| Summary: | Abstract Because of the rapid mutation and high airborne transmission of SARS‐CoV‐2, a universal vaccine preventing the infection in the upper respiratory tract is particularly urgent. Here, a mosaic receptor‐binding domain (RBD) nanoparticle (NP) vaccine is developed, which induces more RBD‐targeted type IV neutralizing antibodies (NAbs) and exhibits broad cross‐protective activity against multiple SARS‐CoV‐2 sublineages including the newly‐emerged BF.7, BQ.1, XBB. As several T‐cell‐reactive epitopes, which are highly conserved in sarbecoviruses, are displayed on the NP surface, it also provokes potent and cross‐reactive cellular immune responses in the respiratory tissue. Through intranasal delivery, it elicits robust mucosal immune responses and full protection without any adjuvants. Therefore, this intranasal mosaic NP vaccine can be further developed as a pan‐sarbecovirus vaccine to block the viral entrance from the upper respiratory tract.
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