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4. 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

5. 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

6. Risk assessment and seroprevalence of SARS-CoV-2 infection in healthcare workers of COVID-19 and non-COVID-19 hospitals in Southern Switzerland

Author

Piccoli, L, Ferrari, P, Piumatti, G, Jovic, S, Rodriguez, BF, Mele, F, Giacchetto-Sasselli, I, Terrot, T, Silacci-Fregni, C, Cameroni, E, Jaconi, S, Sprugasci, N, Bartha, I, Corti, D, Uguccioni, M, Lanzavecchia, A, Garzoni, C, Giannini, O, Bernasconi, E, Elzi, L, Albanese, E, Sallusto, F, Ceschi, A, Piccoli, L, Ferrari, P, Piumatti, G, Jovic, S, Rodriguez, BF, Mele, F, Giacchetto-Sasselli, I, Terrot, T, Silacci-Fregni, C, Cameroni, E, Jaconi, S, Sprugasci, N, Bartha, I, Corti, D, Uguccioni, M, Lanzavecchia, A, Garzoni, C, Giannini, O, Bernasconi, E, Elzi, L, Albanese, E, Sallusto, F, and Ceschi, A

Abstract

Background: Hospital healthcare workers (HCW), in particular those involved in the clinical care of COVID-19 cases, are presumably exposed to a higher risk of acquiring the disease than the general population. Methods: Between April 16 and 30, 2020 we conducted a prospective, SARS-CoV-2 seroprevalence study in HCWs in Southern Switzerland. Participants were hospital personnel with varying COVID-19 exposure risk depending on job function and working site. They provided personal information (including age, sex, occupation, and medical history) and self-reported COVID-19 symptoms. Odds ratio (OR) of seropositivity to IgG antibodies was estimated by univariate and multivariate logistic regressions. Findings: Among 4726 participants, IgG antibodies to SARS-CoV-2 were detected in 9.6% of the HCWs. Seropositivity was higher among HCWs working on COVID-19 wards (14.1% (11.9–16.5)) compared to other hospital areas at medium (10.7% (7.6–14.6)) or low risk exposure (7.3% (6.4–8.3)). OR for high vs. medium wards risk exposure was 1.42 (0.91–2.22), P = 0.119, and 1.98 (1.55–2.53), P<0.001 for high vs. low wards risk exposure. The same was for true for doctors and nurses (10.1% (9.0–11.3)) compared to other employees at medium (7.1% (4.8–10.0)) or low risk exposure (6.6% (5.0–8.4)). OR for high vs. medium profession risk exposure was 1.37 (0.89–2.11), P = 0.149, and 1.75 (1.28–2.40), P = 0.001 for high vs. low profession risk exposure. Moreover, seropositivity was higher among HCWs who had household exposure to COVID-19 cases compared to those without (18.7% (15.3–22.5) vs. 7.7% (6.9–8.6), OR 2.80 (2.14–3.67), P<0.001). Interpretation: SARS-CoV-2 antibodies are detectable in up to 10% of HCWs from acute care hospitals in a region with high incidence of COVID-19 in the weeks preceding the study. HCWs with exposure to COVID-19 patients have only a slightly higher absolute risk of seropositivity compared to those without, suggesting that the use of PPE and other measures aiming at r

