| Abstract | The global dissemination of SARS-CoV-2 led to a worldwide pandemic in March 2020. Even after the official downgrading of the COVID-19 pandemic, infection with SARS-CoV-2 variants continues. The rapid development and deployment of SARS-CoV-2 vaccines helped to mitigate the pandemic to a great extent. However, the current vaccines are suboptimal; they elicit incomplete and short-lived protection and are ineffective against evolving virus variants. Updating the spike antigen according to the prevailing variant and repeated boosters is not the long-term solution. We have designed a lipopeptide-based, mucosal, pan-coronavirus vaccine candidate, derived from highly conserved and/or functional regions of the SARS-CoV-2 spike, nucleocapsid, and membrane proteins. Our studies demonstrate that the designed lipopeptides (LPMix) induced both cellular and humoral (mucosal and systemic) immune responses upon intranasal immunization in mice. Furthermore, the antibodies bound to the wild-type and mutated S proteins of SARS-CoV-2 variants of concern, including Alpha, Beta, Delta and Omicron, and also led to efficient neutralization in a surrogate viral neutralization assay. Our sequence alignment and 3-dimensional molecular modeling studies demonstrated that spike-derived epitopes, P1 and P2, are sequentially and/or structurally conserved among the SARS-CoV-2 variants. The addition of a novel mucosal adjuvant, heat-killed Caulobacter crescentus, to the lipopeptide vaccine significantly bolstered mucosal antibody responses. Finally, the lipopeptide-based intranasal vaccine demonstrated significant improvement in lung pathologies in a hamster model of SARS-CoV-2 infection. These studies are fundamentally important and open new avenues in the investigation of an innovative, broadly protective intranasal vaccine platform for SARS-CoV-2 and its variants. |
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