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3. Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts tropism and fusogenicity

Author

Meng, B., Abdullahi, A., Ferreira, I., Goonawardane, N., Saito, A., Kimura, I., Yamasoba, D., Gerber, P., Fatihi, S., Rathore, S., Zepeda, S., Papa, G., Kemp, S., Ikeda, T., Toyoda, M., Tan, T., Kuramochi, J., Mitsunaga, S., Ueno, T., Shirakawa, K., Takaori-Kondo, A., Brevini, T., Mallery, D., Charles, O., Collaboration, C., Japan, G., Consortium, E., Bowen, J., Joshi, A., Walls, A., Jackson, L., Martin, D., Smith, K., Bradley, J., Briggs, J., Choi, J., Madissoon, E., Meyer, K., Mlcochova, P., Ceron-Gutierrez, L., Doffinger, R., Teichmann, S., Fisher, A., Pizzuto, M., de Marco, A., Corti, D., Hosmillo, M., Lee, J., James, L., Thukral, L., Veesler, D., Sigal, A., Sampaziotis, F., Goodfellow, I., Matheson, N., Sato, K., and Gupta, R.

Subjects
Immune evasion, SARS-CoV-2
Abstract

The SARS-CoV-2 Omicron BA.1 variant emerged in 20211 and bears multiple spike mutations2. Here we show that Omicron spike has higher affinity for ACE2 compared to Delta as well as a marked change of antigenicity conferring significant evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralising antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralisation. Importantly, antiviral drugs remdesivir and molnupiravir retain efficacy against Omicron BA.1. Replication was similar for Omicron and Delta virus isolates in human nasal epithelial cultures. However, in lower airway organoids, lung cells and gut cells, Omicron demonstrated lower replication. Omicron spike protein was less efficiently cleaved compared to Delta. Replication differences mapped to entry efficiency using spike pseudotyped virus (PV) assays. The defect for Omicron PV to enter specific cell types effectively correlated with higher cellular RNA expression of TMPRSS2, and knock down of TMPRSS2 impacted Delta entry to a greater extent than Omicron. Furthermore, drug inhibitors targeting specific entry pathways3 demonstrated that the Omicron spike inefficiently utilises the cellular protease TMPRSS2 that promotes cell entry via plasma membrane fusion, with greater dependency on cell entry via the endocytic pathway. Consistent with suboptimal S1/S2 cleavage and inability to utilise TMPRSS2, syncytium formation by the Omicron spike was markedly impaired compared to the Delta spike. Omicron’s less efficient spike cleavage at S1/S2 is associated with shift in cellular tropism away from TMPRSS2 expressing cells, with implications for altered pathogenesis., SARS-CoV-2オミクロン株による中和抗体回避と感染指向性の変化. 京都大学プレスリリース. 2022-02-03.

Published
2022

4. Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity

Author

Meng, B., Abdullahi, A., Ferreira, I. A. T. M., Goonawardane, N., Saito, A., Kimura, I., Yamasoba, D., Gerber, P. P., Fatihi, S., Rathore, S., Zepeda, S. K., Papa, G., Kemp, S. A., Ikeda, T., Toyoda, M., Tan, T. S., Kuramochi, J., Mitsunaga, S., Ueno, T., Shirakawa, K., Takaori-Kondo, A., Brevini, T., Mallery, D. L., Charles, O. J., Baker, S., Dougan, G., Hess, C., Kingston, N., Lehner, P. J., Lyons, P. A., Matheson, N. J., Ouwehand, W. H., Saunders, C., Summers, C., Thaventhiran, J. E. D., Toshner, M., Weekes, M. P., Maxwell, P., Shaw, A., Bucke, A., Calder, J., Canna, L., Domingo, J., Elmer, A., Fuller, S., Harris, J., Hewitt, S., Kennet, J., Jose, S., Kourampa, J., Meadows, A., O'Brien, C., Price, J., Publico, C., Rastall, R., Ribeiro, C., Rowlands, J., Ruffolo, V., Tordesillas, H., Bullman, B., Dunmore, B. J., Graf, S., Hodgson, J., Huang, C., Hunter, K., Jones, E., Legchenko, E., Matara, C., Martin, J., Mescia, F., O'Donnell, C., Pointon, L., Shih, J., Sutcliffe, R., Tilly, T., Treacy, C., Tong, Z., Wood, J., Wylot, M., Betancourt, A., Bower, G., Cossetti, C., De Sa, A., Epping, M., Fawke, S., Gleadall, N., Grenfell, R., Hinch, A., Jackson, S., Jarvis, I., Krishna, B., Nice, F., Omarjee, O., Perera, M., Potts, M., Richoz, N., Romashova, V., Stefanucci, L., Strezlecki, M., Turner, L., De Bie, E. M. D. D., Bunclark, K., Josipovic, M., Mackay, M., Butcher, H., Caputo, D., Chandler, M., Chinnery, P., Clapham-Riley, D., Dewhurst, E., Fernandez, C., Furlong, A., Graves, B., Gray, J., Hein, S., Ivers, T., Le Gresley, E., Linger, R., Kasanicki, M., King, R., Meloy, S., Moulton, A., Muldoon, F., Ovington, N., Papadia, S., Penkett, C. J., Phelan, I., Ranganath, V., Paraschiv, R., Sage, A., Sambrook, J., Scholtes, I., Schon, K., Stark, H., Stirrups, K. E., Townsend, P., Walker, N., Webster, J., Butlertanaka, E. P., Tanaka, Y. L., Ito, J., Uriu, K., Kosugi, Y., Suganami, M., Oide, A., Yokoyama, M., Chiba, M., Motozono, C., Nasser, H., Shimizu, R., Kitazato, K., Hasebe, H., Irie, T., Nakagawa, S., Wu, J., Takahashi, M., Fukuhara, T., Shimizu, K., Tsushima, K., Kubo, H., Kazuma, Y., Nomura, R., Horisawa, Y., Nagata, K., Kawai, Y., Yanagida, Y., Tashiro, Y., Tokunaga, K., Ozono, S., Kawabata, R., Morizako, N., Sadamasu, K., Asakura, H., Nagashima, M., Yoshimura, K., Cardenas, P., Munoz, E., Barragan, V., Marquez, S., Prado-Vivar, B., Becerra-Wong, M., Caravajal, M., Trueba, G., Rojas-Silva, P., Grunauer, M., Gutierrez, B., Guadalupe, J. J., Fernandez-Cadena, J. C., Andrade-Molina, D., Baldeon, M., Pinos, A., Bowen, J. E., Joshi, A., Walls, A. C., Jackson, L., Martin, D., Smith, K. G. C., Bradley, J., Briggs, J. A. G., Choi, J., Madissoon, E., Meyer, K. B., Mlcochova, P., Ceron-Gutierrez, L., Doffinger, R., Teichmann, S. A., Fisher, A. J., Pizzuto, M. S., de Marco, A., Corti, D., Hosmillo, M., Lee, J. H., James, L. C., Thukral, L., Veesler, D., Sigal, A., Sampaziotis, F., Goodfellow, I. G., Sato, K., and Gupta, R. K.

