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 (preprint)

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) (5g, 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-naive adults (controls, n=479) received a primary series (two injections, 21 days apart) of CoV2 preS dTM-AS03 containing 10g 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

Safety and immunogenicity of a SARS-CoV-2 recombinant protein vaccine with AS03 adjuvant in healthy adults: interim findings from a phase 2, randomised, dose-finding, multi-centre study (preprint)

Background This study evaluated the safety and immunogenicity of an AS03-adjuvanted SARS-CoV-2 recombinant protein candidate vaccine, CoV2 preS dTM. Methods This Phase 2, modified double-blind, parallel-group study (NCT04762680) was conducted in adults, including those at increased risk of severe COVID-19. Participants were randomised 1:1:1, stratified by age (18-59/[≥]60 years), rapid serodiagnostic test (positive/negative) and high-risk medical conditions (yes/no), to receive two injections (day [D]1 and D22) of 5{micro}g, 10{micro}g or 15{micro}g of CoV2 preS dTM antigen with fixed AS03 content. Interim safety and reactogenicity results (to D43) and neutralising antibodies (Nabs) against the D614G variant are presented (primary objectives). Findings Of 722 participants enrolled and randomised between 24 February and 8 March 2021, 721 received [≥]1 injections (5{micro}g, n=240; 10{micro}g, n=239; 15{micro}g, n=242). Four participants reported unsolicited immediate adverse events (AEs), two were vaccine-related (investigator assessment). Five participants reported seven vaccine-related medically-attended AEs. No vaccine-related serious AEs and no AEs of special interest were reported. Solicited reactions (local and systemic) were reported at similar frequencies between study groups; these were mostly mild to moderate and transient, with higher frequency and intensity post-injection 2 than post-injection 1. In SARS-CoV-2 na ive participants at D36, 96'9%, 97.0% and 97'6% of participants had [≥]4-fold-rise in NAb titres from baseline in the 5{micro}g-, 10{micro}g- and 15{micro}g-dose groups, respectively. NAb titres increased with antigen dose in younger (GMTs: 2954, 3951 and 5142 for 5{micro}g-, 10{micro}g- and 15{micro}g-dose groups) but not older adults (GMTs: 1628, 1393 and 1736, respectively). NAb titres in non-na ive adults after one injection were higher than titres after two injections in na ive adults. Interpretation Two injections of CoV2 preS dTM-AS03 demonstrated acceptable safety and reactogenicity, and robust immunogenicity in SARS-CoV-2 na ive and non-na ive adults. These results informed antigen dose selection for progression to Phase 3 evaluation of primary and booster vaccination.

Safety and immunogenicity of SARS-CoV-2 recombinant protein vaccine formulations in healthy adults: a randomised, placebo-controlled, dose-ranging study (preprint)

BackgroundEffective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgently needed. CoV2 preS dTM is a stabilised pre-fusion S protein vaccine produced in a baculovirus expression system. We present interim safety and immunogenicity results of the first-in-human study of the CoV2 preS dTM vaccine with two different adjuvant formulations. MethodsThis Phase I/II, randomised, double-blind study (NCT04537208) is being conducted in healthy, SARS-CoV-2-seronegative adults in the USA. Participants were stratified by age (18-49 and [≥]50 years) and randomised to receive one (on Day[D]1) or two doses (D1, D22) of placebo or candidate vaccine, containing: low-dose (LD, effective dose 1.3 {micro}g) or high-dose (HD, 2.6 {micro}g) antigen with adjuvant AF03 (Sanofi Pasteur) or AS03 (GlaxoSmithKline); or unadjuvanted HD (18-49 years only). Safety was assessed up to D43. SARS-CoV-2 neutralising and binding antibody profiles were assessed in D1, D22 and D36 serum samples. FindingsThe interim safety analyses included 439/441 randomised participants. There were no related unsolicited immediate AEs, serious AEs, medically attended AEs classified as severe, or AE of special interest. More grade 3 solicited reactions were reported than expected after the second dose in the adjuvanted vaccine groups. Neutralising and binding antibody responses after two vaccine doses were higher in adjuvanted versus unadjuvanted groups, in AS03-versus AF03-adjuvanted groups, in HD versus LD groups, and in younger versus older age strata. InterpretationThe lower than expected immune responses, especially in the older age stratum, and the higher than anticipated reactogenicity post dose 2 were likely due to a higher than anticipated host cell protein content and lower than planned antigen dose in the clinical material. Further development of the AS03-adjuvanted candidate vaccine will focus on identifying the optimal antigen formulation and dose.