For best viewing of the website please use Mozilla Firefox or Google Chrome.
Citation: Haoneng Tang, Yong Ke, Yunji Liao, Yanlin Bian, Yunsheng Yuan, Ziqi Wang, Li Yang, Hang Ma, Tao Sun, Baohong Zhang, Xiaoju Zhang, Mingyuan Wu, Jianwei Zhu. Mutational escape prevention by combination of four neutralizing antibodies that target RBD conserved regions and stem helix [J].VIROLOGICA SINICA, 2022, 37(6) : 860-873.  http://dx.doi.org/10.1016/j.virs.2022.11.005

Mutational escape prevention by combination of four neutralizing antibodies that target RBD conserved regions and stem helix

  • New variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appear rapidly every few months. They have showed powerful adaptive ability to circumvent the immune system. To further understand SARS-CoV-2's adaptability so as to seek for strategies to mitigate the emergence of new variants, herein we investigated the viral adaptation in the presence of broadly neutralizing antibodies and their combinations. First, we selected four broadly neutralizing antibodies, including pan-sarbecovirus and pan-betacoronavirus neutralizing antibodies that recognize distinct conserved regions on receptor-binding domain (RBD) or conserved stem-helix region on S2 subunit. Through binding competition analysis, we demonstrated that they were capable of simultaneously binding. Thereafter, a replication-competent vesicular stomatitis virus pseudotyped with SARS-CoV-2 spike protein was employed to study the viral adaptation. Twenty consecutive passages of the virus under the selective pressure of individual antibodies or their combinations were performed. It was found that it was not hard for the virus to adapt to broadly neutralizing antibodies, even for pan-sarbecovirus and pan-betacoronavirus antibodies. The virus was more and more difficult to escape the combinations of two/three/four antibodies. In addition, mutations in the viral population revealed by high-throughput sequencing showed that under the selective pressure of three/four combinational antibodies, viral mutations were not prone to present in the highly conserved region across betacoronaviruses (stem-helix region), while this was not true under the selective pressure of single/two antibodies. Importantly, combining neutralizing antibodies targeting RBD conserved regions and stem helix synergistically prevented the emergence of escape mutations. These studies will guide future vaccine and therapeutic development efforts and provide a rationale for the design of RBD-stem helix tandem vaccine, which may help to impede the generation of novel variants.

  • 加载中
  • 10.1016j.virs.2022.11.005-ESM.docx
    1. Amanat, F., Thapa, M., Lei, T., Ahmed, S.M.S., Adelsberg, D.C., Carreño, J.M.,Strohmeier, S., Schmitz, A.J., Zafar, S., Zhou, J.Q., Rijnink, W., Alshammary, H., Borcherding, N., Reiche, A.G., Srivastava, K., Sordillo, E.M., van Bakel, H., Turner, J.S., Bajic, G., Simon, V., Ellebedy, A.H., Krammer, F., 2021. Sars-cov-2 mrna vaccination induces functionally diverse antibodies to ntd, rbd, and s2. Cell 184, 3936-3948.e10.

    2. Baum, A., Fulton, B.O., Wloga, E., Copin, R., Pascal, K.E., Russo, V., Giordano, S., Lanza, K., Negron, N., Ni, M., Wei, Y., Atwal, G.S., Murphy, A.J., Stahl, N., Yancopoulos, G.D., Kyratsous, C.A., 2020. Antibody cocktail to sars-cov-2 spike protein prevents rapid mutational escape seen with individual antibodies. Science 369, 1014-1018.

    3. Boyoglu-Barnum, S., Ellis, D., Gillespie, R.A., Hutchinson, G.B., Park, Y.J., Moin, S.M., Acton, O.J., Ravichandran, R., Murphy, M., Pettie, D., Matheson, N., Carter, L., Creanga, A., Watson, M.J., Kephart, S., Ataca, S., Vaile, J.R., Ueda, G., Crank, M.C., Stewart, L., Lee, K.K., Guttman, M., Baker, D., Mascola, J.R., Veesler, D., Graham, B.S., King, N.P., Kanekiyo, M., 2021. Quadrivalent influenza nanoparticle vaccines induce broad protection. Nature 592, 623-628.

