Efficacy of a bivalent (D614 + B.1.351) SARS-CoV-2 Protein Vaccine

Background COVID-19 vaccines with alternative strain compositions are needed to provide broad protection against newly emergent SARS-CoV-2 variants of concern. Methods We conducted a global Phase 3, multi-stage efficacy study (NCT04904549) among adults aged [≥]18 years. Participants were randomized 1:1 to receive two intramuscular injections 21 days apart of a bivalent SARS-CoV-2 recombinant protein vaccine with AS03-adjuvant (5 g of ancestral (D614) and 5 g of B.1.351 [beta] variant spike protein) or placebo. Symptomatic COVID-19 was defined as laboratory-confirmed COVID-19 with COVID-19-like illness (CLI) symptoms. The primary efficacy endpoint was the prevention of symptomatic COVID-19 [≥]14 days after the second injection. Results Between 19 Oct 2021 and 15 Feb 2022, 12,924 participants received [≥]1 study injection. 75% of participants were SARS-CoV-2 non-naive. 11,416 participants received both study injections (efficacy-evaluable population [vaccine, n=5,736; placebo, n=5,680]). Up to 15 March 2022, 121 symptomatic COVID-19 cases were reported (32 in the vaccine group and 89 in the placebo group) [≥]14 days after the second injection with a vaccine efficacy (VE) of 64.7% (95% confidence interval [CI] 46.6; 77.2%). VE was 75.1% (95% CI 56.3; 86.6%) in non-naive and 30.9% (95% CI -39.3; 66.7%) in naive participants. Viral genome sequencing identified the infecting strain in 68 cases (Omicron [BA.1 and BA.2 subvariants]: 63; Delta: 4; Omicron and Delta: 1). The vaccine was well-tolerated and had an acceptable safety profile. Conclusions A bivalent vaccine conferred heterologous protection against symptomatic infection with newly emergent Omicron (BA.1 and BA.2) in non-naive adults 18-59 years of age. ClinicalTrials.gov: NCT04904549

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

BackgroundBooster 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). MethodsAdults, 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 (5g, n=1285), MV (B.1351) (5g, n=707) or bivalent (BiV) (2.5g D614 plus 2.5g 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. ResultsAmong 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. ConclusionCoV2 preS dTM-AS03 boosters demonstrated acceptable safety and elicited robust neutralizing antibodies against multiple variants, regardless of priming vaccine. ClinicalTrials.govNCT04762680 FundingSanofi 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.

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

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.