Virus Vaccine Group, BIKEN Innovative Vaccine Research Alliance Laboratories, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Osaka, Japan; The Research Foundation for Microbial Diseases of Osaka University, Suita, Osaka, Japan
Shinya Okamura
Virus Vaccine Group, BIKEN Innovative Vaccine Research Alliance Laboratories, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Osaka, Japan; The Research Foundation for Microbial Diseases of Osaka University, Suita, Osaka, Japan
Shiho Torii
Laboratory of Virus Control, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan; Laboratory of Virus Control, Center for Infectious Disease Education and Research, Osaka University, Suita, Osaka, Japan
Sayuri Komatsu
Virus Vaccine Group, BIKEN Innovative Vaccine Research Alliance Laboratories, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Osaka, Japan; The Research Foundation for Microbial Diseases of Osaka University, Suita, Osaka, Japan
Paola Miyazato
Virus Vaccine Group, BIKEN Innovative Vaccine Research Alliance Laboratories, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Osaka, Japan; The Research Foundation for Microbial Diseases of Osaka University, Suita, Osaka, Japan
Hitomi Sasaki
The Research Foundation for Microbial Diseases of Osaka University, Suita, Osaka, Japan
Shiori Ueno
Department of Infectious Diseases and Host Defense, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
Hidehiko Suzuki
Virus Vaccine Group, BIKEN Innovative Vaccine Research Alliance Laboratories, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Osaka, Japan; The Research Foundation for Microbial Diseases of Osaka University, Suita, Osaka, Japan
Wataru Kamitani
Department of Infectious Diseases and Host Defense, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
Chikako Ono
Laboratory of Virus Control, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan; Laboratory of Virus Control, Center for Infectious Disease Education and Research, Osaka University, Suita, Osaka, Japan
Yoshiharu Matsuura
Laboratory of Virus Control, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan; Laboratory of Virus Control, Center for Infectious Disease Education and Research, Osaka University, Suita, Osaka, Japan
Shiro Takekawa
The Research Foundation for Microbial Diseases of Osaka University, Suita, Osaka, Japan
Koichi Yamanishi
The Research Foundation for Microbial Diseases of Osaka University, Suita, Osaka, Japan
Hirotaka Ebina
Virus Vaccine Group, BIKEN Innovative Vaccine Research Alliance Laboratories, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Osaka, Japan; The Research Foundation for Microbial Diseases of Osaka University, Suita, Osaka, Japan; Virus Vaccine Group, BIKEN Innovative Vaccine Research Alliance Laboratories, Research institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan; Corresponding author
Summary: Live-attenuated vaccines are generally highly effective. Here, we aimed to develop one against SARS-CoV-2, based on the identification of three types of temperature-sensitive (TS) strains with mutations in nonstructural proteins (nsp), impaired proliferation at 37°C–39°C, and the capacity to induce protective immunity in Syrian hamsters. To develop a live-attenuated vaccine, we generated a virus that combined all these TS-associated mutations (rTS-all), which showed a robust TS phenotype in vitro and high attenuation in vivo. The vaccine induced an effective cross-reactive immune response and protected hamsters against homologous or heterologous viral challenges. Importantly, rTS-all rarely reverted to the wild-type phenotype. By combining these mutations with an Omicron spike protein to construct a recombinant virus, protection against the Omicron strain was obtained. We show that immediate and effective live-attenuated vaccine candidates against SARS-CoV-2 variants may be developed using rTS-all as a backbone to incorporate the spike protein of the variants.
