A safe, effective and adaptable live-attenuated SARS-CoV-2 vaccine to reduce disease and transmission using one-to-stop genome modifications
Jacob Schön, G. Tuba Barut, Bettina Salome Trüeb, Nico Joël Halwe, Inês Berenguer Veiga, Annika Kratzel, Lorenz Ulrich, Jenna N. Kelly, Melanie Brügger, Claudia Wylezich, Adriano Taddeo, Étori Aguiar Moreira, Demeter Túrós, Llorenç Grau‐Roma, Ann Kathrin Ahrens, Kore Schlottau, Tobias Britzke, Angele Breithaupt, Björn Corleis, Jana Kochmann, Blandina I. Oliveira Esteves, Lea Almeida, Lisa Thomann, Christelle Devisme, Hanspeter Stalder, Silvio Steiner, Sarah Ochsenbein, Kimberly Schmied, Fabien Labroussaa, Joerg Jores, Philip V’kovski, Vladimir Cmiljanović, Marco P. Alves, Charaf Benarafa, Nadine Ebert, Donata Hoffmann, Martin Beer, Volker Thiel
Abstract
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.