    4. Cai, Y., Zhang, J., Xiao, T., Peng, H., Sterling, S.M., Walsh Jr., R.M., Rawson, S., RitsVolloch, S., Chen, B., 2020. Distinct conformational states of sars-cov-2 spike protein. Science 369, 1586-1592.

    5. Cao, Y., Wang, J., Jian, F., Xiao, T., Song, W., Yisimayi, A., Huang, W., Li, Q., Wang, P., An, R., Wang, J., Wang, Y., Niu, X., Yang, S., Liang, H., Sun, H., Li, T., Yu, Y., Cui, Q., Liu, S., Yang, X., Du, S., Zhang, Z., Hao, X., Shao, F., Jin, R., Wang, X., Xiao, J., Wang, Y., Xie, X.S., 2022a. Omicron escapes the majority of existing sars-cov-2 neutralizing antibodies. Nature 602, 657-663.

    6. Cao, Y., Yisimayi, A., Jian, F., Song, W., Xiao, T., Wang, L., Du, S., Wang, J., Li, Q., Chen, X., Wang, P., Zhang, Z., Liu, P., An, R., Hao, X., Wang, Y., Wang, J., Feng, R., Sun, H., Zhao, L., Zhang, W., Zhao, D., Zheng, J., Yu, L., Li, C., Zhang, N., Wang, R., Niu, X., Yang, S., Song, X., Zheng, L., Li, Z., Gu, Q., Shao, F., Huang, W., Jin, R., Shen, Z., Wang, Y., Wang, X., Xiao, J., Xie, X.S., 2022b. Ba.2.12.1, ba.4 and ba.5 escape antibodies elicited by omicron infection. bioRxiv, 2022.2004.2030.489997.Preprint.

    7. Cerutti, G., Guo, Y., Zhou, T., Gorman, J., Lee, M., Rapp, M., Reddem, E.R., Yu, J., Bahna, F., Bimela, J., Huang, Y., Katsamba, P.S., Liu, L., Nair, M.S., Rawi, R., Olia, A.S., Wang, P., Zhang, B., Chuang, G.Y., Ho, D.D., Sheng, Z., Kwong, P.D., Shapiro, L., 2021. Potent sars-cov-2 neutralizing antibodies directed against spike nterminal domain target a single supersite. Cell Host Microbe 29, 819-833 e817.

    8. Crawford, K.H.D., Dingens, A.S., Eguia, R., Wolf, C.R., Wilcox, N., Logue, J.K., Shuey, K., Casto, A.M., Fiala, B., Wrenn, S., Pettie, D., King, N.P., Greninger, A.L., Chu, H.Y., Bloom, J.D., 2021. Dynamics of neutralizing antibody titers in the months after severe acute respiratory syndrome coronavirus 2 infection. J. Infect. Dis. 223, 197-205.

    9. Dieterle, M.E., Haslwanter, D., Bortz 3rd, R.H., Wirchnianski, A.S., Lasso, G., Vergnolle, O., Abbasi, S.A., Fels, J.M., Laudermilch, E., Florez, C., Mengotto, A., Kimmel, D., Malonis, R.J., Georgiev, G., Quiroz, J., Barnhill, J., Pirofski, L.A., Daily, J.P., Dye, J.M., Lai, J.R., Herbert, A.S., Chandran, K., Jangra, R.K., 2020.A replication-competent vesicular stomatitis virus for studies of sars-cov-2 spikemediated cell entry and its inhibition. Cell Host Microbe 28, 486-496.e6.

    10. Hansen, J., Baum, A., Pascal, K.E., Russo, V., Giordano, S., Wloga, E., Fulton, B.O., Yan, Y., Koon, K., Patel, K., Chung, K.M., Hermann, A., Ullman, E., Cruz, J., Rafique, A., Huang, T., Fairhurst, J., Libertiny, C., Malbec, M., Lee, W.Y., Welsh, R., Farr, G., Pennington, S., Deshpande, D., Cheng, J., Watty, A., Bouffard, P., Babb, R., Levenkova, N., Chen, C., Zhang, B., Romero Hernandez, A., Saotome, K., Zhou, Y., Franklin, M., Sivapalasingam, S., Lye, D.C., Weston, S., Logue, J., Haupt, R., Frieman, M., Chen, G., Olson, W., Murphy, A.J., Stahl, N., Yancopoulos, G.D., Kyratsous, C.A., 2020. Studies in humanized mice and convalescent humans yield a sars-cov-2 antibody cocktail. Science 369, 1010-1014.

