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Preprints with The Lancet is part of SSRN´s First Look, a place where journals identify content of interest prior to publication. Authors have opted in at submission to The Lancet family of journals to post their preprints on Preprints with The Lancet. ...
Posted: 25 Jun 2024
https://ssrn.com/abstract=4874431 or http://dx.doi.org/10.2139/ssrn.4874431
Hu, Jiaxin and Zan, Fuwen and Ou, Xiuyuan and Tang, Xiaolu and Liu, Yan and Lu, Xin and Li, Pei and Mu, Zhixia and Dong, Siwen and Chen, Yahan and Tan, Lin and Cao, Mengmeng and Liu, Pinghuang and Lu, Jian and Qian, Zhaohui
Abstract
SARS-CoV-2 not only infects humans but also various animals, posing reverse zoonotic risks. As SARS-CoV-2 rapidly evolves, newly emerged omicron variants like BA.2.86 and JN.1 have become dominant globally. In this study, we determined the susceptibility of XBB.1.16, EG.5.1, BA.2.86, and JN.1 to 27 different animal angiotensin converting enzyme 2 (ACE2) orthologs using pseudoviruses, and found that, similar to WT (SARS-CoV-2 Wuhan strain with D614G), the omicron variants also exhibited potential broad host ranges, but JN.1 displayed substantially higher overall reverse zoonotic risk potential than other variants except for EG.5.1. Further mechanistic analysis revealed that L455S mutation in JN.1 S proteins might be responsible for significant decrease in overall receptor binding affinity but substantial increase in overall fusogenecity and infectivity with various animal ACE2s and hACE2. L455S change slightly decreased S protein thermostability and enhanced S protein cleavage by trypsin, likely resulting in lowering the overall energy barrier required for conformational changes of S protein after receptor binding. Moreover, using convalescent sera from some vaccinated individuals with breakthrough infection, we found that L455S mutation also enhanced immune evasion of SARS-CoV-2, and XBB breakthrough infection increased the levels of neutralization antibodies against JN.1, suggesting that addition of XBB S protein into vaccine regimen might be helpful against JN.1 infection. Together, our findings offer a better mechanistic understanding of the molecular basis of CoV entry, host range, evolution, and immunogenicity and highlight the importance of surveillance of susceptible hosts to prevent potential outbreaks.
https://elsevier-ssrn-document-store-prod.s3.amazonaws.com/lancet/84225658-9c21-4d51-a0cb-be66b4963c3b-meca.pdf?response-content-disposition=inline&X-Amz-Security-Token=IQoJb3JpZ2luX2VjEPT%2F%2F%2F%2F%2F%2F%2F%2F% 2F%2FwEaCXVzLWVhc3QtMSJHMEUCIQC2dNObReSQz16bZJnM1Z 0jj3U3DdpTsaLx1%2FJClePEkgIgGuO3%2BfQtUGWGxo8GHCNq w%2FHmNIJrM9pyG%2FlJUFPEsG0qxwUIrP%2F%2F%2F%2F%2F% 2F%2F%2F%2F%2FARAEGgwzMDg0NzUzMDEyNTciDAPMblPMX%2B 8LuO2DXSqbBUNEEGY%2BLuvJqNOhJIHOmr7LJ7xop7HO%2Fp2X 54qtqXsH4m%2FdJeYsrpwjLGyhDRpiygqzuq33jBFM573x02rZ TopUbcctBxFr40Km%2BWomMPaEibMG6wa0nncSCeFX%2BL6%2B m5fIA4HmdwaRLp99GBjfGpFpMJTcsCQU%2Fm7W0%2FW2MDriej FM9Qfwu2Tcl8%2BCp4RPHgAMlrpEAixfweJ2%2Flw8QmpVCkJy A8p76KczePv3sGSCRDbuXMbw5oZbzKCgBBkpi9yr5s39X%2Fgb 21OfmGPt7Bv7zOBPAX16lfx4rLUW%2FzOV7%2BECjkA6%2B9Ay quz6Ub%2BSRQh4XgiOL3%2FLR%2BllRnLu%2BxRtlayNgPoecq OP6VGfMiqxfPHjKZflpbsppOW4gjgbDJU4A%2BQtcEJCNLXPw8 14Ecyz9E7LYdjcVbqtcxxSKJ83ko7zgLOsCqNumXU81dYE1b3P GMkBiUvrpKqmZmOcE6LJPPrRbBUMbLamW%2BDFBZuzUzVRFDUa