Development of SARS-CoV-2 as a viral vector: A novel intranasal bivalent vaccine for SARS-CoV-2 and RSV.

Negative-sense RNA viruses have been widely used as viral vectors for vaccine delivery. However, little is known about coronaviruses as vectors for delivering vaccines. Here, we have developed safe SARS-CoV-2 Omicron JN.1-based live attenuated vaccine candidates by combining a mutation (D130A) in the viral nsp16 protein, deletion of the furin cleavage site (dFCS) in the spike protein, deletion of accessory proteins, and/or modification of the transcription regulatory sequences (mTRS). Subsequently, using rJN.1, rJN.1-D130A-dFCS, and rJN.1-mTRS-D130A-dFCS as the backbones, we generated three recombinant viruses expressing a nonfunctional, soluble, and stabilized prefusion F protein of human respiratory syncytial virus (RSVF). Among them, rJN.1-D130A-dFCS-RSVF virus was sufficiently attenuated and highly immunogenic, providing complete protection against challenge with both JN.1 and RSV in hamsters. However, rJN.1-mTRS-D130A-dFCS-RSVF was poorly immunogenic. Collectively, we demonstrate that attenuated SARS-CoV-2 is an effective viral vector for delivering RSV vaccine, warranting further development as a novel intranasal bivalent vaccine for SARS-CoV-2 and RSV.