Strategy to develop broadly effective multivalent COVID-19 vaccines against emerging variants based on Ad5/35 platform

The severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) Omicron strain has evolved into highly divergent variants with several sub- lineages. These newly emerging variants threaten the efficacy of available COVID-19 vaccines. To mitigate the occurrence of breakthrough infections and re- infections, and more importantly, to reduce the disease burden, it is essential to develop a strategy for producing updated multivalent vaccines that can provide broad neutralization against both currently circulating and emerging variants. We developed bivalent vaccine AdCLD- CoV19-1 BA.5/BA.2.75 and trivalent vaccines AdCLD- CoV19-1 XBB/BN.1/BQ.1.1 and AdCLD- CoV19-1 XBB.1.5/BN.1/BQ.1.1 using an Ad5/35 platform - based non- replicating recombinant adenoviral vector. We compared immune responses elicited by the monovalent and multivalent vaccines in mice and macaques. We found that the BA.5/BA.2.75 bivalent and the XBB/BN.1/BQ.1.1 and XBB.1.5/BN.1/BQ.1.1 trivalent vaccines exhibited improved cross- neutralization ability compared to their respective monovalent vaccines. These data suggest that the developed multivalent vaccines enhance immunity against circulating Omicron subvariants and effectively elicit neutralizing antibodies across a broad spectrum of SARS-CoV-2 variants.