A potential broad-spectrum live-attenuated SARS-CoV-2 vaccine derived from pangolin coronavirus and insights into the immune evasion mechanisms of XBB.1.16 variant

Abstract Harnessing SARS-CoV-2 related viruses from wild animals for live vaccines is an underexplored but promising approach, akin to the vaccinia virus used against smallpox. This study evaluated the potential of a live-attenuated vaccine derived from the pangolin coronavirus GX_P2V. We observed that the attenuated mutant, GX_P2V(short_3UTR), conferred significant and long-lasting protection against SARS-CoV-2 in golden hamsters, particularly after two doses. Furthermore, we show that sera from vaccinated convalescents of SARS-CoV-2 variant XBB.1.16 exhibited high titers of neutralizing antibody against GX_P2V(short_3UTR), suggesting GX_P2V(short_3UTR) shares neutralizing epitopes with XBB.1.16. We also show that the same sera from convalescents of XBB.1.16 displayed significantly reduced titers against the XBB.1.16 variant itself, suggesting a decoy-like immune evasion strategy that high-level cross-neutralizing antibodies induced by highly immunogenic epitopes of XBB.1.16 may not be able to efficiently neutralize the virus itself. Our findings emphasize GX_P2V(short_3UTR)'s potential as a broad-spectrum SARS-CoV-2 live vaccine and shed light on novel immune evasion mechanisms of the XBB.1.16 variant.