BdqLaQH8jfY6WWkaCe4vLDgpnH3MKSW8x3GtpNpEvAITGnUOm5 egLgI%2BP6o6iF6U3XzzSWF8LJkAr1lzb%2BOq3P1K9pDISDms i5QPstMN2hBxvQ8qYxpw125CXCpEDaxLjTCK7JjHY0NBCAvA3r sn%2Bem6MsDXpnFrS0PdgMwFFPj9lbxaqc7TRxDR%2F%2FHY3x LvR0oiYiBxiJhfRJJ0XLd2y2k5Hs46apYgagrolrlSXgiLWSph %2FDy8hy17ePzs8Ydzt8wgtexV4WfFrlEB2AU3ufRr8zl7rU7c suiXjr5X58cTEv5cEZyhpEtwJKiEq%2BnZC%2BidKzAe8D5NIQ 7zoDCTMfI6FYNLxKzmAsukyDpg8dd5cXc%2BB5rhbB2sjmcOyL 6Xh6P3rMQwhOqbtAY6sQFPfnG%2FrNHakCSQmPzdbLnPGqBNU1 Uyu9GNE1B3Ws%2Bywo5EQKZXnPY9vb8Yi5OWTFDaGw%2FHuyAA miY8nYscnBXId10jdj4DFOJGsVaU%2BEI%2F5E41GDJDtgcEVT B%2BSBXufNL4eZA0XRnBlTzUjbqH3iMd8zhaQCyWqjKXhY4kQ0 Dk8Cj8guO8P89jH2IzZOvMRHuBSuhmDiyHQVYcYE1d7mPUc%2B RfbkOjfkGdrxgPIk8Kwao%3D&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20240704T201801Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAUPUUPRWE3OWYCXLG%2F20240704%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=b41a743afe35c42219f60b50f4947981af82a501 9f36569c399453136a21210a
(https://papers.ssrn.com/sol3/papers....act_id=4874431)
Ethical Approval: Prior to participation, all volunteers provided informed consent. The study protocol was reviewed and approved by the Ethics Review Board of the National Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College (IPB-2023-01).
Posted: 25 Jun 2024
https://ssrn.com/abstract=4874431 or http://dx.doi.org/10.2139/ssrn.4874431
Hu, Jiaxin and Zan, Fuwen and Ou, Xiuyuan and Tang, Xiaolu and Liu, Yan and Lu, Xin and Li, Pei and Mu, Zhixia and Dong, Siwen and Chen, Yahan and Tan, Lin and Cao, Mengmeng and Liu, Pinghuang and Lu, Jian and Qian, Zhaohui
Abstract
SARS-CoV-2 not only infects humans but also various animals, posing reverse zoonotic risks. As SARS-CoV-2 rapidly evolves, newly emerged omicron variants like BA.2.86 and JN.1 have become dominant globally. In this study, we determined the susceptibility of XBB.1.16, EG.5.1, BA.2.86, and JN.1 to 27 different animal angiotensin converting enzyme 2 (ACE2) orthologs using pseudoviruses, and found that, similar to WT (SARS-CoV-2 Wuhan strain with D614G), the omicron variants also exhibited potential broad host ranges, but JN.1 displayed substantially higher overall reverse zoonotic risk potential than other variants except for EG.5.1. Further mechanistic analysis revealed that L455S mutation in JN.1 S proteins might be responsible for significant decrease in overall receptor binding affinity but substantial increase in overall fusogenecity and infectivity with various animal ACE2s and hACE2. L455S change slightly decreased S protein thermostability and enhanced S protein cleavage by trypsin, likely resulting in lowering the overall energy barrier required for conformational changes of S protein after receptor binding. Moreover, using convalescent sera from some vaccinated individuals with breakthrough infection, we found that L455S mutation also enhanced immune evasion of SARS-CoV-2, and XBB breakthrough infection increased the levels of neutralization antibodies against JN.1, suggesting that addition of XBB S protein into vaccine regimen might be helpful against JN.1 infection. Together, our findings offer a better mechanistic understanding of the molecular basis of CoV entry, host range, evolution, and immunogenicity and highlight the importance of surveillance of susceptible hosts to prevent potential outbreaks.
