Safety and immunogenicity of a variant-adapted SARS-CoV-2 recombinant protein vaccine with AS03 adjuvant as a booster in adults primed with authorized vaccines: a phase 3, parallel-group study


Guy de Bruyn, Sanofi, Swiftwater, PA, USA.
Joyce Wang, Sanofi, Chengdu, China.
Annie Purvis, Sanofi, Waltham, MA, USA.
Martin Sanchez Ruiz, Sanofi, Paris, France.
Haritha Adhikarla, Sanofi, Swiftwater, PA, USA.
Saad Alvi, Chicago Clinical Research Institute, IL, USA.
Matthew I. Bonaparte, Sanofi, Swiftwater, PA, USA.
Daniel Brune, Optimal Research, Peoria, IL, USA.
Agustin Bueso, Demedica, San Pedro Sula, Honduras.
Richard M. Canter, Sanofi, Swiftwater, PA, USA.
Maria Angeles Ceregido, GSK, Wavre, Belgium.
Sachin Deshmukh, Griffith University, Australia.
David Diemert, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA.
Adam Finn, Bristol Vaccine Centre, Schools of Population Health Sciences and of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
Remi Forrat, Sanofi, Marcy l'Etoile, France.
Bo Fu, Sanofi, Swiftwater, PA, USA.
Julie Gallais, Sanofi, Marcy l'Etoile, France.
Paul Griffin, Mater Health, Brisbane, Queensland, Australia.
Marie-Helene Grillet, Sanofi, Lyon, France.
Owen Haney, Sanofi, Swiftwater, PA, USA.
Jeffrey A. Henderson, Black Hills Center for American Indian Health, SD, USA.
Marguerite Koutsoukos, GSK, Wavre, Belgium.
Odile Launay, Université Paris Cité; Inserm, F-CRIN I REIVAC, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France.
Federico Martinon Torres, Pediatrics Department, Translational Pediatrics and Infectious Diseases Section, Santiago de Compostela, Spain.
Roger Masotti, Sanofi, Swiftwater, PA, USA.
Nelson L. Michael, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Juliana Park, Sanofi, Sydney, Australia.
Doris Maribel Rivera-Medina, INVERIME S.A, Tegucigalpa, Honduras.
Natalya Romanyak, Sanofi, Swiftwater, PA, USA.
Chris Rook, Cmax, Adelaide, Australia.
Lode Schuerman, GSK, Wavre, Belgium.
Lawrence D. Sher, Peninsula Research Associates, Rolling Hills Estates, CA, USA.

Document Type

Journal Article

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AS03 adjuvant; B.1.351; Beta; Booster; COVID-19; CoV2 preS dTM-AS03; Immunogenicity; Omicron; Recombinant protein vaccine; SARS-CoV-2; Safety


BACKGROUND: In a parallel-group, international, phase 3 study (ClinicalTrials.govNCT04762680), we evaluated prototype (D614) and Beta (B.1.351) variant recombinant spike protein booster vaccines with AS03-adjuvant (CoV2 preS dTM-AS03). METHODS: Adults, previously primed with mRNA (BNT162b2, mRNA-1273), adenovirus-vectored (Ad26.CoV2.S, ChAdOx1nCoV-19) or protein (CoV2 preS dTM-AS03 [monovalent D614; MV(D614)]) vaccines were enrolled between 29 July 2021 and 22 February 2022. Participants were stratified by age (18-55 and ≥ 56 years) and received one of the following CoV2 preS dTM-AS03 booster formulations: MV(D614) (n = 1285), MV(B.1.351) (n = 707) or bivalent D614 + B.1.351 (BiV; n = 625). Unvaccinated adults who tested negative on a SARS-CoV-2 rapid diagnostic test (control group, n = 479) received two primary doses, 21 days apart, of MV(D614). Anti-D614G and anti-B.1.351 antibodies were evaluated using validated pseudovirus (lentivirus) neutralization (PsVN) assay 14 days post-booster (day [D]15) in 18-55-year-old BNT162b2-primed participants and compared with those pre-booster (D1) and on D36 in 18-55-year-old controls (primary immunogenicity endpoints). PsVN titers to Omicron BA.1, BA.2 and BA.4/5 subvariants were also evaluated. Safety was evaluated over a 12-month follow-up period. Planned interim analyses are presented up to 14 days post-last vaccination for immunogenicity and over a median duration of 5 months for safety. FINDINGS: All three boosters elicited robust anti-D614G or -B.1.351 PsVN responses for mRNA, adenovirus-vectored and protein vaccine-primed groups. Among BNT162b2-primed adults (18-55 years), geometric means of the individual post-booster versus pre-booster titer ratio (95% confidence interval [CI]) were: for MV (D614), 23.37 (18.58-29.38) (anti-D614G); for MV(B.1.351), 35.41 (26.71-46.95) (anti-B.1.351); and for BiV, 14.39 (11.39-18.28) (anti-D614G) and 34.18 (25.84-45.22 (anti-B.1.351). GMT ratios (98.3% CI) versus post-primary vaccination GMTs in controls, were: for MV(D614) booster, 2.16 (1.69; 2.75) [anti-D614G]; for MV(B.1.351), 1.96 (1.54; 2.50) [anti-B.1.351]; and for BiV, 2.34 (1.84; 2.96) [anti-D614G] and 1.39 (1.09; 1.77) [anti-B.1.351]. All booster formulations elicited cross-neutralizing antibodies against Omicron BA.2 (across priming vaccine subgroups), Omicron BA.1 (BNT162b2-primed participants) and Omicron BA.4/5 (BNT162b2-primed participants and MV D614-primed participants). Similar patterns in antibody responses were observed for participants aged ≥56 years. Reactogenicity tended to be transient and mild-to-moderate severity in all booster groups. No safety concerns were identified. INTERPRETATION: CoV2 preS dTM-AS03 boosters demonstrated acceptable safety and elicited robust neutralizing antibodies against multiple variants, regardless of priming vaccine. FUNDING: Sanofi and Biomedical Advanced Research and Development Authority (BARDA).