Subjects
Adult, Male, COVID-19 Vaccines, Virus Replication, Membrane Fusion, Antibodies, Cell Line, Tissue Culture Techniques, Chlorocebus aethiops, 80 and over, Animals, Humans, Viral, Neutralizing, Lung, Aged, Multidisciplinary, Virulence, SARS-CoV-2, Immune Sera, Cell Membrane, Serine Endopeptidases, COVID-19, Convalescence, Middle Aged, Virus Internalization, Spike Glycoprotein, Intestines, Coronavirus, Nasal Mucosa, Mutation, Female, Angiotensin-Converting Enzyme 2, Aged, 80 and over, Antibodies, Neutralizing, Antibodies, Viral, Spike Glycoprotein, Coronavirus
Abstract

The SARS-CoV-2 Omicron BA.1 variant emerged in 20211 and has multiple mutations in its spike protein2. Here we show that the spike protein of Omicron has a higher affinity for ACE2 compared with Delta, and a marked change in its antigenicity increases Omicron’s evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralizing antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralization. Importantly, the antiviral drugs remdesivir and molnupiravir retain efficacy against Omicron BA.1. Replication was similar for Omicron and Delta virus isolates in human nasal epithelial cultures. However, in lung cells and gut cells, Omicron demonstrated lower replication. Omicron spike protein was less efficiently cleaved compared with Delta. The differences in replication were mapped to the entry efficiency of the virus on the basis of spike-pseudotyped virus assays. The defect in entry of Omicron pseudotyped virus to specific cell types effectively correlated with higher cellular RNA expression of TMPRSS2, and deletion of TMPRSS2 affected Delta entry to a greater extent than Omicron. Furthermore, drug inhibitors targeting specific entry pathways3 demonstrated that the Omicron spike inefficiently uses the cellular protease TMPRSS2, which promotes cell entry through plasma membrane fusion, with greater dependency on cell entry through the endocytic pathway. Consistent with suboptimal S1/S2 cleavage and inability to use TMPRSS2, syncytium formation by the Omicron spike was substantially impaired compared with the Delta spike. The less efficient spike cleavage of Omicron at S1/S2 is associated with a shift in cellular tropism away from TMPRSS2-expressing cells, with implications for altered pathogenesis.

Published
2022

6. Computational design of mechanically coupled axle-rotor protein assemblies

Author

Courbet, A., Hansen, J., Hsia, Y., Bethel, N., Park, Y.-J., Xu, C., Moyer, A., Boyken, S.E., Ueda, G., Nattermann, U., Nagarajan, D., Silva, D., Sheffler, W., Quispe, J., Nord, A., King, N., Bradley, P., Veesler, D., Kollman, J., Baker, D., Courbet, A., Hansen, J., Hsia, Y., Bethel, N., Park, Y.-J., Xu, C., Moyer, A., Boyken, S.E., Ueda, G., Nattermann, U., Nagarajan, D., Silva, D., Sheffler, W., Quispe, J., Nord, A., King, N., Bradley, P., Veesler, D., Kollman, J., and Baker, D.

Abstract

Natural molecular machines contain protein components that undergo motion relative to each other. Designing such mechanically constrained nanoscale protein architectures with internal degrees of freedom is an outstanding challenge for computational protein design. Here we explore the de novo construction of protein machinery from designed axle and rotor components with internal cyclic or dihedral symmetry. We find that the axle-rotor systems assemble in vitro and in vivo as designed. Using cryo–electron microscopy, we find that these systems populate conformationally variable relative orientations reflecting the symmetry of the coupled components and the computationally designed interface energy landscape. These mechanical systems with internal degrees of freedom are a step toward the design of genetically encodable nanomachines. © 2022 American Association for the Advancement of Science. All rights reserved.

Published
2022

7. Computational design of mechanically coupled axle-rotor protein assemblies

Author

Courbet, A., primary, Hansen, J., additional, Hsia, Y., additional, Bethel, N., additional, Park, Y.-J., additional, Xu, C., additional, Moyer, A., additional, Boyken, S. E., additional, Ueda, G., additional, Nattermann, U., additional, Nagarajan, D., additional, Silva, D., additional, Sheffler, W., additional, Quispe, J., additional, Nord, A., additional, King, N., additional, Bradley, P., additional, Veesler, D., additional, Kollman, J., additional, and Baker, D., additional

Published
2022
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9. Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies

