Background CoV2 preS dTM is a stabilised pre-fusion spike protein vaccine produced in a baculovirus expression system being developed against SARS-CoV-2. 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 1–2, randomised, double-blind study is being done in healthy, SARS-CoV-2-seronegative adults in ten clinical research centres in the USA. Participants were stratified by age (18–49 years and ≥50 years) and randomly assigned using an interactive response technology system with block randomisation (blocks of varying size) to receive one dose (on day 1) or two doses (on days 1 and 22) of placebo or candidate vaccine, containing low-dose (effective dose 1·3 μg) or high-dose (2·6 μg) antigen with adjuvant AF03 (Sanofi Pasteur) or AS03 (GlaxoSmithKline) or unadjuvanted high-dose antigen (18–49 years only). Primary endpoints were safety, assessed up to day 43, and immunogenicity, measured as SARS-C0V-2 neutralising antibodies (geometric mean titres), assessed on days 1, 22, and 36 serum samples. Safety was assessed according to treatment received in the safety analysis set, which included all randomly assigned participants who received at least one dose. Neutralising antibody titres were assessed in the per-protocol analysis set for immunogenicity, which included participants who received at least one dose, met all inclusion and exclusion criteria, had no protocol deviation, had negative results in the neutralisation test at baseline, and had at least one valid post-dose serology sample. This planned interim analysis reports data up to 43 days after the first vaccination; participants in the trial will be followed up for 12 months after the last study injection. This trial is registered with ClinicalTrials.gov , NCT04537208 , and is ongoing. Findings Between Sept 3 and Sept 29, 2020, 441 individuals (299 aged 18–49 years and 142 aged ≥50 years) were randomly assigned to one of the 11 treatment groups. The interim safety analyses included 439 (>99%) of 441 randomly assigned participants (299 aged 18–49 years and 140 aged ≥50 years). Neutralising antibody titres were analysed in 326 (74%) of 441 participants (235 [79%] of 299 aged 18–49 years and 91 [64%] of 142 aged ≥50 years). There were no vaccine-related unsolicited immediate adverse events, serious adverse events, medically attended adverse events classified as severe, or adverse events of special interest. Among all study participants, solicited local and systemic reactions of any grade after two vaccine doses were reported in 81% (95% CI 61–93; 21 of 26) of participants in the low-dose plus AF03 group, 93% (84–97; 74 of 80) in the low-dose plus AS03 group, 89% (70–98; 23 of 26) in the high-dose plus AF03 group, 95% (88–99; 81 of 85) in the high-dose plus AS03 group, 29% (10–56; five of 17) in the unadjuvanted high-dos...

Background We evaluated our SARS-CoV-2 prefusion spike recombinant protein vaccine (CoV2 preS dTM) with different adjuvants, unadjuvanted, and in a one-injection and two-injection dosing schedule in a previous phase 1–2 study. Based on interim results from that study, we selected a two-injection schedule and the AS03 adjuvant for further clinical development. However, lower than expected antibody responses, particularly in older adults, and higher than expected reactogenicity after the second vaccination were observed. In the current study, we evaluated the safety and immunogenicity of an optimised formulation of CoV2 preS dTM adjuvanted with AS03 to inform progression to phase 3 clinical trial. Methods This phase 2, randomised, parallel-group, dose-ranging study was done in adults (≥18 years old), including those with pre-existing medical conditions, those who were immunocompromised (except those with recent organ transplant or chemotherapy) and those with a potentially increased risk for severe COVID-19, at 20 clinical research centres in the USA and Honduras. Women who were pregnant or lactating or, for those of childbearing potential, not using an effective method of contraception or abstinence, and those who had received a COVID-19 vaccine, were excluded. Participants were randomly assigned (1:1:1) using an interactive response technology system, with stratification by age (18–59 years and ≥60 years), rapid serodiagnostic test result (positive or negative), and high-risk medical conditions (yes or no), to receive two injections (day 1 and day 22) of 5 7mu;g (low dose), 10 7mu;g (medium dose), or 15 7mu;g (high dose) CoV2 preS dTM antigen with fixed AS03 content. All participants and outcome assessors were masked to group assignment; unmasked study staff involved in vaccine preparation were not involved in safety outcome assessments. All laboratory staff performing the assays were masked to treatment. The primary safety objective was to describe the safety profile in all participants, for each candidate vaccine formulation. Safety endpoints were evaluated for all randomised participants who received at least one dose of the study vaccine (safety analysis set), and are presented here for the interim study period (up to day 43). The primary immunogenicity objective was to describe the neutralising antibody titres to the D614G variant 14 days after the second vaccination (day 36) in participants who were SARS-CoV-2 naive who received both injections, provided samples at day 1 and day 36, did not have protocol deviations, and did not receive an authorised COVID-19 vaccine before day 36. Neutralising antibodies were measured using a pseudovirus neutralisation assay and are presented here up to 14 days after the second dose. As a secondary immunogenicity objective, we assessed neutralising antibodies in non-naive participants. This trial is registered with ClinicalTrials.gov (NCT04762680) and is closed to new participants for the cohort reported here. ...

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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 µg) or high-dose (HD, 2.6 µg) 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.

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