Published
2021

7. Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity

Author

Thomson, EC, Rosen, LE, Shepherd, JG, Spreafico, R, da Silva Filipe, A, Wojcechowskyj, JA, Davis, C, Piccoli, L, Pascall, DJ, Dillen, J, Lytras, S, Czudnochowski, N, Shah, R, Meury, M, Jesudason, N, De Marco, A, Li, K, Bassi, J, O'Toole, A, Pinto, D, Colquhoun, RM, Culap, K, Jackson, B, Zatta, F, Rambaut, A, Jaconi, S, Sreenu, VB, Nix, J, Zhang, I, Jarrett, RF, Glass, WG, Beltramello, M, Nomikou, K, Pizzuto, M, Tong, L, Cameroni, E, Croll, TI, Johnson, N, Di Iulio, J, Wickenhagen, A, Ceschi, A, Harbison, AM, Mair, D, Ferrari, P, Smollett, K, Sallusto, F, Carmichael, S, Garzoni, C, Nichols, J, Galli, M, Hughes, J, Riva, A, Ho, A, Schiuma, M, Semple, MG, Openshaw, PJM, Fadda, E, Baillie, JK, Chodera, JD, Rihn, SJ, Lycett, SJ, Virgin, HW, Telenti, A, Corti, D, Robertson, DL, Snell, G, Thomson, EC, Rosen, LE, Shepherd, JG, Spreafico, R, da Silva Filipe, A, Wojcechowskyj, JA, Davis, C, Piccoli, L, Pascall, DJ, Dillen, J, Lytras, S, Czudnochowski, N, Shah, R, Meury, M, Jesudason, N, De Marco, A, Li, K, Bassi, J, O'Toole, A, Pinto, D, Colquhoun, RM, Culap, K, Jackson, B, Zatta, F, Rambaut, A, Jaconi, S, Sreenu, VB, Nix, J, Zhang, I, Jarrett, RF, Glass, WG, Beltramello, M, Nomikou, K, Pizzuto, M, Tong, L, Cameroni, E, Croll, TI, Johnson, N, Di Iulio, J, Wickenhagen, A, Ceschi, A, Harbison, AM, Mair, D, Ferrari, P, Smollett, K, Sallusto, F, Carmichael, S, Garzoni, C, Nichols, J, Galli, M, Hughes, J, Riva, A, Ho, A, Schiuma, M, Semple, MG, Openshaw, PJM, Fadda, E, Baillie, JK, Chodera, JD, Rihn, SJ, Lycett, SJ, Virgin, HW, Telenti, A, Corti, D, Robertson, DL, and Snell, G

Abstract

SARS-CoV-2 can mutate and evade immunity, with consequences for efficacy of emerging vaccines and antibody therapeutics. Here, we demonstrate that the immunodominant SARS-CoV-2 spike (S) receptor binding motif (RBM) is a highly variable region of S and provide epidemiological, clinical, and molecular characterization of a prevalent, sentinel RBM mutation, N439K. We demonstrate N439K S protein has enhanced binding affinity to the hACE2 receptor, and N439K viruses have similar in vitro replication fitness and cause infections with similar clinical outcomes as compared to wild type. We show the N439K mutation confers resistance against several neutralizing monoclonal antibodies, including one authorized for emergency use by the US Food and Drug Administration (FDA), and reduces the activity of some polyclonal sera from persons recovered from infection. Immune evasion mutations that maintain virulence and fitness such as N439K can emerge within SARS-CoV-2 S, highlighting the need for ongoing molecular surveillance to guide development and usage of vaccines and therapeutics. Epidemiological, clinical, molecular, and structural characterization of the N439K mutation in the SARS-CoV-2 spike receptor binding motif demonstrates that it results in similar viral fitness compared to wild-type while conferring resistance against some neutralizing monoclonal antibodies and reducing the activity of some polyclonal antibody responses.

Published
2021

9. 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

11. Specificity, cross-reactivity, and function of antibodies elicited by Zika virus infection

Author

Stettler, K, Beltramello, M, Espinosa, DA, Graham, V, Cassotta, A, Bianchi, S, Vanzetta, F, Minola, A, Jaconi, S, Mele, F, Foglierini, M, Pedotti, M, Simonelli, L, Dowall, S, Atkinson, B, Percivalle, E, Simmons, CP, Varani, L, Blum, J, Baldanti, F, Cameroni, E, Hewson, R, Harris, E, Lanzavecchia, A, Sallusto, F, Corti, D, Stettler, K, Beltramello, M, Espinosa, DA, Graham, V, Cassotta, A, Bianchi, S, Vanzetta, F, Minola, A, Jaconi, S, Mele, F, Foglierini, M, Pedotti, M, Simonelli, L, Dowall, S, Atkinson, B, Percivalle, E, Simmons, CP, Varani, L, Blum, J, Baldanti, F, Cameroni, E, Hewson, R, Harris, E, Lanzavecchia, A, Sallusto, F, and Corti, D

