Lei, Z.; Bian, S.; Zhai, S.; Yuan, X.; Wang, R.; Wang, P.; Pandey, V.; Zhang, C. Y.; Yu, D.; Chen, Z.; Qin, P.

The ongoing emergence of new strains of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants challenges available SARS-CoV-2 vaccines for adequate control of outbreaks. Currently, there is a lack of universal vaccines for SARS-CoV-2 variants that do not necessitate strain matching between mRNA vaccines and the viruses. In this study, a nucleoside-modified twenty-valent lipid nanoparticle mRNA vaccine was designed and manufactured. The primary objective is to provide protection against various recent variants via the twenty-valent mRNA vaccine after efficacy assessment. Furthermore, the protection efficiency of bivalent and quadrivalent mRNA vaccines was compared with the universal vaccine. The neutralizing antibody activity against BA.4/5, XBB.1.5, BQ.1.1, and EG.5.1 was evaluated using enzyme-linked immunosorbent assay, pseudovirus neutralization test, and a rapid fiber-optic biolayer interferometry-based biosensor. Our universal multivalent vaccine provided robust protection against both prevailing and emerging, previously unidentified SARS-CoV-2 strains.