tetano
Editor, Senior Moderator
Innovation (N Y)
. 2022 Mar 2;100221.
doi: 10.1016/j.xinn.2022.100221. Online ahead of print.
A highly immunogenic live-attenuated vaccine candidate prevents SARS-CoV-2 infection and transmission in hamsters
Xiao-Feng Li[SUP] 1 [/SUP], Zhen Cui[SUP] 2 [/SUP], Hang Fan[SUP] 1 [/SUP], Qi Chen[SUP] 1 [/SUP], Lei Cao[SUP] 2 [/SUP], Hong-Ying Qiu[SUP] 1 [/SUP], Na-Na Zhang[SUP] 1 3 [/SUP], Yan-Peng Xu[SUP] 1 [/SUP], Rong-Rong Zhang[SUP] 1 [/SUP], Chao Zhou[SUP] 1 [/SUP], Qing Ye[SUP] 1 [/SUP], Yong-Qiang Deng[SUP] 1 [/SUP], Yan Guo[SUP] 1 [/SUP], Si Qin[SUP] 1 [/SUP], Kaiyue Fan[SUP] 2 [/SUP], Lei Wang[SUP] 2 [/SUP], Zijing Jia[SUP] 2 [/SUP], Yujun Cui[SUP] 1 [/SUP], Xiangxi Wang[SUP] 2 [/SUP], Cheng-Feng Qin[SUP] 1 4 [/SUP]
Affiliations
Abstract
The highly pathogenic and readily transmissible SARS-CoV-2 has caused a global coronavirus pandemic, urgently requiring effective countermeasures against its rapid expansion. All available vaccine platforms are being utilized to generate safe and effective COVID-19 vaccines. Here, we generated a live-attenuated candidate vaccine strain by serial passaging of a SARS-CoV-2 clinical isolate in Vero cells. Deep sequencing revealed the dynamic adaptation of SARS-CoV-2 in Vero cells, resulting in a stable clone with a deletion of seven amino acids (N[SUB]679[/SUB]SPRRAR[SUB]685[/SUB]) at the S1/S2 junction of the S protein (named VAS5). VAS5 showed significant attenuation of replication in multiple human cell lines, human airway epithelium organoids, and hACE2 mice. Viral fitness competition assays demonstrated that VAS5 showed specific tropism to Vero cells but decreased fitness in human cells compared to the parental virus. More importantly, a single intranasal injection of VAS5 elicited a high level of neutralizing antibodies and prevented SARS-CoV-2 infection in mice as well as close contact transmission in golden Syrian hamsters. Structural and biochemical analysis revealed a stable and locked prefusion conformation of the S trimer of VAS5, which most resembles SARS-CoV-2-3Q-2P, an advanced vaccine immunogen (NVAX-CoV2373). Further systematic antigenic profiling and immunogenicity validation confirmed that the VAS5 S trimer presents an enhanced antigenic mimic of the wild-type S trimer. Our results not only provide a potent live-attenuated vaccine candidate against COVID-19 but also clarify the molecular and structural basis for the highly attenuated and super immunogenic phenotype of VAS5.
Keywords: Adaptation; Fitness; SARS-CoV-2; Spike S1/S2 variant; Transmission.
. 2022 Mar 2;100221.
doi: 10.1016/j.xinn.2022.100221. Online ahead of print.
A highly immunogenic live-attenuated vaccine candidate prevents SARS-CoV-2 infection and transmission in hamsters
Xiao-Feng Li[SUP] 1 [/SUP], Zhen Cui[SUP] 2 [/SUP], Hang Fan[SUP] 1 [/SUP], Qi Chen[SUP] 1 [/SUP], Lei Cao[SUP] 2 [/SUP], Hong-Ying Qiu[SUP] 1 [/SUP], Na-Na Zhang[SUP] 1 3 [/SUP], Yan-Peng Xu[SUP] 1 [/SUP], Rong-Rong Zhang[SUP] 1 [/SUP], Chao Zhou[SUP] 1 [/SUP], Qing Ye[SUP] 1 [/SUP], Yong-Qiang Deng[SUP] 1 [/SUP], Yan Guo[SUP] 1 [/SUP], Si Qin[SUP] 1 [/SUP], Kaiyue Fan[SUP] 2 [/SUP], Lei Wang[SUP] 2 [/SUP], Zijing Jia[SUP] 2 [/SUP], Yujun Cui[SUP] 1 [/SUP], Xiangxi Wang[SUP] 2 [/SUP], Cheng-Feng Qin[SUP] 1 4 [/SUP]
Affiliations
- PMID: 35252935
- PMCID: PMC8888354
- DOI: 10.1016/j.xinn.2022.100221
Abstract
The highly pathogenic and readily transmissible SARS-CoV-2 has caused a global coronavirus pandemic, urgently requiring effective countermeasures against its rapid expansion. All available vaccine platforms are being utilized to generate safe and effective COVID-19 vaccines. Here, we generated a live-attenuated candidate vaccine strain by serial passaging of a SARS-CoV-2 clinical isolate in Vero cells. Deep sequencing revealed the dynamic adaptation of SARS-CoV-2 in Vero cells, resulting in a stable clone with a deletion of seven amino acids (N[SUB]679[/SUB]SPRRAR[SUB]685[/SUB]) at the S1/S2 junction of the S protein (named VAS5). VAS5 showed significant attenuation of replication in multiple human cell lines, human airway epithelium organoids, and hACE2 mice. Viral fitness competition assays demonstrated that VAS5 showed specific tropism to Vero cells but decreased fitness in human cells compared to the parental virus. More importantly, a single intranasal injection of VAS5 elicited a high level of neutralizing antibodies and prevented SARS-CoV-2 infection in mice as well as close contact transmission in golden Syrian hamsters. Structural and biochemical analysis revealed a stable and locked prefusion conformation of the S trimer of VAS5, which most resembles SARS-CoV-2-3Q-2P, an advanced vaccine immunogen (NVAX-CoV2373). Further systematic antigenic profiling and immunogenicity validation confirmed that the VAS5 S trimer presents an enhanced antigenic mimic of the wild-type S trimer. Our results not only provide a potent live-attenuated vaccine candidate against COVID-19 but also clarify the molecular and structural basis for the highly attenuated and super immunogenic phenotype of VAS5.
Keywords: Adaptation; Fitness; SARS-CoV-2; Spike S1/S2 variant; Transmission.