Immunogenicity and safety of a live-attenuated SARS-CoV-2 vaccine candidate based on multiple attenuation mechanisms
mRNA vaccines against SARS-CoV-2 were rapidly developed and were effective during the pandemic. However, some limitations remain to be resolved, such as the short-lived induced immune response and certain adverse effects. Therefore, there is an urgent need to develop new vaccines that address these...
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| Format: | Article |
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eLife Sciences Publications Ltd
2025-02-01
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| Online Access: | https://elifesciences.org/articles/97532 |
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| author | Mie Suzuki Okutani Shinya Okamura Tang Gis Hitomi Sasaki Suni Lee Akiho Kashiwabara Simon Goto Mai Matsumoto Mayuko Yamawaki Toshiaki Miyazaki Tatsuya Nakagawa Masahito Ikawa Wataru Kamitani Shiro Takekawa Koichi Yamanishi Hirotaka Ebina |
| author_facet | Mie Suzuki Okutani Shinya Okamura Tang Gis Hitomi Sasaki Suni Lee Akiho Kashiwabara Simon Goto Mai Matsumoto Mayuko Yamawaki Toshiaki Miyazaki Tatsuya Nakagawa Masahito Ikawa Wataru Kamitani Shiro Takekawa Koichi Yamanishi Hirotaka Ebina |
| author_sort | Mie Suzuki Okutani |
| collection | DOAJ |
| description | mRNA vaccines against SARS-CoV-2 were rapidly developed and were effective during the pandemic. However, some limitations remain to be resolved, such as the short-lived induced immune response and certain adverse effects. Therefore, there is an urgent need to develop new vaccines that address these issues. While live-attenuated vaccines are a highly effective modality, they pose a risk of adverse effects, including virulence reversion. In the current study, we constructed a live-attenuated vaccine candidate, BK2102, combining naturally occurring virulence-attenuating mutations in the NSP14, NSP1, spike, and ORF7-8 coding regions. Intranasal inoculation with BK2102 induced humoral and cellular immune responses in Syrian hamsters without apparent tissue damage in the lungs, leading to protection against a SARS-CoV-2 D614G and an Omicron BA.5 strains. The neutralizing antibodies induced by BK2102 persisted for up to 364 days, which indicated that they confer long-term protection against infection. Furthermore, we confirmed the safety of BK2102 using transgenic (Tg) mice expressing human ACE2 (hACE2) that are highly susceptible to SARS-CoV-2. BK2102 did not kill the Tg mice, even when virus was administered at a dose of 106 plaque-forming units (PFUs), while 102 PFU of the D614G strain or an attenuated strain lacking the furin cleavage site of the spike was sufficient to kill mice. These results suggest that BK2102 is a promising live-vaccine candidate strain that confers long-term protection without significant virulence. |
| format | Article |
| id | doaj-art-c809b6b6b0d14b97a6b2569aac1eb8e0 |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-c809b6b6b0d14b97a6b2569aac1eb8e02025-02-11T15:27:34ZengeLife Sciences Publications LtdeLife2050-084X2025-02-011310.7554/eLife.97532Immunogenicity and safety of a live-attenuated SARS-CoV-2 vaccine candidate based on multiple attenuation mechanismsMie Suzuki Okutani0Shinya Okamura1https://orcid.org/0000-0002-3969-2855Tang Gis2Hitomi Sasaki3Suni Lee4Akiho Kashiwabara5Simon Goto6Mai Matsumoto7Mayuko Yamawaki8Toshiaki Miyazaki9Tatsuya Nakagawa10Masahito Ikawa11https://orcid.org/0000-0001-9859-6217Wataru Kamitani12Shiro Takekawa13Koichi Yamanishi14Hirotaka Ebina15https://orcid.org/0000-0003-0001-7825The Research Foundation for Microbial Diseases of Osaka University, Suita, Japan; Virus Vaccine Group, BIKEN Innovative Vaccine Research Alliance Laboratories, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, JapanThe Research Foundation for Microbial Diseases of Osaka University, Suita, Japan; Virus Vaccine Group, BIKEN Innovative Vaccine Research Alliance Laboratories, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, JapanThe Research Foundation for Microbial Diseases of Osaka University, Suita, JapanThe Research Foundation for Microbial Diseases of Osaka University, Suita, JapanThe Research Foundation for Microbial Diseases of Osaka University, Suita, JapanThe Research Foundation for Microbial Diseases of Osaka University, Suita, Japan; Virus Vaccine Group, BIKEN Innovative Vaccine Research Alliance Laboratories, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, JapanThe Research Foundation for Microbial