Author

Collier, D. A., De Marco, A., Ferreira, I. A. T. M., Meng, B., Datir, R. P., Walls, A. C., Kemp, S. A., Bassi, J., Pinto, D., Silacci-Fregni, C., Bianchi, S., Tortorici, M. A., Bowen, J., Culap, K., Jaconi, S., Cameroni, E., Snell, G., Pizzuto, M. S., Pellanda, A. F., Garzoni, C., Riva, A., Baker, S., Dougan, G., Hess, C., Kingston, N., Lehner, P. J., Lyons, P. A., Matheson, N. J., Owehand, W. H., Saunders, C., Summers, C., Thaventhiran, J. E. D., Toshner, M., Weekes, M. P., Bucke, A., Calder, J., Canna, L., Domingo, J., Elmer, A., Fuller, S., Harris, J., Hewitt, S., Kennet, J., Jose, S., Kourampa, J., Meadows, A., O'Brien, C., Price, J., Publico, C., Rastall, R., Ribeiro, C., Rowlands, J., Ruffolo, V., Tordesillas, H., Bullman, B., Dunmore, B. J., Fawke, S., Graf, S., Hodgson, J., Huang, C., Hunter, K., Jones, E., Legchenko, E., Matara, C., Martin, J., Mescia, F., O'Donnell, C., Pointon, L., Pond, N., Shih, J., Sutcliffe, R., Tilly, T., Treacy, C., Tong, Z., Wood, J., Wylot, M., Bergamaschi, L., Betancourt, A., Bower, G., Cossetti, C., De Sa, A., Epping, M., Grenfell, R., Hinch, A., Huhn, O., Jackson, S., Jarvis, I., Lewis, D., Marsden, J., Nice, F., Okecha, G., Omarjee, O., Perera, M., Richoz, N., Romashova, V., Yarkoni, N. S., Sharma, R., Stefanucci, L., Stephens, J., Strezlecki, M., Turner, L., De Bie, E. M. D. D., Bunclark, K., Josipovic, M., Mackay, M., Rossi, S., Selvan, M., Spencer, S., Yong, C., Ansaripour, A., Michael, A., Mwaura, L., Patterson, C., Polwarth, G., Polgarova, P., di Stefano, G., Fahey, C., Michel, R., Bong, S. -H., Coudert, J. D., Holmes, E., Allison, J., Butcher, H., Caputo, D., Clapham-Riley, D., Dewhurst, E., Furlong, A., Graves, B., Gray, J., Ivers, T., Kasanicki, M., Le Gresley, E., Linger, R., Meloy, S., Muldoon, F., Ovington, N., Papadia, S., Phelan, I., Stark, H., Stirrups, K. E., Townsend, P., Walker, N., Webster, J., Mccoy, L. E., Smith, K. G. C., Bradley, J. R., Temperton, N., Ceron-Gutierrez, L., Barcenas-Morales, G., Robson, S. C., Loman, N. J., Connor, T. R., Golubchik, T., Martinez Nunez, R. T., Ludden, C., Corden, S., Johnston, I., Bonsall, D., Smith, C. P., Awan, A. R., Bucca, G., Torok, M. E., Saeed, K., Prieto, J. A., Jackson, D. K., Hamilton, W. L., Snell, L. B., Moore, C., Harrison, E. M., Goncalves, S., Fairley, D. J., Loose, M. W., Watkins, J., Livett, R., Moses, S., Amato, R., Nicholls, S., Bull, M., Smith, D. L., Barrett, J., Aanensen, D. M., Curran, M. D., Parmar, S., Aggarwal, D., Shepherd, J. G., Parker, M. D., Glaysher, S., Bashton, M., Underwood, A. P., Pacchiarini, N., Loveson, K. F., Carabelli, A. M., Templeton, K. E., Langford, C. F., Sillitoe, J., de Silva, T. I., Wang, D., Kwiatkowski, D., Rambaut, A., O'Grady, J., Cottrell, S., Holden, M. T. G., Thomson, E. C., Osman, H., Andersson, M., Chauhan, A. J., Hassan-Ibrahim, M. O., Lawniczak, M., Alderton, A., Chand, M., Constantinidou, C., Unnikrishnan, M., Darby, A. C., Hiscox, J. A., Paterson, S., Martincorena, I., Robertson, D. L., Volz, E. M., Page, A. J., Pybus, O. G., Bassett, A. R., Ariani, C. V., Spencer Chapman, M. H., K. K., Li, Shah, R. N., Jesudason, N. G., Taha, Y., Mchugh, M. P., Dewar, R., Jahun, A. S., Mcmurray, C., Pandey, S., Mckenna, J. P., Nelson, A., Young, G. R., Mccann, C. M., Elliott, S., Lowe, H., Temperton, B., Roy, S., Price, A., Rey, S., Wyles, M., Rooke, S., Shaaban, S., de Cesare, M., Letchford, L., Silveira, S., Pelosi, E., Wilson-Davies, E., Hosmillo, M., O'Toole, A., Hesketh, A. R., Stark, R., du Plessis, L., Ruis, C., Adams, H., Bourgeois, Y., Michell, S. L., Gramatopoulos, D., Edgeworth, J., Breuer, J., Todd, J. A., Fraser, C., Buck, D., John, M., Kay, G. L., Palmer, S., Peacock, S. J., Heyburn, D., Weldon, D., Robinson, E., Mcnally, A., Muir, P., Vipond, I. B., Boyes, J., Sivaprakasam, V., Salluja, T., Dervisevic, S., Meader, E. J., Park, N. R., Oliver, K., Jeffries, A. R., Ott, S., da Silva Filipe, A., Simpson, D. A., Williams, C., Masoli, J. A. H., Knight, B. A., Jones, C. R., Koshy, C., Ash, A., Casey, A., Bosworth, A., Ratcliffe, L., Xu-McCrae, L., Pymont, H. M., Hutchings, S., Berry, L., Jones, K., Halstead, F., Davis, T., Holmes, C., Iturriza-Gomara, M., Lucaci, A. O., Randell, P. A., Cox, A., Madona, P., Harris, K. A., Brown, J. R., Mahungu, T. W., Irish-Tavares, D., Haque, T., Hart, J., Witele, E., Fenton, M. L., Liggett, S., Graham, C., Swindells, E., Collins, J., Eltringham, G., Campbell, S., Mcclure, P. C., Clark, G., Sloan, T. J., Jones, C., Lynch, J., Warne, B., Leonard, S., Durham, J., Williams, T., Haldenby, S. T., Storey, N., Alikhan, N. -F., Holmes, N., Carlile, M., Perry, M., Craine, N., Lyons, R. A., Beckett, A. H., Goudarzi, S., Fearn, C., Cook, K., Dent, H., Paul, H., Davies, R., Blane, B., Girgis, S. T., Beale, M. A., Bellis, K. L., Dorman, M. J., Drury, E., Kane, L., Kay, S., Mcguigan, S., Nelson, R., Prestwood, L., Rajatileka, S., Batra, R., Williams, R. J., Kristiansen, M., Green, A., Justice, A., Mahanama, A. I. K., Samaraweera, B., Hadjirin, N. F., Quick, J., Poplawski, R., Kermack, L. M., Reynolds, N., Hall, G., Chaudhry, Y., Pinckert, M. L., Georgana, I., Moll, R. J., Thornton, A., Myers, R., Stockton, J., Williams, C. A., Yew, W. C., Trotter, A. J., Trebes, A., MacIntyre-Cockett, G., Birchley, A., Adams, A., Plimmer, A., Gatica-Wilcox, B., Mckerr, C., Hilvers, E., Jones, H., Asad, H., Coombes, J., Evans, J. M., Fina, L., Gilbert, L., Graham, L., Cronin, M., Kumziene-Summerhayes, S., Taylor, S., Jones, S., Groves, D. C., Zhang, P., Gallis, M., Louka, S. F., Starinskij, I., Jackson, C., Gourtovaia, M., Tonkin-Hill, G., Lewis, K., Tovar-Corona, J. M., James, K., Baxter, L., Alam, M. T., Orton, R. J., Hughes, J., Vattipally, S., Ragonnet-Cronin, M., Nascimento, F. F., Jorgensen, D., Boyd, O., Geidelberg, L., Zarebski, A. E., Raghwani, J., Kraemer, M. U. G., Southgate, J., Lindsey, B. B., Freeman, T. M., Keatley, J. -P., Singer, J. B., de Oliveira Martins, L., Yeats, C. A., Abudahab, K., Taylor, B. E. W., Menegazzo, M., Danesh, J., Hogsden, W., Eldirdiri, S., Kenyon, A., Mason, J., Robinson, T. I., Holmes, A., Hartley, J. A., Curran, T., Mather, A. E., Shankar, G., Jones, R., Howe, R., Morgan, S., Wastenge, E., Chapman, M. R., Mookerjee, S., Stanley, R., Smith, W., Peto, T., Eyre, D., Crook, D., Vernet, G., Kitchen, C., Gulliver, H., Merrick, I., Guest, M., Munn, R., Bradley, D. T., Wyatt, T., Beaver, C., Foulser, L., Churcher, C. M., Brooks, E., Smith, K. S., Galai, K., Mcmanus, G. M., Bolt, F., Coll, F., Meadows, L., Attwood, S. W., Davies, A., De