https://elsevier-ssrn-document-store-prod.s3.amazonaws.com/lancet/84225658-9c21-4d51-a0cb-be66b4963c3b-meca.pdf?response-content-disposition=inline&X-Amz-Security-Token=IQoJb3JpZ2luX2VjEPT%2F%2F%2F%2F%2F%2F%2F%2F% 2F%2FwEaCXVzLWVhc3QtMSJHMEUCIQC2dNObReSQz16bZJnM1Z 0jj3U3DdpTsaLx1%2FJClePEkgIgGuO3%2BfQtUGWGxo8GHCNq w%2FHmNIJrM9pyG%2FlJUFPEsG0qxwUIrP%2F%2F%2F%2F%2F% 2F%2F%2F%2F%2FARAEGgwzMDg0NzUzMDEyNTciDAPMblPMX%2B 8LuO2DXSqbBUNEEGY%2BLuvJqNOhJIHOmr7LJ7xop7HO%2Fp2X 54qtqXsH4m%2FdJeYsrpwjLGyhDRpiygqzuq33jBFM573x02rZ TopUbcctBxFr40Km%2BWomMPaEibMG6wa0nncSCeFX%2BL6%2B m5fIA4HmdwaRLp99GBjfGpFpMJTcsCQU%2Fm7W0%2FW2MDriej FM9Qfwu2Tcl8%2BCp4RPHgAMlrpEAixfweJ2%2Flw8QmpVCkJy A8p76KczePv3sGSCRDbuXMbw5oZbzKCgBBkpi9yr5s39X%2Fgb 21OfmGPt7Bv7zOBPAX16lfx4rLUW%2FzOV7%2BECjkA6%2B9Ay quz6Ub%2BSRQh4XgiOL3%2FLR%2BllRnLu%2BxRtlayNgPoecq OP6VGfMiqxfPHjKZflpbsppOW4gjgbDJU4A%2BQtcEJCNLXPw8 14Ecyz9E7LYdjcVbqtcxxSKJ83ko7zgLOsCqNumXU81dYE1b3P GMkBiUvrpKqmZmOcE6LJPPrRbBUMbLamW%2BDFBZuzUzVRFDUa BdqLaQH8jfY6WWkaCe4vLDgpnH3MKSW8x3GtpNpEvAITGnUOm5 egLgI%2BP6o6iF6U3XzzSWF8LJkAr1lzb%2BOq3P1K9pDISDms i5QPstMN2hBxvQ8qYxpw125CXCpEDaxLjTCK7JjHY0NBCAvA3r sn%2Bem6MsDXpnFrS0PdgMwFFPj9lbxaqc7TRxDR%2F%2FHY3x LvR0oiYiBxiJhfRJJ0XLd2y2k5Hs46apYgagrolrlSXgiLWSph %2FDy8hy17ePzs8Ydzt8wgtexV4WfFrlEB2AU3ufRr8zl7rU7c suiXjr5X58cTEv5cEZyhpEtwJKiEq%2BnZC%2BidKzAe8D5NIQ 7zoDCTMfI6FYNLxKzmAsukyDpg8dd5cXc%2BB5rhbB2sjmcOyL 6Xh6P3rMQwhOqbtAY6sQFPfnG%2FrNHakCSQmPzdbLnPGqBNU1 Uyu9GNE1B3Ws%2Bywo5EQKZXnPY9vb8Yi5OWTFDaGw%2FHuyAA miY8nYscnBXId10jdj4DFOJGsVaU%2BEI%2F5E41GDJDtgcEVT B%2BSBXufNL4eZA0XRnBlTzUjbqH3iMd8zhaQCyWqjKXhY4kQ0 Dk8Cj8guO8P89jH2IzZOvMRHuBSuhmDiyHQVYcYE1d7mPUc%2B RfbkOjfkGdrxgPIk8Kwao%3D&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20240704T201801Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAUPUUPRWE3OWYCXLG%2F20240704%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=b41a743afe35c42219f60b50f4947981af82a501 9f36569c399453136a21210a
(https://papers.ssrn.com/sol3/papers....act_id=4874431)
Ethical Approval: Prior to participation, all volunteers provided informed consent. The study protocol was reviewed and approved by the Ethics Review Board of the National Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College (IPB-2023-01).