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

Background Effective 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. Methods This 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 g) or high-dose (HD, 2.6 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. Findings The 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. Interpretation The 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. Funding: Sanofi Pasteur and Biomedical Advanced Research and Development Authority (BARDA)