Lacy, E., Downing, F., Edwards, S., Scarlett, G. P., Jeremiah, S., Smith, N., Leek, D., Sridhar, S., Forrest, S., Cormie, C., Gill, H. K., Dias, J., Higginson, E. E., Maes, M., Young, J., Wantoch, M., Jamrozy, D., Lo, S., Patel, M., Hill, V., Bewshea, C. M., Ellard, S., Auckland, C., Harrison, I., Bishop, C., Chalker, V., Richter, A., Beggs, A., Best, A., Percival, B., Mirza, J., Megram, O., Mayhew, M., Crawford, L., Ashcroft, F., Moles-Garcia, E., Cumley, N., Hopes, R., Asamaphan, P., Niebel, M. O., Gunson, R. N., Bradley, A., Maclean, A., Mollett, G., Blacow, R., Bird, P., Helmer, T., Fallon, K., Tang, J., Hale, A. D., Macfarlane-Smith, L. R., Harper, K. L., Carden, H., Machin, N. W., Jackson, K. A., Ahmad, S. S. Y., George, R. P., Turtle, L., O'Toole, E., Watts, J., Breen, C., Cowell, A., Alcolea-Medina, A., Charalampous, T., Patel, A., Levett, L. J., Heaney, J., Rowan, A., Taylor, G. P., Shah, D., Atkinson, L., Lee, J. C. D., Westhorpe, A. P., Jannoo, R., Lowe, H. L., Karamani, A., Ensell, L., Chatterton, W., Pusok, M., Dadrah, A., Symmonds, A., Sluga, G., Molnar, Z., Baker, P., Bonner, S., Essex, S., Barton, E., Padgett, D., Scott, G., Greenaway, J., Payne, B. A. I., Burton-Fanning, S., Waugh, S., Raviprakash, V., Sheriff, N., Blakey, V., Williams, L. -A., Moore, J., Stonehouse, S., Smith, L., Davidson, R. K., Bedford, L., Coupland, L., Wright, V., Chappell, J. G., Tsoleridis, T., Ball, J., Khakh, M., Fleming, V. M., Lister, M. M., Howson-Wells, H. C., Boswell, T., Joseph, A., Willingham, I., Duckworth, N., Walsh, S., Wise, E., Moore, N., Mori, M., Cortes, N., Kidd, S., Williams, R., Gifford, L., Bicknell, K., Wyllie, S., Lloyd, A., Impey, R., Malone, C. S., Cogger, B. J., Levene, N., Monaghan, L., Keeley, A. J., Partridge, D. G., Raza, M., Evans, C., Johnson, K., Betteridge, E., Farr, B. W., Goodwin, S., Quail, M. A., Scott, C., Shirley, L., Thurston, S. A. J., Rajan, D., Bronner, I. F., Aigrain, L., Redshaw, N. M., Lensing, S. V., Mccarthy, S., Makunin, A., Balcazar, C. E., Gallagher, M. D., Williamson, K. A., Stanton, T. D., Michelsen, M. L., Warwick-Dugdale, J., Manley, R., Farbos, A., Harrison, J. W., Sambles, C. M., Studholme, D. J., Lackenby, A., Mbisa, T., Platt, S., Miah, S., Bibby, D., Manso, C., Hubb, J., Dabrera, G., Ramsay, M., Bradshaw, D., Schaefer, U., Groves, N., Gallagher, E., Lee, D., Williams, D., Ellaby, N., Hartman, H., Manesis, N., Patel, V., Ledesma, J., Twohig, K. A., Allara, E., Pearson, C., Cheng, J. K. J., Bridgewater, H. E., Frost, L. R., Taylor-Joyce, G., Brown, P. E., Tong, L., Broos, A., Mair, D., Nichols, J., Carmichael, S. N., Smollett, K. L., Nomikou, K., Aranday-Cortes, E., Johnson, N., Nickbakhsh, S., Vamos, E. E., Hughes, M., Rainbow, L., Eccles, R., Nelson, C., Whitehead, M., Gregory, R., Gemmell, M., Wierzbicki, C., Webster, H. J., Fisher, C. L., Signell, A. W., Betancor, G., Wilson, H. D., Nebbia, G., Flaviani, F., Cerda, A. C., Merrill, T. V., Wilson, R. E., Cotic, M., Bayzid, N., Thompson, T., Acheson, E., Rushton, S., O'Brien, S., Baker, D. J., Rudder, S., Aydin, A., Sang, F., Debebe, J., Francois, S., Vasylyeva, T. I., Zamudio, M. E., Gutierrez, B., Marchbank, A., Maksimovic, J., Spellman, K., Mccluggage, K., Morgan, M., Beer, R., Afifi, S., Workman, T., Fuller, W., Bresner, C., Angyal, A., Green, L. R., Parsons, P. J., Tucker, R. M., Brown, R., Whiteley, M., Bonfield, J., Puethe, C., Whitwham, A., Liddle, J., Rowe, W., Siveroni, I., Le-Viet, T., Gaskin, A., Johnson, R., Abnizova, I., Ali, M., Allen, L., Anderson, R., Ariani, C., Austin-Guest, S., Bala, S., Bassett, A., Battleday, K., Beal, J., Beale, M., Bellany, S., Bellerby, T., Bellis, K., Berger, D., Berriman, M., Bevan, P., Binley, S., Bishop, J., Blackburn, K., Boughton, N., Bowker, S., Brendler-Spaeth, T., Bronner, I., Brooklyn, T., Buddenborg, S. K., Bush, R., Caetano, C., Cagan, A., Carter, N., Cartwright, J., Monteiro, T. C., Chapman, L., Chillingworth, T. -J., Clapham, P., Clark, R., Clarke, A., Clarke, C., Cole, D., Cook, E., Coppola, M., Cornell, L., Cornwell, C., Corton, C., Crackett, A., Cranage, A., Craven, H., Craw, S., Crawford, M., Cutts, T., Dabrowska, M., Davies, M., Dawson, J., Day, C., Densem, A., Dibling, T., Dockree, C., Dodd, D., Dogga, S., Dougherty, M., Dove, A., Drummond, L., Dudek, M., Durrant, L., Easthope, E., Eckert, S., Ellis, P., Farr, B., Fenton, M., Ferrero, M., Flack, N., Fordham, H., Forsythe, G., Francis, M., Fraser, A., Freeman, A., Galvin, A., Garcia-Casado, M., Gedny, A., Girgis, S., Glover, J., Gould, O., Gray, A., Gray, E., Griffiths, C., Gu, Y., Guerin, F., Hamilton, W., Hanks, H., Harrison, E., Harrott, A., Harry, E., Harvison, J., Heath, P., Hernandez-Koutoucheva, A., Hobbs, R., Holland, D., Holmes, S., Hornett, G., Hough, N., Huckle, L., Hughes-Hallet, L., Hunter, A., Inglis, S., Iqbal, S., Jackson, A., Jackson, D., Verdejo, C. J., Jones, M., Kallepally, K., Kay, K., Keatley, J., Keith, A., King, A., Kitchin, L., Kleanthous, M., Klimekova, M., Korlevic, P., Krasheninnkova, K., Lane, G., Langford, C., Laverack, A., Law, K., Lensing, S., Lewis-Wade, A., Lin, Q., Lindsay, S., Linsdell, S., Long, R., Lovell, J., Mack, J., Maddison, M., Mamun, I., Mansfield, J., Marriott, N., Martin, M., Mayho, M., Mcclintock, J., Mchugh, S., Mcminn, L., Meadows, C., Mobley, E., Moll, R., Morra, M., Morrow, L., Murie, K., Nash, S., Nathwani, C., Naydenova, P., Neaverson, A., Nerou, E., Nicholson, J., Nimz, T., Noell, G. G., O'Meara, S., Ohan, V., Olney, C., Ormond, D., Oszlanczi, A., Pang, Y. F., Pardubska, B., Park, N., Parmar, A., Patel, G., Payne, M., Peacock, S., Petersen, A., Plowman, D., Preston, T., Quail, M., Rance, R., Rawlings, S., Redshaw, N., Reynolds, J., Reynolds, M., Rice, S., Richardson, M., Roberts, C., Robinson, K., Robinson, M., Robinson, D., Rogers, H., Rojo, E. M., Roopra, D., Rose, M., Rudd, L., Sadri, R., Salmon, N., Saul, D., Schwach, F., Seekings, P., Simms, A., Sinnott, M., Sivadasan, S., Siwek, B., Sizer, D., Skeldon, K., Skelton, J., Slater-Tunstill, J., Sloper, L., Smerdon, N., Smith, C., Smith, J., Smith, K., Smith, M., Smith, S., Smith, T., Sneade, L., Soria, C. D., Sousa, C., Souster, E., Sparkes, A., Spencer-Chapman, M., Squares, J., Steed, C., Stickland, T., Still, I., Stratton, M., Strickland, M., Swann, A., Swiatkowska, A., Sycamore, N., Swift, E., Symons, E., Szluha, S., Taluy, E., Tao, N., Taylor, K., Thompson, S., Thompson, M., Thomson, M., Thomson, N., Thurston, S., Toombs, D., Topping, B., Tovar-Corona, J., Ungureanu, D., Uphill, J., Urbanova, J., Van, P. J., Vancollie, V., Voak, P., Walker, D., Walker, M., Waller, M., Ward, G., Weatherhogg, C., Webb, N., Wells, A., Wells, E., Westwood, L., Whipp, T., Whiteley, T., Whitton, G., Widaa, S., Williams, M., Wilson, M., Wright, S., Harvey, W., Virgin, H. W., Lanzavecchia, A., Piccoli, L., Doffinger, R., Wills, M., Veesler, D., Corti, D., and Gupta, R. K.