Abstract

Zika virus (ZIKV), a mosquito-borne flavivirus with homology to Dengue virus (DENV), has become a public health emergency. By characterizing memory lymphocytes from ZIKV-infected patients, we dissected ZIKV-specific and DENV-cross-reactive immune responses. Antibodies to nonstructural protein 1 (NS1) were largely ZIKV-specific and were used to develop a serological diagnostic tool. In contrast, antibodies against E protein domain I/II (EDI/II) were cross-reactive and, although poorly neutralizing, potently enhanced ZIKV and DENV infection in vitro and lethally enhanced DENV disease in mice. Memory T cells against NS1 or E proteins were poorly cross-reactive, even in donors preexposed to DENV. The most potent neutralizing antibodies were ZIKV-specific and targeted EDIII or quaternary epitopes on infectious virus. An EDIII-specific antibody protected mice from lethal ZIKV infection, illustrating the potential for antibody-based therapy.

Published
2016

12. Prevention of Viral Spread, Viremia Reduction and HBsAg Clearance in Hepatitis B and D Coinfected Humanized Mice by a Human Neutralizing Monoclonal Antibody

Author

Corti, D., primary, Volz, T., additional, Giersch, K., additional, Agatic, G., additional, Cameroni, E., additional, Kah, J., additional, Allweiss, L., additional, Schulze, A., additional, Lohse, A.W., additional, Petersen, J., additional, Urban, S., additional, Lütgehetmann, M., additional, Lanzavecchia, A., additional, and Dandri, M., additional

Published
2016
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14. DETERMINANTS OF 6-MONTH MORTALITY IN SURVIVORS OF MYOCARDIAL-INFARCTION AFTER THROMBOLYSIS - RESULTS OF THE GISSI-2 DATA-BASE