Diseases of Osaka University, Suita, JapanThe Research Foundation for Microbial Diseases of Osaka University, Suita, JapanThe Research Foundation for Microbial Diseases of Osaka University, Suita, JapanThe Research Foundation for Microbial Diseases of Osaka University, Suita, JapanDepartment of Experimental Genome Research, Research Institute for Microbial Diseases, Osaka University, Suita, JapanDepartment of Experimental Genome Research, Research Institute for Microbial Diseases, Osaka University, Suita, Japan; Center for Advanced Modalities and DDS (CAMaD), Osaka University, Suita, Japan; Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, JapanDepartment of Infectious Diseases and Host Defense, Gunma University Graduate School of Medicine, Maebashi, JapanThe Research Foundation for Microbial Diseases of Osaka University, Suita, JapanThe Research Foundation for Microbial Diseases of Osaka University, Suita, JapanThe Research Foundation for Microbial Diseases of Osaka University, Suita, Japan; Virus Vaccine Group, BIKEN Innovative Vaccine Research Alliance Laboratories, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan; Center for Advanced Modalities and DDS (CAMaD), Osaka University, Suita, Japan; Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Japan; Virus Vaccine Group, BIKEN Innovative Vaccine Research Alliance Laboratories, Research institute for Microbial Diseases, Osaka University, Suita, JapanmRNA vaccines against SARS-CoV-2 were rapidly developed and were effective during the pandemic. However, some limitations remain to be resolved, such as the short-lived induced immune response and certain adverse effects. Therefore, there is an urgent need to develop new vaccines that address these issues. While live-attenuated vaccines are a highly effective modality, they pose a risk of adverse effects, including virulence reversion. In the current study, we constructed a live-attenuated vaccine candidate, BK2102, combining naturally occurring virulence-attenuating mutations in the NSP14, NSP1, spike, and ORF7-8 coding regions. Intranasal inoculation with BK2102 induced humoral and cellular immune responses in Syrian hamsters without apparent tissue damage in the lungs, leading to protection against a SARS-CoV-2 D614G and an Omicron BA.5 strains. The neutralizing antibodies induced by BK2102 persisted for up to 364 days, which indicated that they confer long-term protection against infection. Furthermore, we confirmed the safety of BK2102 using transgenic (Tg) mice expressing human ACE2 (hACE2) that are highly susceptible to SARS-CoV-2. BK2102 did not kill the Tg mice, even when virus was administered at a dose of 106 plaque-forming units (PFUs), while 102 PFU of the D614G strain or an attenuated strain lacking the furin cleavage site of the spike was sufficient to kill mice. These results suggest that BK2102 is a promising live-vaccine candidate strain that confers long-term protection without significant virulence.https://elifesciences.org/articles/97532SARS-CoV-2live-attenuated vaccinenon-clinical studyintranasal vaccine |
| spellingShingle | Mie Suzuki Okutani Shinya Okamura Tang Gis Hitomi Sasaki Suni Lee Akiho Kashiwabara Simon Goto Mai Matsumoto Mayuko Yamawaki Toshiaki Miyazaki Tatsuya Nakagawa Masahito Ikawa Wataru Kamitani Shiro Takekawa Koichi Yamanishi Hirotaka Ebina Immunogenicity and safety of a live-attenuated SARS-CoV-2 vaccine candidate based on multiple attenuation mechanisms eLife SARS-CoV-2 live-attenuated vaccine non-clinical study intranasal vaccine |
| title | Immunogenicity and safety of a live-attenuated SARS-CoV-2 vaccine candidate based on multiple attenuation mechanisms |
| title_full | Immunogenicity and safety of a live-attenuated SARS-CoV-2 vaccine candidate based on multiple attenuation mechanisms |
| title_fullStr | Immunogenicity and safety of a live-attenuated SARS-CoV-2 vaccine candidate based on multiple attenuation mechanisms |
| title_full_unstemmed | Immunogenicity and safety of a live-attenuated SARS-CoV-2 vaccine candidate based on multiple attenuation mechanisms |
| title_short | Immunogenicity and safety of a live-attenuated SARS-CoV-2 vaccine candidate based on multiple attenuation mechanisms |
| title_sort | immunogenicity and safety of a live attenuated sars cov 2 vaccine candidate based on multiple attenuation mechanisms |
| topic | SARS-CoV-2 live-attenuated vaccine non-clinical study intranasal vaccine |
| url | https://elifesciences.org/articles/97532 |
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