Subjects
0301 basic medicine, Male, Models, Molecular, Passive, Antibodies, Viral, Neutralization, 0302 clinical medicine, Models, Monoclonal, 80 and over, Viral, Neutralizing antibody, Neutralizing, Aged, 80 and over, Vaccines, Vaccines, Synthetic, Multidisciplinary, biology, Antibodies, Monoclonal, C500, Middle Aged, C700, Spike Glycoprotein, Vaccination, Spike Glycoprotein, Coronavirus, Female, Angiotensin-Converting Enzyme 2, Antibody, Aged, Antibodies, Neutralizing, COVID-19, COVID-19 Vaccines, HEK293 Cells, Humans, Immune Evasion, Immunization, Passive, Mutation, Neutralization Tests, SARS-CoV-2, medicine.drug_class, B100, Monoclonal antibody, Antibodies, Virus, 03 medical and health sciences, Immune system, medicine, COVID-19 Serotherapy, QR355, Synthetic, Molecular, Virology, Coronavirus, 030104 developmental biology, Immunization, biology.protein, 030217 neurology & neurosurgery
Abstract

Transmission of SARS-CoV-2 is uncontrolled in many parts of the world; control is compounded in some areas by the higher transmission potential of the B.1.1.7 variant1, which has now been reported in 94 countries. It is unclear whether the response of the virus to vaccines against SARS-CoV-2 on the basis of the prototypic strain will be affected by the mutations found in B.1.1.7. Here we assess the immune responses of individuals after vaccination with the mRNA-based vaccine BNT162b22. We measured neutralizing antibody responses after the first and second immunizations using pseudoviruses that expressed the wild-type spike protein or a mutated spike protein that contained the eight amino acid changes found in the B.1.1.7 variant. The sera from individuals who received the vaccine exhibited a broad range of neutralizing titres against the wild-type pseudoviruses that were modestly reduced against the B.1.1.7 variant. This reduction was also evident in sera from some patients who had recovered from COVID-19. Decreased neutralization of the B.1.1.7 variant was also observed for monoclonal antibodies that target the N-terminal domain (9 out of 10) and the receptor-binding motif (5 out of 31), but not for monoclonal antibodies that recognize the receptor-binding domain that bind outside the receptor-binding motif. Introduction of the mutation that encodes the E484K substitution in the B.1.1.7 background to reflect a newly emerged variant of concern (VOC 202102/02) led to a more-substantial loss of neutralizing activity by vaccine-elicited antibodies and monoclonal antibodies (19 out of 31) compared with the loss of neutralizing activity conferred by the mutations in B.1.1.7 alone. The emergence of the E484K substitution in a B.1.1.7 background represents a threat to the efficacy of the BNT162b2 vaccine.

Published
2021

10. Spread of a SARS-CoV-2 variant through Europe in the summer of 2020

Author

Hodcroft, EB, Zuber, M, Nadeau, S, Vaughan, TG, Crawford, KHD, Althaus, CL, Reichmuth, ML, Bowen, JE, Walls, AC, Corti, D, Bloom, JD, Veesler, D, Mateo, D, Hernando, A, Comas, I, Candelas, FG, Stadler, T, Neher, RA, Rabella N., Navarro F., Miró E., Fernandez-Cadenas I, and Parra Grande, Monica

Abstract

Following its emergence in late 2019, the spread of SARS-CoV-21,2 has been tracked by phylogenetic analysis of viral genome sequences in unprecedented detail(3-5). Although the virus spread globally in early 2020 before borders closed, intercontinental travel has since been greatly reduced. However, travel within Europe resumed in the summer of 2020. Here we report on a SARS-CoV-2 variant, 20E (EU1), that was identified in Spain in early summer 2020 and subsequently spread across Europe. We find no evidence that this variant has increased transmissibility, but instead demonstrate how rising incidence in Spain, resumption of travel, and lack of effective screening and containment may explain the variant's success. Despite travel restrictions, we estimate that 20E (EU1) was introduced hundreds of times to European countries by summertime travellers, which is likely to have undermined local efforts to minimize infection with SARS-CoV-2. Our results illustrate how a variant can rapidly become dominant even in the absence of a substantial transmission advantage in favourable epidemiological settings. Genomic surveillance is critical for understanding how travel can affect transmission of SARS-CoV-2, and thus for informing future containment strategies as travel resumes.

