A highly immunogenic live-attenuated vaccine candidate prevents SARS-CoV-2 infection and transmission in hamsters

Xiao Feng Li; Zhen Cui; Hang Fan; Qi Chen; Lei Cao; Hong Ying Qiu; Na Na Zhang; Yan Peng Xu; Rong Rong Zhang; Chao Zhou; Qing Ye; Yong Qiang Deng; Yan Guo; Si Qin; Kaiyue Fan; Lei Wang; Zijing Jia; Yujun Cui; Xiangxi Wang; Cheng Feng Qin

doi:10.1016/j.xinn.2022.100221

A highly immunogenic live-attenuated vaccine candidate prevents SARS-CoV-2 infection and transmission in hamsters

Xiao Feng Li, Zhen Cui, Hang Fan, Qi Chen, Lei Cao, Hong Ying Qiu, Na Na Zhang, Yan Peng Xu, Rong Rong Zhang, Chao Zhou, Qing Ye, Yong Qiang Deng, Yan Guo, Si Qin, Kaiyue Fan, Lei Wang, Zijing Jia, Yujun Cui, Xiangxi Wang, Cheng Feng Qin

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

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 used 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 (N₆₇₉SPRRAR₆₈₅) 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 with 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.

Original language	English
Article number	100221
Journal	Innovation
Volume	3
Issue number	2
DOIs	https://doi.org/10.1016/j.xinn.2022.100221
State	Published - 29 Mar 2022
Externally published	Yes

Keywords

SARS-CoV-2
adaptation
fitness
spike S1/S2 variant
transmission

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10.1016/j.xinn.2022.100221

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Li, X. F., Cui, Z., Fan, H., Chen, Q., Cao, L., Qiu, H. Y., Zhang, N. N., Xu, Y. P., Zhang, R. R., Zhou, C., Ye, Q., Deng, Y. Q., Guo, Y., Qin, S., Fan, K., Wang, L., Jia, Z., Cui, Y., Wang, X., & Qin, C. F. (2022). A highly immunogenic live-attenuated vaccine candidate prevents SARS-CoV-2 infection and transmission in hamsters. Innovation, 3(2), Article 100221. https://doi.org/10.1016/j.xinn.2022.100221

@article{df69dc2b58484277be2165d4d8906957,

title = "A highly immunogenic live-attenuated vaccine candidate prevents SARS-CoV-2 infection and transmission in hamsters",

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 used 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 (N679SPRRAR685) 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 with 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 = "SARS-CoV-2, adaptation, fitness, spike S1/S2 variant, transmission",

author = "Li, {Xiao Feng} and Zhen Cui and Hang Fan and Qi Chen and Lei Cao and Qiu, {Hong Ying} and Zhang, {Na Na} and Xu, {Yan Peng} and Zhang, {Rong Rong} and Chao Zhou and Qing Ye and Deng, {Yong Qiang} and Yan Guo and Si Qin and Kaiyue Fan and Lei Wang and Zijing Jia and Yujun Cui and Xiangxi Wang and Qin, {Cheng Feng}",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = mar,

day = "29",

doi = "10.1016/j.xinn.2022.100221",

language = "English",

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Li, XF, Cui, Z, Fan, H, Chen, Q, Cao, L, Qiu, HY, Zhang, NN, Xu, YP, Zhang, RR, Zhou, C, Ye, Q, Deng, YQ, Guo, Y, Qin, S, Fan, K, Wang, L, Jia, Z, Cui, Y, Wang, X & Qin, CF 2022, 'A highly immunogenic live-attenuated vaccine candidate prevents SARS-CoV-2 infection and transmission in hamsters', Innovation, vol. 3, no. 2, 100221. https://doi.org/10.1016/j.xinn.2022.100221

TY - JOUR

T1 - A highly immunogenic live-attenuated vaccine candidate prevents SARS-CoV-2 infection and transmission in hamsters

AU - Li, Xiao Feng

AU - Cui, Zhen

AU - Fan, Hang

AU - Chen, Qi

AU - Cao, Lei

AU - Qiu, Hong Ying

AU - Zhang, Na Na

AU - Xu, Yan Peng

AU - Zhang, Rong Rong

AU - Zhou, Chao

AU - Ye, Qing

AU - Deng, Yong Qiang

AU - Guo, Yan

AU - Qin, Si

AU - Fan, Kaiyue

AU - Wang, Lei

AU - Jia, Zijing

AU - Cui, Yujun

AU - Wang, Xiangxi

AU - Qin, Cheng Feng

PY - 2022/3/29

Y1 - 2022/3/29

N2 - 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 used 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 (N679SPRRAR685) 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 with 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.

AB - 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 used 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 (N679SPRRAR685) 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 with 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.

KW - SARS-CoV-2

KW - adaptation

KW - fitness

KW - spike S1/S2 variant

KW - transmission

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DO - 10.1016/j.xinn.2022.100221

M3 - Article

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SN - 2666-6758

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JO - Innovation

JF - Innovation

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M1 - 100221

ER -

A highly immunogenic live-attenuated vaccine candidate prevents SARS-CoV-2 infection and transmission in hamsters

Abstract

Keywords

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