Schön, Jacob; Barut, G Tuba; Trüeb, Bettina Salome; Halwe, Nico Joel; Berenguer Veiga, Inês; Kratzel, Annika; Ulrich, Lorenz; Kelly, Jenna N; Brügger, Melanie; Wylezich, Claudia; Taddeo, Adriano; Aguiar Moreira, Etori; Túrós, Demeter; Grau-Roma, Llorenç; Ahrens, Ann Kathrin; Schlottau, Kore; Britzke, Tobias; Breithaupt, Angele; Corleis, Björn; Kochmann, Jana; ... (2024). A safe, effective and adaptable live-attenuated SARS-CoV-2 vaccine to reduce disease and transmission using one-to-stop genome modifications. Nature microbiology, 9(8), pp. 2099-2112. Springer Nature 10.1038/s41564-024-01755-1
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s41564-024-01755-1.pdf - Published Version Available under License Creative Commons: Attribution (CC-BY). Download (7MB) | Preview |
Approved vaccines are effective against severe COVID-19, but broader immunity is needed against new variants and transmission. Therefore, we developed genome-modified live-attenuated vaccines (LAV) by recoding the SARS-CoV-2 genome, including 'one-to-stop' (OTS) codons, disabling Nsp1 translational repression and removing ORF6, 7ab and 8 to boost host immune responses, as well as the spike polybasic cleavage site to optimize the safety profile. The resulting OTS-modified SARS-CoV-2 LAVs, designated as OTS-206 and OTS-228, are genetically stable and can be intranasally administered, while being adjustable and sustainable regarding the level of attenuation. OTS-228 exhibits an optimal safety profile in preclinical animal models, with no side effects or detectable transmission. A single-dose vaccination induces a sterilizing immunity in vivo against homologous WT SARS-CoV-2 challenge infection and a broad protection against Omicron BA.2, BA.5 and XBB.1.5, with reduced transmission. Finally, this promising LAV approach could be applicable to other emerging viruses.
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