tetano
Editor, Senior Moderator
Elife
. 2025 Feb 11:13:RP97532.
doi: 10.7554/eLife.97532. Immunogenicity and safety of a live-attenuated SARS-CoV-2 vaccine candidate based on multiple attenuation mechanisms
Mie Suzuki Okutani[SUP] #[/SUP][SUP] 1 2 [/SUP], Shinya Okamura[SUP] #[/SUP][SUP] 1 2 [/SUP], Tang Gis[SUP] 1 [/SUP], Hitomi Sasaki[SUP] 1 [/SUP], Suni Lee[SUP] 1 [/SUP], Akiho Kashiwabara[SUP] 1 2 [/SUP], Simon Goto[SUP] 1 [/SUP], Mai Matsumoto[SUP] 1 [/SUP], Mayuko Yamawaki[SUP] 1 [/SUP], Toshiaki Miyazaki[SUP] 1 [/SUP], Tatsuya Nakagawa[SUP] 3 [/SUP], Masahito Ikawa[SUP] 3 4 5 [/SUP], Wataru Kamitani[SUP] 6 [/SUP], Shiro Takekawa[SUP] 1 [/SUP], Koichi Yamanishi[SUP] 1 [/SUP], Hirotaka Ebina[SUP] 1 2 4 5 7 [/SUP]
Affiliations
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 10[SUP]6[/SUP] plaque-forming units (PFUs), while 10[SUP]2[/SUP] 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.
Keywords: SARS-CoV-2; infectious disease; intranasal vaccine; live-attenuated vaccine; microbiology; non-clinical study; viruses.
. 2025 Feb 11:13:RP97532.
doi: 10.7554/eLife.97532. Immunogenicity and safety of a live-attenuated SARS-CoV-2 vaccine candidate based on multiple attenuation mechanisms
Mie Suzuki Okutani[SUP] #[/SUP][SUP] 1 2 [/SUP], Shinya Okamura[SUP] #[/SUP][SUP] 1 2 [/SUP], Tang Gis[SUP] 1 [/SUP], Hitomi Sasaki[SUP] 1 [/SUP], Suni Lee[SUP] 1 [/SUP], Akiho Kashiwabara[SUP] 1 2 [/SUP], Simon Goto[SUP] 1 [/SUP], Mai Matsumoto[SUP] 1 [/SUP], Mayuko Yamawaki[SUP] 1 [/SUP], Toshiaki Miyazaki[SUP] 1 [/SUP], Tatsuya Nakagawa[SUP] 3 [/SUP], Masahito Ikawa[SUP] 3 4 5 [/SUP], Wataru Kamitani[SUP] 6 [/SUP], Shiro Takekawa[SUP] 1 [/SUP], Koichi Yamanishi[SUP] 1 [/SUP], Hirotaka Ebina[SUP] 1 2 4 5 7 [/SUP]
Affiliations
- PMID: 39932490
- PMCID: PMC11813227
- DOI: 10.7554/eLife.97532
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 10[SUP]6[/SUP] plaque-forming units (PFUs), while 10[SUP]2[/SUP] 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.
Keywords: SARS-CoV-2; infectious disease; intranasal vaccine; live-attenuated vaccine; microbiology; non-clinical study; viruses.