Published
2021

11. Spread of a SARS-CoV-2 variant through Europe in the summer of 2020

Author

Hodcroft E.B., Zuber M., Nadeau S., Vaughan T.G., Crawford K.H.D., Althaus C.L., Reichmuth M.L., Bowen J.E., Walls A.C., Corti D., Bloom J.D., Veesler D., Mateo D., Hernando A., Comas I., González-Candelas F., Goig G.A., Chiner-Oms Á., Cancino-Muñoz I., López M.G., Torres-Puente M., Gomez-Navarro I., Jiménez-Serrano S., Ruiz-Roldán L., Bracho M.A., García-González N., Martínez-Priego L., Galán-Vendrell I., Ruiz-Hueso P., De Marco G., Ferrús M.L., Carbó-Ramírez S., D’Auria G., Coscollá M., Ruiz-Rodríguez P., Roig-Sena F.J., Sanmartín I., Garcia-Souto D., Pequeno-Valtierra A., Tubio J.M.C., Rodríguez-Castro J., Rabella N., Navarro F., Miró E., Rodríguez-Iglesias M., Galán-Sanchez F., Rodriguez-Pallares S., de Toro M., Escudero M.B., Azcona-Gutiérrez J.M., Alberdi M.B., Mayor A., García-Basteiro A.L., Moncunill G., Dobaño C., Cisteró P., García-de-Viedma D., Pérez-Lago L., Herranz M., Sicilia J., Catalán-Alonso P., Muñoz P., Muñoz-Cuevas C., Rodríguez-Rodríguez G., Alberola-Enguidanos J., Nogueira J.M., Camarena J.J., Rezusta A., Tristancho-Baró A., Milagro A., Martínez-Cameo N.F., Gracia-Grataloup Y., Martró E., Bordoy A.E., Not A., Antuori-Torres A., Benito R., Algarate S., Bueno J., del Pozo J.L., Boga J.A., Castelló-Abietar C., Rojo-Alba S., Alvarez-Argüelles M.E., Melon S., Aranzamendi-Zaldumbide M., Vergara-Gómez A., Fernández-Pinero J., Martínez M.J., Vila J., Rubio E., Peiró-Mestres A., Navero-Castillejos J., Posada D., Valverde D., Estévez-Gómez N., Fernandez-Silva I., de Chiara L., Gallego-García P., Varela N., Moreno R., Tirado M.D., Gomez-Pinedo U., Gozalo-Margüello M., Eliecer-Cano M., Méndez-Legaza J.M., Rodríguez-Lozano J., Siller M., Pablo-Marcos D., Oliver A., Reina J., López-Causapé C., Canut-Blasco A., Hernáez-Crespo S., Cordón M.L.A., Lecároz-Agara M.-C., Gómez-González C., Aguirre-Quiñonero A., López-Mirones J.I., Fernández-Torres M., Almela-Ferrer M.R., Gonzalo-Jiménez N., Ruiz-García M.M., Galiana A., Sanchez-Almendro J., Cilla G., Montes M., Piñeiro L., Sorarrain A., Marimón J.M., Gomez-Ruiz M.D., López-Hontangas J.L., González Barberá E.M., Navarro-Marí J.M., Pedrosa-Corral I., Sanbonmatsu-Gámez S., Pérez-González C., Chamizo-López F., Bordes-Benítez A., Navarro D., Albert E., Torres I., Gascón I., Torregrosa-Hetland C.J., Pastor-Boix E., Cascales-Ramos P., Fuster-Escrivá B., Gimeno-Cardona C., Ocete M.D., Medina-Gonzalez R., González-Cantó J., Martínez-Macias O., Palop-Borrás B., de Toro I., Mediavilla-Gradolph M.C., Pérez-Ruiz M., González-Recio Ó., Gutiérrez-Rivas M., Simarro-Córdoba E., Lozano-Serra J., Robles-Fonseca L., de Salazar A., Viñuela-González L., Chueca N., García F., Gómez-Camarasa C., Carvajal A., de la Puente R., Martín-Sánchez V., Fregeneda-Grandes J.-M., Molina A.J., Argüello H., Fernández-Villa T., Farga-Martí M.A., Domínguez-Márquez V., Costa-Alcalde J.J., Trastoy R., Barbeito-Castiñeiras G., Coira A., Pérez-del-Molino M.L., Aguilera A., Planas A.M., Soriano A., Fernandez-Cádenas I., Pérez-Tur J., Marcos M.Á., Moreno-Docón A., Viedma E., Mingorance J., Galán-Montemayor J.C., Parra-Grande M., Stadler T., Neher R.A., Swiss National Science Foundation, European Commission, University of Basel, ETH Zurich, National Institute of General Medical Sciences (US), National Institute of Allergy and Infectious Diseases (US), Burroughs Wellcome Fund, Instituto de Salud Carlos III, Consejo Superior de Investigaciones Científicas (España), European Research Council, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Howard Hughes Medical Institute, Hodcroft, Emma B. [0000-0002-0078-2212], Zuber, Moira [0000-0002-4275-8739], Nadeau, Sarah [0000-0003-1008-8918], Vaughan, Timothy G. [0000-0001-6220-2239], Crawford, Katharine H. D. [0000-0002-6223-4019], Althaus, Christian L. [0000-0002-5230-6760], Reichmuth, Martina L. [0000-0001-9345-851X], Bowen, John E. [0000-0003-3590-9727], Walls, Alexandra C. [0000-0002-9636-8330], Corti, Davide [0000-0002-5797-1364], Bloom, Jesse D. [0000-0003-1267-3408], Veesler, David [0000-0002-6019-8675], Mateo, David [0000-0002-1590-4163], Hernando de Castro, Alberto [0000-0003-1180-1068], Comas, Iñaki [0000-0001-5504-9408], González-Candelas, Fernando [0000-0002-0879-5798], Stadler, Tanja [0000-0001-6431-535X], Neher, Richard A. [0000-0003-2525-1407], Hodcroft, Emma B., Zuber, Moira, Nadeau, Sarah, Vaughan, Timothy G., Crawford, Katharine H. D., Althaus, Christian L., Reichmuth, Martina L., Bowen, John E., Walls, Alexandra C., Corti, Davide, Bloom, Jesse D., Veesler, David, Mateo, David, Hernando de Castro, Alberto, Comas, Iñaki, González-Candelas, Fernando, Stadler, Tanja, and Neher, Richard A.

