Safety and immunogenicity of an AS03-adjuvanted SARS-CoV-2 recombinant protein vaccine (CoV2 preS dTM) in healthy adults: interim findings from a phase 2, randomised, dose-finding, multicentre study

Abstract

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. ...

Safety and immunogenicity of a SARS-CoV-2 recombinant protein nanoparticle vaccine (GBP510) adjuvanted with AS03: a phase 1/2, randomized, placebo-controlled, observer-blinded trial

“…20 In addition, an increased reactogenicity post-dose as compared to post-dose 1 was observed with other AS03-containing COVID-19 vaccines. 21,22 The limitations of this study include the small sample size, especially for older adults, and short follow-up period. Nevertheless, the sample size provides a meaningful initial assessment of the frequency and intensity of the solicited AEs.…”

“…20 In addition, an increased reactogenicity post-dose 2 as compared to post-dose 1 was observed with other AS03-containing COVID-19 vaccines. 21,22…”

Homologous or heterogenous vaccination boosters enhance neutralizing activities against SARS‐CoV‐2 Omicron BA.1 variant

“…A number of other recombinant protein vaccines are undergoing clinical trials with promising results. 35 , 36 , 37 However, to move ahead of the COVID‐19 pandemic may require the development of a pan‐coronavirus vaccine. 38 , 39 …”

“…The data we present in this study regarding the neutralizing efficacy of a recombinant RBD protein vaccine against the Omicron variant are indeed promising. A number of other recombinant protein vaccines are undergoing clinical trials with promising results 35–37 . However, to move ahead of the COVID‐19 pandemic may require the development of a pan‐coronavirus vaccine 38,39 …”

“…A number of other recombinant protein vaccines are undergoing clinical trials with promising results. [35][36][37] However, to move ahead of the COVID-19 pandemic may require the development of a pan-coronavirus vaccine. 38,39 Nevertheless, our findings add to an emerging clinical picture that while the efficacy of neutralizing antibodies is impaired against the Omicron BA.1 variant, the severity of the disease caused by the Omicron BA.1 variant is less compared with the Delta variant.…”