Gene delivery of a single,structurally engineered Coronavirus vaccine antigen elicits SARS-CoV-2 Omicron and pan-Sarbecovirus neutralisation

Of the coronaviruses that have caused zoonotic spill overs in past two decades, the diverse group of beta-coronaviruses (β-CoVs) represent the greatest threats. Towards achieving broad vaccine protection from these viruses, vaccines composed of multiple antigens, each capable of eliciting broad neutralising responses across a subgroup will be required. Utilising a novel platform for selecting immune optimized, structurally engineered antigens capable of eliciting protective responses across a group of related viruses, we demonstrate proof-concept against the greater sarbecoviruses sub-genus with a single antigen structure. From an array of phylogenetically informed antigen structures displaying different broad neutralising epitopes, synthetic genes expressing these were selected based on broad immune responses in BALB/C mice. Improved protection against the Delta variant was further observed in K18-hACE2 mice on boosting with the lead designs of mice primed by an approved COVID-19 vaccine. Immunogenicity of the lead vaccine antigen and breadth of neutralisation against the SARS-CoV, SARS-CoV-2, WIV16, and RaTG13 was confirmed in guinea pigs using needleless intradermal immunisation. Immunogenicity was further confirmed in rabbits with GMP manufactured DNA immunogen. Notably, given the increasing number of mutations acquired by SARS-CoV-2 variants of concern (VOCs), the rabbit sera were tested for the capacity to neutralise VOCs - Beta, Gamma, Delta, as well as the most diverse Omicron variant. The consistent neutralising ability of the vaccine sera against the emerging VOCs validate broad specificity of the vaccine design. Here, we demonstrate proof-of-concept of this Digitally Immune Optimised, Selected vaccine (DIOSvax) antigen pipeline for the in vivo selection of single nucleic acid-based immunogens. Such gene-based antigens can be readily delivered alone or in combination, and seamlessly scaled with vaccine delivery modalities such as viral vector or mRNA-based vaccines.