistical analysis plan, and dataset specifications. Patient-level data will be anonymised and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at https://vivli.org/.