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. 2023 Jul 22:62:102109.
doi: 10.1016/j.eclinm.2023.102109. eCollection 2023 Aug.

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  1 , Joyce Wang  2 , Annie Purvis  3 , Martin Sanchez Ruiz  4 , Haritha Adhikarla  1 , Saad Alvi  5 , Matthew I Bonaparte  1 , Daniel Brune  6 , Agustin Bueso  7 , Richard M Canter  1 , Maria Angeles Ceregido  8 , Sachin Deshmukh  9 , David Diemert  10 , Adam Finn  11 , Remi Forrat  12 , Bo Fu  1 , Julie Gallais  12 , Paul Griffin  13   14 , Marie-Helene Grillet  15 , Owen Haney  1 , Jeffrey A Henderson  16 , Marguerite Koutsoukos  8 , Odile Launay  17 , Federico Martinon Torres  18   19   20 , Roger Masotti  1 , Nelson L Michael  21 , Juliana Park  22 , Doris Maribel Rivera-Medina  23 , Natalya Romanyak  1 , Chris Rook  24 , Lode Schuerman  8 , Lawrence D Sher  25 , Fernanda Tavares-Da-Silva  8 , Ashley Whittington  26 , Roman M Chicz  3 , Sanjay Gurunathan  1 , Stephen Savarino  1 , Saranya Sridhar  27 ; VAT00002 booster cohorts study team
Collaborators, Affiliations

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 et al. EClinicalMedicine. .

Abstract

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).

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

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Conflict of interest statement

GdB, JW, AP, MSR, HA, MIB, RMCa, RF, BF, JG, M-HG, SG, OH, RM, JP, NR, RMCh and SSr are Sanofi employees. GdB, AP, MIB, BF, OH, NR, RMCh and SSr hold stock or stock options in Sanofi. SSa was a Sanofi employee at the time of study conduct and held shares and/or stock options in the company at the time of study conduct. GdB, SSr, RMCh, 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. FMT declares trial fees paid to their institution by Sanofi; honoraria received from GSK group of companies, Pfizer Inc., Sanofi, MSD, Moderna, Biofabri, AstraZeneca, Novavax, Janssen; meeting and/or travel fees received from Pfizer Inc, MSD, GSK and Sanofi; data safety monitoring board or advisory board participation for Pfizer and Biofabri; being a member of ETAGE–WHO Europe, coordinator of the Spanish Pediatric Critical Trials Network and coordinator of the WHO Collaborating Centre for Vaccines Safety of Santiago de Compostela; and payments made to their institution for their role as principal investigator in randomized controlled trials for Ablynx, Abbot, Seqirus, Sanofi, MSD, Merck, Pfizer, Roche, Regeneron, Janssen, Medimmune, Novavax, Novartis and GSK. DMRM declares that her institution received funding from Sanofi. 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. OL declares that their institution received funding for conducting the trial. NLM received travel support from Sanofi and chaired a Scientific Advisory Board for them, unrelated to current study. LDS received a research grant from Sanofi. SD, SA, DB, AB, DD, PG, JAH, CR and AW declare no conflicts of interest.

Figures

Fig. 1
Fig. 1
Study design. Footnote: ∗Naïve or non-naïve status (control group) was determined based on serological detection of anti-S antibodies on study day 1 and detection of SARS-CoV-2 nucleic acid in nasopharyngeal swabs on days 1 and 22. Participants were categorized as naïve if both tests showed negative results on day 1 and day 22. †Participants were primed with two injections of a monovalent CoV2 preS dTM-AS03 D614 formulation containing 5, 10 or 15 μg antigen as part of the original phase 2 study. ‡mRNA COVID19 priming vaccines: BNT162b2 or mRNA-1273; adenovirus-vectored COVID19-priming vaccine: ChAdOx1nCoV-19 or Ad26.CoV2.S. §Age groups: 18–55 years and ≥56 years mo, months; MV, monovalent.
Fig. 2
Fig. 2
Booster pseudovirus neutralizing antibody responses against D614G or B.1.351 strains for (A) monovalent D614 (B) monovalent B.1.351 and (C and D) bivalent D614 + B.1.351 among 18–55-year-olds, by prior priming vaccine – PPAS. Antibody levels were measured using a lentivirus-based pseudovirus neutralization assay. Graphs are annotated with geometric mean titers (above each bar) and geometric means of individual titer ratios (above grouped bars), calculated based on paired post-vaccination/pre-vaccination results. Error bars denote 95% CIs for the GMTs. ∗95% confidence not calculated due to small number of participants analyzed (n = 4). Table shows number of participants with available data for at each timepoint. D1, study day 1 (pre-booster); D15, study day 15 (14 days post-booster); BNT, BNT162b2-primed; Mod, mRNA-1273-primed; ChAd, ChAdOx1nCoV-19-primed; Ad26, Ad26.CoV2.S-primed; MVD614, CoV2 preS dTM-AS03 monovalent (D614)-primed.
Fig. 3
Fig. 3
Cross-neutralizing titers elicited by monovalent and bivalent CoV2 preS dTM-AS03 formulations against Omicron subvariants (A) BA.2 (B) BA.1 and (C) BA.4/5, by age category. BiV, bivalent; MV, monovalent. Antibody levels were measured using a lentivirus-based pseudovirus neutralization assay. Graphs are annotated with geometric mean titers (above each bar) and geometric means of individual titer ratios (above grouped bars), calculated based on paired post-vaccination/pre-vaccination results. Error bars denote 95% CIs for the GMTs, calculated using normal approximation of log-transformed titers. Tables show number of participants with available data at each timepoint. ∗Assessed on available samples across all vaccine priming vaccine subgroups; †Assessed on available samples in BNT162b2-primed subgroups; ‡Assessed on available samples in BNT162b2-primed subgroups and in CoV2 preS dTM-AS03 primed subgroups.
Fig. 3
Fig. 3
Cross-neutralizing titers elicited by monovalent and bivalent CoV2 preS dTM-AS03 formulations against Omicron subvariants (A) BA.2 (B) BA.1 and (C) BA.4/5, by age category. BiV, bivalent; MV, monovalent. Antibody levels were measured using a lentivirus-based pseudovirus neutralization assay. Graphs are annotated with geometric mean titers (above each bar) and geometric means of individual titer ratios (above grouped bars), calculated based on paired post-vaccination/pre-vaccination results. Error bars denote 95% CIs for the GMTs, calculated using normal approximation of log-transformed titers. Tables show number of participants with available data at each timepoint. ∗Assessed on available samples across all vaccine priming vaccine subgroups; †Assessed on available samples in BNT162b2-primed subgroups; ‡Assessed on available samples in BNT162b2-primed subgroups and in CoV2 preS dTM-AS03 primed subgroups.
Fig. 4
Fig. 4
Solicited injection site reactions up to 7 days following vaccination in CoV2 preS dTM-AS03 booster groups and the control group, by age category – SafAS. The percentages of participants experiencing at least one of the specified reactions are shown. Error bars denote 95% CIs for the percentages after any injection, calculated using the Clopper-Pearson method. MV, monovalent; BiV, bivalent.
Fig. 5
Fig. 5
Solicited systemic reactions up to 7 days following vaccination in CoV2 preS dTM-AS03 booster groups and the control group, by age category – SafAS. The percentages of participants experiencing at least one of the specified reactions are shown. Error bars denote 95% CIs for the percentages after any injection, calculated using the Clopper-Pearson method. MV, monovalent; BiV, bivalent.
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