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; Joyce Wang; Annie  Purvis; Martin  Sanchez Ruiz; Haritha  Adhikarla; Saad Alvi; Matthew I Bonaparte; Daniel  Brune; Agustin  Bueso; Richard M Canter; Maria Angeles Ceregido; Sachin  Deschmukh; David Diemert; Adam H R Finn; Remi Forrat; Bo  Fu; Julie Gallais; Paul  Griffin; marie-Helene Grillet; Owen Haney; Jeffery A Henderson; Marguerite Koutsoukos; Odile Launay; Federico Martinon Torres; Roger  Masotti; Nelson L Michael; Juliana Park; Doris Maribel Rivera-Medina; Natalya Romanayak; Chris Rook; Lode Schuerman; Lawrence D Sher; Fernanda Tavares-Da-Silva; Ashley Whittington; Roman M Chicz; Sanjay Gurunathan; Stephen Savarino; Saranya  Sridhar

doi:10.1016/j.eclinm.2023.102109

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^*, Joyce Wang, Annie Purvis, Martin Sanchez Ruiz, Haritha Adhikarla, Saad Alvi, Matthew I Bonaparte, Daniel Brune, Agustin Bueso, Richard M Canter, Maria Angeles Ceregido, Sachin Deschmukh, David Diemert, Adam H R Finn, Remi Forrat, Bo Fu, Julie Gallais, Paul Griffin, marie-Helene Grillet, Owen HaneyJeffery A Henderson, Marguerite Koutsoukos, Odile Launay, Federico Martinon Torres, Roger Masotti, Nelson L Michael, Juliana Park, Doris Maribel Rivera-Medina, Natalya Romanayak, Chris Rook, Lode Schuerman, Lawrence D Sher, Fernanda Tavares-Da-Silva, Ashley Whittington, Roman M Chicz, Sanjay Gurunathan, Stephen Savarino, Saranya Sridhar

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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Abstract

Background
In a parallel-group, international, phase 3 study (ClinicalTrials.gov NCT04762680), 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).

Original language	English
Article number	102109
Journal	EClinicalMedicine
Volume	62
Issue number	102109
DOIs	https://doi.org/10.1016/j.eclinm.2023.102109
Publication status	Published - 21 Jul 2023

Bibliographical note

Funding Information:
Sanofi and Biomedical Advanced Research and Development Authority (BARDA).The authors thank all participants, investigators, and study site personnel who took part in this study. The authors acknowledge Juliette Gray of inScience Communications, Springer Healthcare Ltd, London, UK, for providing editorial assistance with the preparation of this manuscript, funded by Sanofi. The authors also thank Hanson Geevarghese for providing manuscript coordination on behalf of Sanofi. This work was done in collaboration with GSK, who provided access to, and use of, the AS03 Adjuvant System.

Publisher Copyright:
© 2023 The Author(s)

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de Bruyn, G., Wang, J., Purvis, A., Sanchez Ruiz, M., Adhikarla, H., Alvi, S., Bonaparte, M. I., Brune, D., Bueso, A., Canter, R. M., Ceregido, M. A., Deschmukh, S., Diemert, D., Finn, A. H. R., Forrat, R., Fu, B., Gallais, J., Griffin, P., Grillet, M.-H., ... Sridhar, S. (2023). 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. EClinicalMedicine, 62(102109), Article 102109. https://doi.org/10.1016/j.eclinm.2023.102109

@article{3e876864a33e4e5c9b16db743f3bc4ed,

title = "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",

abstract = "BackgroundIn a parallel-group, international, phase 3 study (ClinicalTrials.gov NCT04762680), we evaluated prototype (D614) and Beta (B.1.351) variant recombinant spike protein booster vaccines with AS03-adjuvant (CoV2 preS dTM-AS03).MethodsAdults, 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.FindingsAll 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.InterpretationCoV2 preS dTM-AS03 boosters demonstrated acceptable safety and elicited robust neutralizing antibodies against multiple variants, regardless of priming vaccine.FundingSanofi and Biomedical Advanced Research and Development Authority (BARDA).",

author = "{de Bruyn}, Guy and Joyce Wang and Annie Purvis and {Sanchez Ruiz}, Martin and Haritha Adhikarla and Saad Alvi and Bonaparte, {Matthew I} and Daniel Brune and Agustin Bueso and Canter, {Richard M} and Ceregido, {Maria Angeles} and Sachin Deschmukh and David Diemert and Finn, {Adam H R} and Remi Forrat and Bo Fu and Julie Gallais and Paul Griffin and marie-Helene Grillet and Owen Haney and Henderson, {Jeffery A} and Marguerite Koutsoukos and Odile Launay and {Martinon Torres}, Federico and Roger Masotti and Michael, {Nelson L} and Juliana Park and Rivera-Medina, {Doris Maribel} and Natalya Romanayak and Chris Rook and Lode Schuerman and Sher, {Lawrence D} and Fernanda Tavares-Da-Silva and Ashley Whittington and Chicz, {Roman M} and Sanjay Gurunathan and Stephen Savarino and Saranya Sridhar",