    11. Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., Schiergens, T.S., Herrler, G., Wu, N.H., Nitsche, A., Müller, M.A., Drosten, C., Pöhlmann, S., 2020. Sars-cov-2 cell entry depends on ace2 and tmprss2 and is blocked by a clinically proven protease inhibitor. Cell 181, 271-280.e8.

    12. Jackson, C.B., Farzan, M., Chen, B., Choe, H., 2022. Mechanisms of sars-cov-2 entry into cells. Nat. Rev. Mol. Cell Biol. 23, 3-20.

    13. Kanekiyo, M., Joyce, M.G., Gillespie, R.A., Gallagher, J.R., Andrews, S.F., Yassine, H.M., Wheatley, A.K., Fisher, B.E., Ambrozak, D.R., Creanga, A., Leung, K., Yang, E.S., Boyoglu-Barnum, S., Georgiev, I.S., Tsybovsky, Y., Prabhakaran, M.S., Andersen, H., Kong, W.P., Baxa, U., Zephir, K.L., Ledgerwood, J.E., Koup, R.A., Kwong, P.D., Harris, A.K., McDermott, A.B., Mascola, J.R., Graham, B.S., 2019. Mosaic nanoparticle display of diverse influenza virus hemagglutinins elicits broad b cell responses. Nat. Immunol. 20, 362-372.

    14. Krammer, F., 2020. Sars-cov-2 vaccines in development. Nature 586, 516-527.

    15. Li, M., Wang, H., Tian, L., Pang, Z., Yang, Q., Huang, T., Fan, J., Song, L., Tong, Y., Fan, H., 2022. Covid-19 vaccine development: milestones, lessons and prospects. Signal Transduct. Targeted Ther. 7, 146.

    16. Li, W., Chen, Y., Prévost, J., Ullah, I., Lu, M., Gong, S.Y., Tauzin, A., Gasser, R., Vézina, D., Anand, S.P., Goyette, G., Chaterjee, D., Ding, S., Tolbert, W.D., Grunst, M.W., Bo, Y., Zhang, S., Richard, J., Zhou, F., Huang, R.K., Esser, L., Zeher, A., Cot ^ é, M., Kumar, P., Sodroski, J., Xia, D., Uchil, P.D., Pazgier, M., Finzi, A., Mothes, W., 2022. Structural basis and mode of action for two broadly neutralizing antibodies against sars-cov-2 emerging variants of concern. Cell Rep. 38, 110210.

    17. Li, Y., Ma, M.L., Lei, Q., Wang, F., Hong, W., Lai, D.Y., Hou, H., Xu, Z.W., Zhang, B., Chen, H., Yu, C., Xue, J.B., Zheng, Y.X., Wang, X.N., Jiang, H.W., Zhang, H.N., Qi, H., Guo, S.J., Zhang, Y., Lin, X., Yao, Z., Wu, J., Sheng, H., Zhang, Y., Wei, H., Sun, Z., Fan, X., Tao, S.C., 2021. Linear epitope landscape of the sars-cov-2 spike protein constructed from 1,051 covid-19 patients. Cell Rep. 34, 108915.

    18. Liu, L., Iketani, S., Guo, Y., Chan, J.F., Wang, M., Liu, L., Luo, Y., Chu, H., Huang, Y., Nair, M.S., Yu, J., Chik, K.K., Yuen, T.T., Yoon, C., To, K.K., Chen, H., Yin, M.T., Sobieszczyk, M.E., Huang, Y., Wang, H.H., Sheng, Z., Yuen, K.Y., Ho, D.D., 2022. Striking antibody evasion manifested by the omicron variant of sars-cov-2. Nature 602, 676-681.

    19. Ma, H., Tseng, C.-T.K., Zong, H., Liao, Y., Ke, Y., Tang, H., Wang, L., Wang, Z., He, Y., Chang, Y., Wang, S., Drelich, A., Hsu, J., Tat, V., Yuan, Y., Wu, M., Liu, J., Yue, Y., Xu, W., Zhang, X., Wang, Z., Yang, L., Chen, H., Bian, Y., Zhang, B., Yin, H., Chen, Y., Zhang, E., Zhang, X., Gilly, J., Sun, T., Han, L., Xie, Y., Jiang, H., Zhu, J., 2022a. Efficient neutralization of sars-cov-2 omicron and other vocs by a broad spectrum antibody 8g3. bioRxiv, 2022.2002.2025.482049. Preprint.