Author

VOLPI A, DEVITA C, FRANZOSI MG, GERACI E, MAGGIONI AP, MAURI F, NEGRI E, SANTORO E, TAVAZZI L, TOGNONI G, FERUGLIO GA, LOTTO A, ROVELLI F, SOLINAS P, BRUNO M, CAPPELLO T, COPPINI A, FINCATI F, MANTOVANI G, PANGRAZZI J, POGNA M, TURAZZA FM, ANSELMI M, BARBONAGLIA L, BIGI R, CAVALLI A, FRIGERIO M, GIORDANO A, GUALTIEROTTI C, TORTA D, CAROLA R, GIORDANO F, BARLOTTI R, LOPARCO G, VIGLINO GL, RUGGERI G, GIAMUNDO L, DANESI A, PACIARONI E, GAMBINI C, URBANO G, PURCARO A, FRANCESCONI M, FIGLIOLIA S, CANNONE M, ANTOLINI R, DEVOTI G, CRISTALLINI P, PORCIELLO PI, TEONI P, BURALI A, ZUCCONELLI V, DEMATTEIS C, IERVOGLINI A, SCATASTA M, AMABILI S, CARATTI CA, ZOLA G, FERRAGUTO P, SALICI G, CENTARO A, ROTIROTI D, GENOVESE M, GINEVRINO P, DAMATO N, ALTAMURA CM, COLONNA L, CASTELLANETA G, BOVENZI F, MESSINA D, GALANTINO A, CAMPOREALE N, CUCCHINI F, CAMPOSTELLA L, MALACRIDA R, GENONI M, PELLEGRINI P, BRIDDA A, RIGGI L, ACONE L, MOSCATIELLO G, BRUNO A, INVERNIZZI G, TESPILI M, GUAGLIUMI G, CASARI A, ALBANO T, TOMASSINI B, DIBIASE G, SCARAMUZZINO G, RUGGERO S, BRACCHETTI D, DECASTRO U, FULVI M, BRAITO E, ERLICHER A, OBERLECHNER W, GAGLIARDI RS, BIGHIGNOLI L, BONIZZATO G, RIZZI GM, SCAZZINA L, PERRINI A, STRANEO G, STRANEO U, SCIRE A, VERRIENTI A, GUADALUPI M, STORELLI A, ZUCCA L, DABUSTI M, ALBONICO B, DEPETRA V, TABACCHI GC, SCERVINO R, MEREU D, MAXIA P, BIANCO A, CRABU E, MANGIAMELI S, CENTAMORE G, MALFITANO D, AMICO C, VANCHERI F, SANTOPUOLI G, BALDINI F, PANTALEONI A, CONTESSOTTO F, TERLIZZI R, MERIGHI A, TURCHI E, TEGLIO V, PIGNATTI F, PEZZANA A, GOZZOLINO G, GIGLIO M, PETTINATI G, IEVA M, CIRICUGNO S, CORREALE E, ROMANO S, DIFUCCIA A, CASTELLANO B, NATALE A, CERNETTI C, CELEGON L, CANDELPERGHER G, ARIENZO F, RUSSO F, DEVIVO L, MAY L, ACHILLI G, BLASI A, SORRENTINO F, DATO A, GALLONE P, PALUMBO C, DELLAMONICA R, PAGANO L, ALBERTI A, ORSELLI L, DEPONTI C, PARMIGIANI ML, FERRARI M, ACITO P, BUSI F, DELLAVITTORIA G, BELLET C, BORTOLINI F, ROSSI A, CORONA C, BONDI S, NICCOLINI D, GAMBERI G, ARCURI G, MAIOLINO P, CARROZZA A, DELIO U, CAPRETTI G, MARINONI C, GUASCONI C, SONNINO S, PAGLIEI M, FERRARI G, LOMBARDI R, AGNELLI D, DERINALDIS G, CALCAGNILE A, SIGNORELLI S, BENDINELLI S, LUSETTI L, MOLLAIOLI M, COSMI F, PLASTINA F, VENNERI N, FERACO E, CATELLI P, POLUZZI C, DISTANTE S, BIANCHI C, COPPETTI S, ZAMPAGLIONE G, GATTO C, ZURLO R, USLENGHI E, MARGARIA F, MILANESE U, LOMANTO B, ZIACCHI V, RIVA D, BERTOCCHI P, TIRELLA G, DAULERIO M, SAURO G, BINI A, MAZZONI V, POGGI P, MARESTA A, JACOPI F, PATRONCINI A, PUPITA F, GAGGI S, FRAUSINI G, ANTONIOLI GE, MALACARNE C, CODECA L, CAPPATO R, ANDREOLI L, VARACCA S, BUIO E, FAZZINI PF, PUCCI P, SARRO F, VERGASSOLA R, BARCHIELLI M, DEMATTEIS D, CARRONE M, BRUNOZZI LT, MENICONI L, LIBERATI R, RADOGNA M, TALLONE M, CONTE R, IERI A, ZIPOLI A, SANSONI M, CANZIANI R, GUIDALI P, CRISTALLO E, MARIELLO F, MUZIO L, BENVENUTO MR, BALDINI MR, VECCHIO C, CHIARELLA F, FALCIDIENO M, CECCHI A, GIULIANO G, SEU V, PERUGINI P, TOSELLI A, BASSO F, CORTI E, ROSSI P, DELFINO R, CAPONNETTO S, GNECCO G, GHIGLIOTTI