Subjects
Phylogenetics, Sars-Cov-2, Viral infection, 0303 health sciences, 2019-20 coronavirus outbreak, Multidisciplinary, Coronavirus disease 2019 (COVID-19), SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 610 Medicine & health, 3. Good health, law.invention, 03 medical and health sciences, 0302 clinical medicine, Transmission (mechanics), Geography, 360 Social problems & social services, law, Development economics, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Following its emergence in late 2019, the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1,2 has been tracked via phylogenetic analysis of viral genome sequences in unprecedented detail3–5. While the virus spread globally in early 2020 before borders closed, intercontinental travel has since been greatly reduced. However, within Europe travel resumed in the summer of 2020. Here we report on a novel SARS-CoV-2 variant, 20E (EU1), that emerged in Spain in early summer, and subsequently spread across Europe. We find no evidence of increased transmissibility, but instead demonstrate how rising incidence in Spain, resumption of travel, and lack of effective screening and containment may explain the variant’s success. Despite travel restrictions, we estimate 20E (EU1) was introduced hundreds of times to European countries by summertime travelers, likely undermining local efforts to keep SARS-CoV-2 cases low. Our results demonstrate how a variant can rapidly become dominant even in absence of a substantial transmission advantage in favorable epidemiological settings. Genomic surveillance is critical to understanding how travel can impact SARS-CoV-2 transmission, and thus for informing future containment strategies as travel resumes., This work was supported by the Swiss National Science Foundation (SNSF) through grant numbers 31CA30 196046 (to RAN, EBH, CLA), 31CA30 196267 (to TS), European Union’s Horizon 2020 research and innovation programme - project EpiPose (No 101003688) (MLR, CLA), core funding by the University of Basel and ETH Zürich, the National Institute of General Medical Sciences (R01GM120553 to DV), the National Institute of Allergy and Infectious Diseases (DP1AI158186 and HHSN272201700059C to DV), a Pew Biomedical Scholars Award (DV), an Investigators in the Pathogenesis of Infectious Disease Awards from the Burroughs Wellcome Fund (DV and JDB), a Fast Grants (DV), and NIAID grants R01AI141707 (JDB) and F30AI149928 (KHDC). SeqCOVID-SPAIN is funded by the Instituto de Salud Carlos III project COV20/00140, Spanish National Research Council and ERC StG 638553 to IC and BFU2017-89594R from MICIN to FGC. JDB is an Investigator of the Howard Hughes Medical Institute.

Published
2021
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12. Broad betacoronavirus neutralization by a stem helix–specific human antibody

Author

Pinto, D, Sauer, MM, Czudnochowski, N, Low, JS, Alejandra Tortorici, M, Housley, MP, Noack, J, Walls, AC, Bowen, JE, Guarino, B, Rosen, LE, 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, Cippà, PE, Giannini, O, Ceruti, S, Garzoni, C, Riva, A, Benigni, F, Cameroni, E, Piccoli, L, Pizzuto, MS, Smithey, M, Hong, D, Telenti, A, Lempp, FA, Neyts, J, Havenar-Daughton, C, Lanzavecchia, A, Sallusto, F, Snell, G, Virgin, HW, Beltramello, M, Corti, D, Veesler, D, Pinto, D, Sauer, MM, Czudnochowski, N, Low, JS, Alejandra Tortorici, M, Housley, MP, Noack, J, Walls, AC, Bowen, JE, Guarino, B, Rosen, LE, 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, Cippà, PE, Giannini, O, Ceruti, S, Garzoni, C, Riva, A, Benigni, F, Cameroni, E, Piccoli, L, Pizzuto, MS, Smithey, M, Hong, D, Telenti, A, Lempp, FA, Neyts, J, Havenar-Daughton, C, Lanzavecchia, A, Sallusto, F, Snell, G, Virgin, HW, Beltramello, M, Corti, D, and Veesler, D

Abstract

The spillovers of betacoronaviruses in humans and the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants highlight the need for broad coronavirus countermeasures. We describe five monoclonal antibodies (mAbs) cross-reacting with the stem helix of multiple betacoronavirus spike glycoproteins isolated from COVID-19 convalescent individuals. Using structural and functional studies, we show that the mAb with the greatest breadth (S2P6) neutralizes pseudotyped viruses from three different subgenera through the inhibition of membrane fusion, and we delineate the molecular basis for its cross-reactivity. S2P6 reduces viral burden in hamsters challenged with SARS-CoV-2 through viral neutralization and Fc-mediated effector functions. Stem helix antibodies are rare, oftentimes of narrow specificity, and can acquire neutralization breadth through somatic mutations. These data provide a framework for structure-guided design of pan-betacoronavirus vaccines eliciting broad protection.

Published
2021

13. Mapping Neutralizing and Immunodominant Sites on the SARS-CoV-2 Spike Receptor-Binding Domain by Structure-Guided High-Resolution Serology

Author

Piccoli, L, Park, YJ, Tortorici, MA, Czudnochowski, N, Walls, AC, Beltramello, M, Silacci-Fregni, C, Pinto, D, Rosen, LE, Bowen, JE, Acton, OJ, Jaconi, S, Guarino, B, Minola, A, Zatta, F, Sprugasci, N, Bassi, J, Peter, A, De Marco, A, Nix, JC, Mele, F, Jovic, S, Rodriguez, BF, Gupta, SV, Jin, F, Piumatti, G, Lo Presti, G, Pellanda, AF, Biggiogero, M, Tarkowski, M, Pizzuto, MS, 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, HW, Lanzavecchia, A, Corti, D, Veesler, D, Piccoli, L, Park, YJ, Tortorici, MA, Czudnochowski, N, Walls, AC, Beltramello, M, Silacci-Fregni, C, Pinto, D, Rosen, LE, Bowen, JE, Acton, OJ, Jaconi, S, Guarino, B, Minola, A, Zatta, F, Sprugasci, N, Bassi, J, Peter, A, De Marco, A, Nix, JC, Mele, F, Jovic, S, Rodriguez, BF, Gupta, SV, Jin, F, Piumatti, G, Lo Presti, G, Pellanda, AF, Biggiogero, M, Tarkowski, M, Pizzuto, MS, 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, HW, Lanzavecchia, A, Corti, D, and Veesler, D

Abstract

Analysis of the specificity and kinetics of neutralizing antibodies (nAbs) elicited by SARS-CoV-2 infection is crucial for understanding immune protection and identifying targets for vaccine design. In a cohort of 647 SARS-CoV-2-infected subjects, we found that both the magnitude of Ab responses to SARS-CoV-2 spike (S) and nucleoprotein and nAb titers correlate with clinical scores. The receptor-binding domain (RBD) is immunodominant and the target of 90% of the neutralizing activity present in SARS-CoV-2 immune sera. Whereas overall RBD-specific serum IgG titers waned with a half-life of 49 days, nAb titers and avidity increased over time for some individuals, consistent with affinity maturation. We structurally defined an RBD antigenic map and serologically quantified serum Abs specific for distinct RBD epitopes leading to the identification of two major receptor-binding motif antigenic sites. Our results explain the immunodominance of the receptor-binding motif and will guide the design of COVID-19 vaccines and therapeutics.