    20. Ma, H., Guo, Y., Tang, H., Tseng, C.-T.K., Wang, L., Zong, H., Wang, Z., He, Y., Chang, Y., Wang, S., Huang, H., Ke, Y., Yuan, Y., Wu, M., Zhang, Y., Drelich, A., Kempaiah, K.R., Peng, B.-H., Wang, A., Yang, K., Yin, H., Liu, J., Yue, Y., Xu, W., Zhu, S., Ji, T., Zhang, X., Wang, Z., Li, G., Liu, G., Song, J., Mu, L., Xiang, Z., Song, Z., Chen, H., Bian, Y., Zhang, B., Chen, H., Zhang, J., Liao, Y., Zhang, L., Yang, L., Chen, Y., Gilly, J., Xiao, X., Han, L., Jiang, H., Xie, Y., Zhou, Q., Zhu, J., 2022b. Broad ultrapotent neutralization of sars-cov-2 variants by monoclonal antibodies specific to the tip of rbd. Cell Discovery 8, 16.

    21. McCallum, M., De Marco, A., Lempp, F.A., Tortorici, M.A., Pinto, D., Walls, A.C., Beltramello, M., Chen, A., Liu, Z., Zatta, F., Zepeda, S., di Iulio, J., Bowen, J.E., Montiel-Ruiz, M., Zhou, J., Rosen, L.E., Bianchi, S., Guarino, B., Fregni, C.S., Abdelnabi, R., Foo, S.C., Rothlauf, P.W., Bloyet, L.M., Benigni, F., Cameroni, E., Neyts, J., Riva, A., Snell, G., Telenti, A., Whelan, S.P.J., Virgin, H.W., Corti, D., Pizzuto, M.S., Veesler, D., 2021. N-terminal domain antigenic mapping reveals a site of vulnerability for sars-cov-2. Cell 184, 2332-2347.e16.

    22. Pettersen, E.F., Goddard, T.D., Huang, C.C., Couch, G.S., Greenblatt, D.M., Meng, E.C., Ferrin, T.E., 2004. Ucsf chimera-a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605-1612.

    23. Piccoli, L., Park, Y.J., Tortorici, M.A., Czudnochowski, N., Walls, A.C., Beltramello, M., Silacci-Fregni, C., Pinto, D., Rosen, L.E., Bowen, J.E., Acton, O.J., Jaconi, S., Guarino, B., Minola, A., Zatta, F., Sprugasci, N., Bassi, J., Peter, A., De Marco, A., Nix, J.C., Mele, F., Jovic, S., Rodriguez, B.F., Gupta, S.V., Jin, F., Piumatti, G., Lo Presti, G., Pellanda, A.F., Biggiogero, M., Tarkowski, M., Pizzuto, M.S., Cameroni, E., Havenar-Daughton, C., Smithey, M., Hong, D., Lepori, V., Albanese, E., Ceschi, A., Bernasconi, E., Elzi, L., Ferrari, P., Garzoni, C., Riva, A., Snell, G., Sallusto, F., Fink, K., Virgin, H.W., Lanzavecchia, A., Corti, D., Veesler, D., 2020. Mapping neutralizing and immunodominant sites on the sars-cov-2 spike receptor-binding domain by structure-guided high-resolution serology. Cell 183, 1024-1042.e21.

    24. Pinto, D., Sauer, M.M., Czudnochowski, N., Low, J.S., Tortorici, M.A., Housley, M.P., Noack, J., Walls, A.C., Bowen, J.E., Guarino, B., Rosen, L.E., di Iulio, J., Jerak, J., Kaiser, H., Islam, S., Jaconi, S., Sprugasci, N., Culap, K., Abdelnabi, R., Foo, C., Coelmont, L., Bartha, I., Bianchi, S., Silacci-Fregni, C., Bassi, J., Marzi, R., Vetti, E., Cassotta, A., Ceschi, A., Ferrari, P., Cippá, P.E., Giannini, O., Ceruti, S., Garzoni, C., Riva, A., Benigni, F., Cameroni, E., Piccoli, L., Pizzuto, M.S., Smithey, M., Hong, D., Telenti, A., Lempp, F.A., Neyts, J., Havenar-Daughton, C., Lanzavecchia, A., Sallusto, F., Snell, G., Virgin, H.W., Beltramello, M., Corti, D., Veesler, D., 2021. Broad betacoronavirus neutralization by a stem helix-specific human antibody. Science 373, 1109-1116.