note = "Funding Information: Sanofi and Biomedical Advanced Research and Development Authority (BARDA).The authors thank all participants, investigators, and study site personnel who took part in this study. The authors acknowledge Juliette Gray of inScience Communications, Springer Healthcare Ltd, London, UK, for providing editorial assistance with the preparation of this manuscript, funded by Sanofi. The authors also thank Hanson Geevarghese for providing manuscript coordination on behalf of Sanofi. This work was done in collaboration with GSK, who provided access to, and use of, the AS03 Adjuvant System. Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = jul,

day = "21",

doi = "10.1016/j.eclinm.2023.102109",

language = "English",

volume = "62",

journal = "EClinicalMedicine",

issn = "2589-5370",

publisher = "Lancet Publishing Group",

number = "102109",

}

de Bruyn, G, Wang, J, Purvis, A, Sanchez Ruiz, M, Adhikarla, H, Alvi, S, Bonaparte, MI, Brune, D, Bueso, A, Canter, RM, Ceregido, MA, Deschmukh, S, Diemert, D, Finn, AHR, Forrat, R, Fu, B, Gallais, J, Griffin, P, Grillet, M-H, Haney, O, Henderson, JA, Koutsoukos, M, Launay, O, Martinon Torres, F, Masotti, R, Michael, NL, Park, J, Rivera-Medina, DM, Romanayak, N, Rook, C, Schuerman, L, Sher, LD, Tavares-Da-Silva, F, Whittington, A, Chicz, RM, Gurunathan, S, Savarino, S & Sridhar, S 2023, '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', EClinicalMedicine, vol. 62, no. 102109, 102109. https://doi.org/10.1016/j.eclinm.2023.102109

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. / de Bruyn, Guy ; Wang, Joyce; Purvis, Annie et al.
In: EClinicalMedicine, Vol. 62, No. 102109, 102109, 21.07.2023.

Research output: Contribution to journal › Article (Academic Journal) › peer-review

TY - JOUR

T1 - 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

AU - de Bruyn, Guy

AU - Wang, Joyce

AU - Purvis, Annie

AU - Sanchez Ruiz, Martin

AU - Adhikarla, Haritha

AU - Alvi, Saad

AU - Bonaparte, Matthew I

AU - Brune, Daniel

AU - Bueso, Agustin

AU - Canter, Richard M

AU - Ceregido, Maria Angeles

AU - Deschmukh, Sachin

AU - Diemert, David

AU - Finn, Adam H R

AU - Forrat, Remi

AU - Fu, Bo

AU - Gallais, Julie

AU - Griffin, Paul

AU - Grillet, marie-Helene

AU - Haney, Owen

AU - Henderson, Jeffery A

AU - Koutsoukos, Marguerite

AU - Launay, Odile

AU - Martinon Torres, Federico

AU - Masotti, Roger

AU - Michael, Nelson L

AU - Park, Juliana

AU - Rivera-Medina, Doris Maribel

AU - Romanayak, Natalya

AU - Rook, Chris

AU - Schuerman, Lode

AU - Sher, Lawrence D

AU - Tavares-Da-Silva, Fernanda

AU - Whittington, Ashley

AU - Chicz, Roman M

AU - Gurunathan, Sanjay

AU - Savarino, Stephen

AU - Sridhar, Saranya

N1 - Funding Information: Sanofi and Biomedical Advanced Research and Development Authority (BARDA).The authors thank all participants, investigators, and study site personnel who took part in this study. The authors acknowledge Juliette Gray of inScience Communications, Springer Healthcare Ltd, London, UK, for providing editorial assistance with the preparation of this manuscript, funded by Sanofi. The authors also thank Hanson Geevarghese for providing manuscript coordination on behalf of Sanofi. This work was done in collaboration with GSK, who provided access to, and use of, the AS03 Adjuvant System. Publisher Copyright: © 2023 The Author(s)

PY - 2023/7/21

Y1 - 2023/7/21

N2 - BackgroundIn a parallel-group, international, phase 3 study (ClinicalTrials.gov NCT04762680), we evaluated prototype (D614) and Beta (B.1.351) variant recombinant spike protein booster vaccines with AS03-adjuvant (CoV2 preS dTM-AS03).MethodsAdults, 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.FindingsAll 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.InterpretationCoV2 preS dTM-AS03 boosters demonstrated acceptable safety and elicited robust neutralizing antibodies against multiple variants, regardless of priming vaccine.FundingSanofi and Biomedical Advanced Research and Development Authority (BARDA).

AB - BackgroundIn a parallel-group, international, phase 3 study (ClinicalTrials.gov NCT04762680), we evaluated prototype (D614) and Beta (B.1.351) variant recombinant spike protein booster vaccines with AS03-adjuvant (CoV2 preS dTM-AS03).MethodsAdults, 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.FindingsAll 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.InterpretationCoV2 preS dTM-AS03 boosters demonstrated acceptable safety and elicited robust neutralizing antibodies against multiple variants, regardless of priming vaccine.FundingSanofi and Biomedical Advanced Research and Development Authority (BARDA).

U2 - 10.1016/j.eclinm.2023.102109

DO - 10.1016/j.eclinm.2023.102109

M3 - Article (Academic Journal)

C2 - 37533419

SN - 2589-5370

VL - 62

JO - EClinicalMedicine

JF - EClinicalMedicine

IS - 102109

M1 - 102109

ER -

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

Abstract

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