A phase I, needle free, dose escalation clinical trial of pEVAC-PS, a candidate pan-Sarbecovirus Vaccine

Abstract

Background: Coronaviruses such as SARS, SARS-CoV-2 and related Sarbeco-Coronaviruses continue to pose global health threats, underscoring the need for vaccines capable of inducing broad cross-sarbecovirus protection. The pEVAC-PS vaccine was developed using Digitally Immune Optimised Synthetic Vaccine (DIOSynVax) technology and pre-clinically selected for the ability to induce broadly protective immune responses across the Sarbecoviruses including SARS, SARS-CoV-2, and related viruses representing potential zoonotic spillovers. For this first-in-human study, the antigen was delivered as a DNA vaccine to enable thermostability and needle-free intradermal administration to support future deployment in resource-limited settings. Methods: This open label phase I dose escalation study investigated the safety, tolerability and immunogenicity of the pEVAC-PS vaccine candidate against SARS, SARS-CoV-2 and related Sarbeco Coronaviruses via needle-free intra-dermal delivery using the PharmaJet Tropis Device. Healthy volunteers aged 18 to 50 who had received two or three prior doses of COVID-19 vaccine, and without recent confirmed COVID-19 infection, were enrolled sequentially to receive a dose escalation regime of 0.2 mg, 0.4 mg, 0.8 mg, and 1.2 mg of pEVAC-PS, administered at day zero and day 28. The primary outcomes were safety and reactogenicity, documented by solicited and unsolicited adverse events, serious adverse events and adverse events of special interest. Secondary outcomes were immunogenicity measured primarily by humoral responses to SARS-CoV-1 and SARS-CoV-2 antigens at day 56 (28 days after the second dose of vaccine). International Clinical Trials Registry Platform registered, ISRCTN87813400. Findings: Between December 2021 and September 2023, a total of 39 volunteers were vaccinated. The vaccine was well tolerated at all four doses with no significant safety concerns elicited. Interpretation of immunogenicity outcomes was influenced by high baseline antibody levels and heterogeneous exposure histories due to ongoing waves of Omicron variant infections during recruitment, which differed across dose-escalation cohorts and introduced unavoidable immune bias. Interpretation: Needle-free intradermal delivery of this novel computationally designed PanSarbeco vaccine was safe and well tolerated. Although immunogenicity was modest in the context of substantial pre-existing immunity, participants developed measurable responses to conserved, vaccine-encoded sarbecovirus epitopes, supporting the feasibility of this antigen design strategy.