    25. Planas, D., Saunders, N., Maes, P., Guivel-Benhassine, F., Planchais, C., Buchrieser, J., Bolland, W.H., Porrot, F., Staropoli, I., Lemoine, F., Péré, H., Veyer, D., Puech, J., Rodary, J., Baele, G., Dellicour, S., Raymenants, J., Gorissen, S., Geenen, C., Vanmechelen, B., Wawina-Bokalanga, T., Martí-Carreras, J., Cuypers, L., Séve, A., Hocqueloux, L., Prazuck, T., Rey, F.A., Simon-Loriere, E., Bruel, T., Mouquet, H., André, E., Schwartz, O., 2022. Considerable escape of sars-cov-2 omicron to antibody neutralization. Nature 602, 671-675.

    26. Rockett, R., Basile, K., Maddocks, S., Fong, W., Agius, J.E., Johnson-Mackinnon, J., Arnott, A., Chandra, S., Gall, M., Draper, J., Martinez, E., Sim, E.M., Lee, C., Ngo, C., Ramsperger, M., Ginn, A.N., Wang, Q., Fennell, M., Ko, D., Lim, H.L., Gilroy, N., O'Sullivan, M.V.N., Chen, S.C., Kok, J., Dwyer, D.E., Sintchenko, V., 2022. Resistance mutations in sars-cov-2 delta variant after sotrovimab use. N. Engl. J. Med. 386, 1477-1479.

    27. Sakharkar, M., Rappazzo, C.G., Wieland-Alter, W.F., Hsieh, C.L., Wrapp, D., Esterman, E.S., Kaku, C.I., Wec, A.Z., Geoghegan, J.C., McLellan, J.S., Connor, R.I., Wright, P.F., Walker, L.M., 2021. Prolonged evolution of the human b cell response to sars-cov-2 infection. Sci Immunol 6, 1-14.

    28. Sauer, M.M., Tortorici, M.A., Park, Y.J., Walls, A.C., Homad, L., Acton, O.J., Bowen, J.E., Wang, C., Xiong, X., de van der Schueren, W., Quispe, J., Hoffstrom, B.G., Bosch, B.J., McGuire, A.T., Veesler, D., 2021. Structural basis for broad coronavirus neutralization. Nat. Struct. Mol. Biol. 28, 478-486.

    29. Shah, P., Canziani, G.A., Carter, E.P., Chaiken, I., 2021. The case for s2: the potential benefits of the s2 subunit of the sars-cov-2 spike protein as an immunogen in fighting the covid-19 pandemic. Front. Immunol. 12, 637-651.

    30. Starr, T.N., Greaney, A.J., Addetia, A., Hannon, W.W., Choudhary, M.C., Dingens, A.S., Li, J.Z., Bloom, J.D., 2021. Prospective mapping of viral mutations that escape antibodies used to treat covid-19. Science 371, 850-854.

    31. Tang, H., Ke, Y., Wang, L., Wu, M., Sun, T., Zhu, J., 2022. Recombinant decoy exhibits broad protection against omicron and resistance potential to future variants.Pharmaceuticals 15, 1-18.

    32. Tao, K., Tzou, P.L., Nouhin, J., Gupta, R.K., de Oliveira, T., Kosakovsky Pond, S.L., Fera, D., Shafer, R.W., 2021. The biological and clinical significance of emerging sarscov-2 variants. Nat. Rev. Genet. 22, 757-773.

