Low-sugar universal mRNA vaccine against coronavirus variants with deletion of glycosites in the S2 or stem of SARS-CoV-2 spike messenger RNA (mRNA)

Abstract

Since the outbreak of Severe Acute Respiratory Syndrome Virus-2 (SARS-CoV-2) in 2019, more than 15 million spike protein sequences have been identified, raising a new challenge for the development of a broadly protective vaccine against the various emerging variants. We found that the virus, like most other human viruses, depends on host-made glycans to shield the conserved epitopes on spike protein from immune response and demonstrated that deletion of the glycan shields exposed highly conserved epitopes and elicited broadly protective immune responses. In this study, we identified 17 conserved epitopes from 14 million spike protein sequences and 11 of the conserved epitopes are in the S2 domain, including the six most conserved epitopes in the stem region. We also demonstrated that deletion of the glycosites in the spike messenger RNA (mRNA) S2 domain or the stem region exposed the highly conserved epitopes and elicited broadly protective immune responses, particularly CD-8 + T cell response against various SARS-CoV-2 variants, and other human coronaviruses including MERS, SARS viruses, and those causing common cold.

A broadly generalizable stabilization strategy for sarbecovirus fusion machinery vaccines

“…The broadly generalizable prefusion-stabilization strategy described here provides a robust platform for elicitation of fusion machinery-directed antibody responses and the designed antigens will enable studies of such immune responses. Future engineering efforts may further improve the immunogenicity of this vaccine candidate through (i) multivalent display at the surface of a nanoparticle, as exemplified for the SKYcovione SARS-CoV-2 RBD vaccine 54 – 56 ; (ii) mRNA-launching of a membrane-anchored SARS-CoV-2 S 2 subunit vaccine, a vaccine platform which yielded multiple efficacious SARS-CoV-2 S 2P vaccines 1 ; or (iii) a recently proposed targeted deglycosylation approach of the SARS-CoV-2 S 2 subunit to enhance neutralizing antibody titers 57 .…”