Published
2020

19. Germline VRC01 antibody recognition of a modified clade C HIV-1 envelope trimer, 2 Fabs bound, sharpened map

Author

Borst, A.J., primary, Weidle, C.E., additional, Gray, M.D., additional, Frenz, B., additional, Snijder, J., additional, Joyce, M.G., additional, Georgiev, I.S., additional, Stewart-Jones, G.B.E., additional, Kwong, P.D., additional, McGuire, A.T., additional, DiMaio, F., additional, Stamatatos, L., additional, Pancera, M., additional, and Veesler, D., additional

Published
2018
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20. Germline VRC01 antibody recognition of a modified clade C HIV-1 envelope trimer, 3 Fabs bound, sharpened map

Author

Borst, A.J., primary, Weidle, C.E., additional, Gray, M.D., additional, Frenz, B., additional, Snijder, J., additional, Joyce, M.G., additional, Georgiev, I.S., additional, Stewart-Jones, G.B.E., additional, Kwong, P.D., additional, McGuire, A.T., additional, DiMaio, F., additional, Stamatatos, L., additional, Pancera, M., additional, and Veesler, D., additional

Published
2018
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33. Crystal structure and function of a DARPin neutralizing inhibitor of lactococcal phage TP901-1: comparison of DARPin and camelid VHH binding mode

Author

Veesler, D, Dreier, B, Blangy, S, Lichière, J, Tremblay, D, Moineau, S, Spinelli, S, Tegoni, M, Plückthun, A, Campanacci, V, Cambillau, C, University of Zurich, and Campanacci, V

Subjects
1307 Cell Biology, 1303 Biochemistry, 10019 Department of Biochemistry, 1312 Molecular Biology, 570 Life sciences, biology
Published
2009
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35. Studying 18 MDa Virus Assemblies with Native Mass Spectrometry

Author

Biomolecular Mass Spectrometry and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Sub Biomol.Mass Spect. and Proteomics, Snijder, J., Rose, R.J., Veesler, D., Johnson, J.A., Heck, A.J.R., Biomolecular Mass Spectrometry and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Sub Biomol.Mass Spect. and Proteomics, Snijder, J., Rose, R.J., Veesler, D., Johnson, J.A., and Heck, A.J.R.

Published
2013

39. Phage TP901-1 baseplate tripod

Author

Veesler, D., primary, Spinelli, S., additional, Mahony, J., additional, Lichiere, J., additional, Blangy, S., additional, Bricogne, G., additional, Legrand, P., additional, Ortiz-Lombardia, M., additional, Campanacci, V.I., additional, van Sinderen, D., additional, and Cambillau, C., additional

Published
2012
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40. N-terminal domain of phage TP901-1 ORF48

Author

Veesler, D., primary, Spinelli, S., additional, Mahony, J., additional, Lichiere, J., additional, Blangy, S., additional, Bricogne, G., additional, Legrand, P., additional, Ortiz-Lombardia, M., additional, Campanacci, V.I., additional, van Sinderen, D., additional, and Cambillau, C., additional

Published
2012
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48. Molecular basis of convergent evolution of ACE2 receptor utilization among HKU5 coronaviruses.

Author

Park YJ, Liu C, Lee J, Brown JT, Ma CB, Liu P, Xiong Q, Stewart C, Addetia A, Craig CJ, Tortorici MA, Alshukari A, Starr T, Yan H, and Veesler D

Abstract

DPP4 was considered a canonical receptor for merbecoviruses until the recent discovery of African bat-borne MERS-related coronaviruses using ACE2. The extent and diversity with which merbecoviruses engage ACE2 and their receptor species tropism remain unknown. Here, we reveal that HKU5 enters host cells utilizing Pipistrellus abramus (P.abr) and several non-bat mammalian ACE2s through a binding mode distinct from that of any other known ACE2-using coronaviruses. These results show that several merbecovirus clades independently evolved ACE2 utilization, which appears to be a broadly shared property among these pathogens, through an extraordinary diversity of ACE2 recognition modes. We show that MERS-CoV and HKU5 have markedly distinct antigenicity, due to extensive genetic divergence, and identified several HKU5 inhibitors, including two clinical compounds. Our findings profoundly alter our understanding of coronavirus evolution and pave the way for developing countermeasures against viruses poised for human emergence.

Published
2024
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49. Mapping immunodominant sites on the MERS-CoV spike glycoprotein targeted by infection-elicited antibodies in humans.

Author

Addetia A, Stewart C, Seo AJ, Sprouse KR, Asiri AY, Al-Mozaini M, Memish ZA, Alshukairi AN, and Veesler D

Subjects
Humans, Animals, Immunodominant Epitopes immunology, Coronavirus Infections immunology, Coronavirus Infections virology, Epitope Mapping, Camelus immunology, Female, Spike Glycoprotein, Coronavirus immunology, Middle East Respiratory Syndrome Coronavirus immunology, Antibodies, Neutralizing immunology, Antibodies, Viral immunology
Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) first emerged in 2012 and causes human infections in endemic regions. Vaccines and therapeutics in development against MERS-CoV focus on the spike (S) glycoprotein to prevent viral entry into target cells. These efforts are limited by a poor understanding of antibody responses elicited by infection. Here, we analyze S-directed antibody responses in plasma collected from MERS-CoV-infected individuals. We observe that binding and neutralizing antibodies peak 1-6 weeks after symptom onset/hospitalization, persist for at least 6 months, and neutralize human and camel MERS-CoV strains. We show that the MERS-CoV S 1 subunit is immunodominant and that antibodies targeting S 1 , particularly the receptor-binding domain (RBD), account for most plasma neutralizing activity. Antigenic site mapping reveals that plasma antibodies frequently target RBD epitopes, whereas targeting of S 2 subunit epitopes is rare. Our data reveal the humoral immune responses elicited by MERS-CoV infection, which will guide vaccine and therapeutic design., Competing Interests: Declaration of interests D.V. is named as inventor on patents for coronavirus vaccines filed by the University of Washington., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2024
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50. A pan-variant miniprotein inhibitor protects against SARS-CoV-2 variants.

Author

Lee J, Case JB, Park YJ, Ravichandran R, Asarnow D, Tortorici MA, Brown JT, Sanapala S, Carter L, Baker D, Diamond MS, and Veesler D

Abstract

The continued evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has compromised neutralizing antibody responses elicited by prior infection or vaccination and abolished the utility of most monoclonal antibody therapeutics. We previously described a computationally-designed, homotrimeric miniprotein inhibitor, designated TRI2-2, that protects mice against pre-Omicron SARS-CoV-2 variants. Here, we show that TRI2-2 exhibits pan neutralization of variants that evolved during the 4.5 years since the emergence of SARS-CoV-2 and protects mice against BQ.1.1, XBB.1.5 and BA.2.86 challenge when administered post-exposure by an intranasal route. The resistance of TRI2-2 to viral escape and its direct delivery to the upper airways rationalize a path toward clinical advancement., Competing Interests: J.B.C., Y.J.P., R.R., D.B., M.S.D. and D.V. are co-inventors on a patent application that incorporates discoveries described in this article (application no.: PCT/US2021/034069, title: SARS-CoV-2 inhibitors). M.S.D. is a consultant or advisor for Inbios, Vir Biotechnology, IntegerBio, Moderna, Merck, and GlaxoSmithKline. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Vir Biotechnology, Moderna, Emergent BioSolutions, and IntegerBio.

Published
2024
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