    33. Tortorici, M.A., Veesler, D., 2019. Structural insights into coronavirus entry. Adv. Virus Res. 105, 93-116.

    34. Tortorici, M.A., Czudnochowski, N., Starr, T.N., Marzi, R., Walls, A.C., Zatta, F., Bowen, J.E., Jaconi, S., Di Iulio, J., Wang, Z., De Marco, A., Zepeda, S.K., Pinto, D., Liu, Z., Beltramello, M., Bartha, I., Housley, M.P., Lempp, F.A., Rosen, L.E., Dellota Jr., E., Kaiser, H., Montiel-Ruiz, M., Zhou, J., Addetia, A., Guarino, B., Culap, K., Sprugasci, N., Saliba, C., Vetti, E., Giacchetto-Sasselli, I., Fregni, C.S., Abdelnabi, R., Foo, S.C., Havenar-Daughton, C., Schmid, M.A., Benigni, F., Cameroni, E., Neyts, J., Telenti, A., Virgin, H.W., Whelan, S.P.J., Snell, G., Bloom, J.D., Corti, D., Veesler, D., Pizzuto, M.S., 2021. Broad sarbecovirus neutralization by a human monoclonal antibody. Nature 597, 103-108.

    35. Ullah, I., Prévost, J., Ladinsky, M.S., Stone, H., Lu, M., Anand, S.P., BeaudoinBussiéres, G., Symmes, K., Benlarbi, M., Ding, S., Gasser, R., Fink, C., Chen, Y., Tauzin, A., Goyette, G., Bourassa, C., Medjahed, H., Mack, M., Chung, K., Wilen, C.B., Dekaban, G.A., Dikeakos, J.D., Bruce, E.A., Kaufmann, D.E., Stamatatos, L., McGuire, A.T., Richard, J., Pazgier, M., Bjorkman, P.J., Mothes, W., Finzi, A., Kumar, P., Uchil, P.D., 2021. Live imaging of sars-cov-2 infection in mice reveals that neutralizing antibodies require fc function for optimal efficacy. Immunity 54, 2143-2158.e15.

    36. Viana, R., Moyo, S., Amoako, D.G., Tegally, H., Scheepers, C., Althaus, C.L., Anyaneji, U.J., Bester, P.A., Boni, M.F., Chand, M., Choga, W.T., Colquhoun, R., Davids, M., Deforche, K., Doolabh, D., du Plessis, L., Engelbrecht, S., Everatt, J., Giandhari, J., Giovanetti, M., Hardie, D., Hill, V., Hsiao, N.Y., Iranzadeh, A., Ismail, A., Joseph, C., Joseph, R., Koopile, L., Kosakovsky Pond, S.L., Kraemer, M.U.G., Kuate-Lere, L., Laguda-Akingba, O., Lesetedi-Mafoko, O., Lessells, R.J., Lockman, S., Lucaci, A.G., Maharaj, A., Mahlangu, B., Maponga, T., Mahlakwane, K., Makatini, Z., Marais, G., Maruapula, D., Masupu, K., Matshaba, M., Mayaphi, S., Mbhele, N., Mbulawa, M.B., Mendes, A., Mlisana, K., Mnguni, A., Mohale, T., Moir, M., Moruisi, K., Mosepele, M., Motsatsi, G., Motswaledi, M.S., Mphoyakgosi, T., Msomi, N., Mwangi, P.N., Naidoo, Y., Ntuli, N., Nyaga, M., Olubayo, L., Pillay, S., Radibe, B., Ramphal, Y., Ramphal, U., San, J.E., Scott, L., Shapiro, R., Singh, L., Smith-Lawrence, P., Stevens, W., Strydom, A., Subramoney, K., Tebeila, N., Tshiabuila, D., Tsui, J., van Wyk, S., Weaver, S., Wibmer, C.K., Wilkinson, E., Wolter, N., Zarebski, A.E., Zuze, B., Goedhals, D., Preiser, W., Treurnicht, F., Venter, M., Williamson, C., Pybus, O.G., Bhiman, J., Glass, A., Martin, D.P., Rambaut, A., Gaseitsiwe, S., von Gottberg, A., de Oliveira, T., 2022.Rapid epidemic expansion of the sars-cov-2 omicron variant in southern africa. Nature 603, 679-686.

    37. Voss, W.N., Hou, Y.J., Johnson, N.V., Delidakis, G., Kim, J.E., Javanmardi, K., Horton, A.P., Bartzoka, F., Paresi, C.J., Tanno, Y., Chou, C.W., Abbasi, S.A., Pickens, W., George, K., Boutz, D.R., Towers, D.M., McDaniel, J.R., Billick, D., Goike, J., Rowe, L., Batra, D., Pohl, J., Lee, J., Gangappa, S., Sambhara, S., Gadush, M., Wang, N., Person, M.D., Iverson, B.L., Gollihar, J.D., Dye, J.M., Herbert, A.S., Finkelstein, I.J., Baric, R.S., McLellan, J.S., Georgiou, G., Lavinder, J.J., Ippolito, G.C., 2021. Prevalent, protective, and convergent igg recognition of sarscov-2 non-rbd spike epitopes. Science 372, 1108-1112.

    38. Wall, E.C., Wu, M., Harvey, R., Kelly, G., Warchal, S., Sawyer, C., Daniels, R., Hobson, P., Hatipoglu, E., Ngai, Y., Hussain, S., Nicod, J., Goldstone, R., Ambrose, K., Hindmarsh, S., Beale, R., Riddell, A., Gamblin, S., Howell, M., Kassiotis, G., Libri, V., Williams, B., Swanton, C., Gandhi, S., Bauer, D.L., 2021. Neutralising antibody activity against sars-cov-2 vocs b.1.617.2 and b.1.351 by bnt162b2 vaccination. Lancet 397, 2331-2333.

    39. Walls, A.C., Park, Y.J., Tortorici, M.A., Wall, A., McGuire, A.T., Veesler, D., 2020a. Structure, function, and antigenicity of the sars-cov-2 spike glycoprotein. Cell 181, 281-292 e286.

    40. Walls, A.C., Fiala, B., Schäfer, A., Wrenn, S., Pham, M.N., Murphy, M., Tse, L.V., Shehata, L., O'Connor, M.A., Chen, C., Navarro, M.J., Miranda, M.C., Pettie, D., Ravichandran, R., Kraft, J.C., Ogohara, C., Palser, A., Chalk, S., Lee, E.C., Guerriero, K., Kepl, E., Chow, C.M., Sydeman, C., Hodge, E.A., Brown, B., Fuller, J.T., Dinnon 3rd, K.H., Gralinski, L.E., Leist, S.R., Gully, K.L., Lewis, T.B., Guttman, M., Chu, H.Y., Lee, K.K., Fuller, D.H., Baric, R.S., Kellam, P., Carter, L., Pepper, M., Sheahan, T.P., Veesler, D., King, N.P., 2020b. Elicitation of potent neutralizing antibody responses by designed protein nanoparticle vaccines for sars-cov-2. Cell 183, 1367-1382 e1317.

    41. Wang, L., Zhou, T., Zhang, Y., Yang, E.S., Schramm, C.A., Shi, W., Pegu, A., Oloniniyi, O.K., Henry, A.R., Darko, S., Narpala, S.R., Hatcher, C., Martinez, D.R., Tsybovsky, Y., Phung, E., Abiona, O.M., Antia, A., Cale, E.M., Chang, L.A., Choe, M., Corbett, K.S., Davis, R.L., DiPiazza, A.T., Gordon, I.J., Hait, S.H., Hermanus, T., Kgagudi, P., Laboune, F., Leung, K., Liu, T., Mason, R.D., Nazzari, A.F., Novik, L., O'Connell, S., O'Dell, S., Olia, A.S., Schmidt, S.D., Stephens, T., Stringham, C.D., Talana, C.A., Teng, I.T., Wagner, D.A., Widge, A.T., Zhang, B., Roederer, M., Ledgerwood, J.E., Ruckwardt, T.J., Gaudinski, M.R., Moore, P.L., Doria-Rose, N.A., Baric, R.S., Graham, B.S., McDermott, A.B., Douek, D.C., Kwong, P.D., Mascola, J.R., Sullivan, N.J., Misasi, J., 2021. Ultrapotent antibodies against diverse and highly transmissible sars-cov-2 variants. Science 373, 1-14.

    42. Wang, P., Nair, M.S., Liu, L., Iketani, S., Luo, Y., Guo, Y., Wang, M., Yu, J., Zhang, B., Kwong, P.D., Graham, B.S., Mascola, J.R., Chang, J.Y., Yin, M.T., Sobieszczyk, M., Kyratsous, C.A., Shapiro, L., Sheng, Z., Huang, Y., Ho, D.D., 2021. Antibody resistance of sars-cov-2 variants b.1.351 and b.1.1.7. Nature 593, 130-135.

    43. Whelan, S.P., Ball, L.A., Barr, J.N., Wertz, G.T., 1995. Efficient recovery of infectious vesicular stomatitis virus entirely from cdna clones. Proc. Natl. Acad. Sci. U. S. A. 92, 8388-8392.

    44. Woo, H., Park, S.J., Choi, Y.K., Park, T., Tanveer, M., Cao, Y., Kern, N.R., Lee, J., Yeom, M.S., Croll, T.I., Seok, C., Im, W., 2020. Developing a fully glycosylated fulllength sars-cov-2 spike protein model in a viral membrane. J. Phys. Chem. B 124, 7128-7137.

    45. Yu, X., Wei, D., Xu, W., Liu, C., Guo, W., Li, X., Tan, W., Liu, L., Zhang, X., Qu, J., Yang, Z., Chen, E., 2022. Neutralizing activity of bbibp-corv vaccine-elicited sera against beta, delta and other sars-cov-2 variants of concern. Nat. Commun. 13, 1788.

    46. Zhou, P., Yuan, M., Song, G., Beutler, N., Shaabani, N., Huang, D., He, W.T., Zhu, X., Callaghan, S., Yong, P., Anzanello, F., Peng, L., Ricketts, J., Parren, M., Garcia, E., Rawlings, S.A., Smith, D.M., Nemazee, D., Teijaro, J.R., Rogers, T.F., Wilson, I.A., Burton, D.R., Andrabi, R., 2022. A human antibody reveals a conserved site on betacoronavirus spike proteins and confers protection against sars-cov-2 infection. Sci.Transl. Med. 14, eabi9215.

  • 加载中

Article Metrics

Article views(244) PDF downloads(2) Cited by()

Related
Proportional views
    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Mutational escape prevention by combination of four neutralizing antibodies that target RBD conserved regions and stem helix

      Corresponding author: Baohong Zhang, bhzhang@sjtu.edu.cn
      Corresponding author: Xiaoju Zhang, zhangxiaoju@zzu.edu.cn
      Corresponding author: Mingyuan Wu, wumingyuan@sjtu.edu.cn
      Corresponding author: Jianwei Zhu, jianweiz@sjtu.edu.cn
    • a Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, Shanghai, 200240, China;
    • b School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China;
    • c School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, 200240, China;
    • d Shanghai Municipal Veterinary Key Laboratory, Shanghai, 200240, China;
    • e Department of Respiratory and Critical Care Medicine, Zhengzhou University People's Hospital/Henan Provincial People's Hospital, Zhengzhou, 450003, China;
    • f Jecho Institute, Shanghai, 200240, China

    Abstract: New variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appear rapidly every few months. They have showed powerful adaptive ability to circumvent the immune system. To further understand SARS-CoV-2's adaptability so as to seek for strategies to mitigate the emergence of new variants, herein we investigated the viral adaptation in the presence of broadly neutralizing antibodies and their combinations. First, we selected four broadly neutralizing antibodies, including pan-sarbecovirus and pan-betacoronavirus neutralizing antibodies that recognize distinct conserved regions on receptor-binding domain (RBD) or conserved stem-helix region on S2 subunit. Through binding competition analysis, we demonstrated that they were capable of simultaneously binding. Thereafter, a replication-competent vesicular stomatitis virus pseudotyped with SARS-CoV-2 spike protein was employed to study the viral adaptation. Twenty consecutive passages of the virus under the selective pressure of individual antibodies or their combinations were performed. It was found that it was not hard for the virus to adapt to broadly neutralizing antibodies, even for pan-sarbecovirus and pan-betacoronavirus antibodies. The virus was more and more difficult to escape the combinations of two/three/four antibodies. In addition, mutations in the viral population revealed by high-throughput sequencing showed that under the selective pressure of three/four combinational antibodies, viral mutations were not prone to present in the highly conserved region across betacoronaviruses (stem-helix region), while this was not true under the selective pressure of single/two antibodies. Importantly, combining neutralizing antibodies targeting RBD conserved regions and stem helix synergistically prevented the emergence of escape mutations. These studies will guide future vaccine and therapeutic development efforts and provide a rationale for the design of RBD-stem helix tandem vaccine, which may help to impede the generation of novel variants.

    Reference (46) Relative (20)

    目录

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return