G, PENNESI A, LOMBARDI G, RUGGIERI A, BERTOLO L, SLOMP L, LANZETTA T, MAZZARONE L, CRESTI A, BELLODI G, ZUARINI AM, VENERI L, PARCHI C, GIOVANELLI N, NEGRONI S, DETHOMATIS M, BARGHINI A, MARINO E, RICCI D, LEMME P, DIGIACOMO U, AQUARO G, RONZANI G, OTTELLO B, VONTI V, MORETTI S, PALERMO R, MARSILI P, SIDERI F, RAGAZZINI G, GRAMENZI S, BATTISTINI S, DIODATO T, VALERIO A, TUCCI C, DEPASQUALE B, GELFO PG, BERTULLA A, BOLLINI R, DEMARCHI E, BACCA F, DEGIORGI V, LOCATELLI V, SAVOIA MT, FERRACINI C, BARBARESI F, COTOGNI A, FRANCO G, PASSONI F, DURBANO M, MORETTI G, PEROTTI S, CAPRETTI M, DELBENE P, CASCONE M, BALDINI U, ORLANDI M, ODDONE A, CAIZZI V, MASINI G, LAZZARI M, BALLERINI B, BOZZI L, MOCETTI T, BERTOLINI A, PASOTTI E, SANGUINETTI M, MANTOVANI R, TOGNOLI T, MAGGI A, TUSA M, CAMERONI E, GUERRA GP, REGGIANI A, REDAELLI S, GIUSTI S, TANTALO L, RIZZI A, DIGIOVANNI N, GUZZO V, GABRIELE M, COLOMBO G, ALBERZONI A, SALVIOLI G, GALFETTI F, DOVICO E, BELLUZZI F, GOLA E, CASELLATO F, LECCHI G, CONSOLO F, SACCA CB, CONSOLO A, PICCOLO E, GASPARINI G, MASSA D, BELLI C, DOSSENA MG, CORSINI C, SANNA GP, AZZOLLINI M, TRUAZZA F, NADOR F, DEMARTINI M, BOZZI G, SEREGNI R, PASTINE I, MORPURGO M, CASAZZA F, REGALIA F, MAGGIOLINI S, RIGO R, PANCALDI S, POZZETTI D, PASCOTTO P, FRANCESCHI L, DAINESE F, MELINI L, CAPPELLI C, BERNARDI C, PALMIERI M, BORGIONI L, ZILIO G, SANDRI R, ALITTO F, MASARO G, VALAGUSSA F, SCHIAVINA R, RAVESI D, DANIELLO L, PIANTADOSI FR, BARRA P, ROMEO D, MININNI N, SEVERINO S, MOSTACCI M, CASTELLARI M, BANDA D, ROLANDI R, VILLA WD, CARBONE V, ALLEGRI M, FASCIOLO L, PITTALIS M, MUREDDU V, SORO F, DELEDDA MG, MARRAS E, MARCHI SM, DELUCA C, MANETTA M, VOLTA SD, SPERANDEO V, DONZELLI M, VITRANO MG, PITROLO F, LAMONICA S, BELLANCA G, MESSINA G, MIRTO U, RAINERI A, TRAINA M, DIBENEDETTO A, RIBAUDO E, DIFRANCESCO M, RONCHITELLI R, CARONE M, DIGREGORIO D, DIPAOLO G, PASQUALE M, COREA L, COCCHIERI M, ALUNNI G, PAPI L, CHIRIATTI G, LUPETTI M, GAZZOLA U, ARRUZZOLI S, VILLANI GQ, MELLINI M, MADRUZZA L, PIAZZA R, MICHELI G, FRANCHINI C, BECHI S, MARTINES C, MARCHESE D, GABBIA G, BIGALLI A, CIUTI M, CABANI E, DELCITERNA F, ALFIERI A, CHITI M, LONGHINI J, CODELUPPI P, NEGRELLI M, ZANUTTINI D, NICOLOSI GL, MARTIN G, PETRELLA A, BARDAZZI L, BIANCO GA, CELLAMARE G, GIANNELLI F, LICITRA G, LICITRA R, LETTICA GV, TUMIOTTO G, BELLANTI G, BOSI S, CASALI G, MONDUCCI I, BARONE A, PARENTI F, HEYMAN J, COZZI E, BALDACCI G, BACCOS D, BRIGHI F, DESANCTIS A, BOCK R, ROSSI F, AMATI P, SEMPRINI P, NARDELLI A, BOTTERO G, VARTOLO C, MILAZZOTTO F, DICROCE G, DIMARIO F, ANGRISANI G, AZZOLINI P, NEJA CP, MANZOLI U, ROSSI E, TRANI C, MASINI V, SEBASTIANI F, TOPAI M, BORGIA MC, LUCIANI C, FERRI F, DEPAOLA D, CAPURSO S, TUGNOLI F, VETTA C, ALTIERI T, BORZI M, VISCOMI A, STRIANO U, SALITURI S, ZONZIN P, FIORENCIS R, BADIN A, RAVERA B, BALDI C, SILVESTRI F, ALLEMANO P, REYNAUD S, SANSON A, MILANI L, DESIMONE MV, RUSSO A, VILLELLA A, GRAZINI M, AMIDEI S, ANSELMI L, PICCANICOLINO R, MASCELLI G, TAGLIAMONTE A, MESSINA V, TEDESCHI C, BOSSI M, BISIOLI M, TACCHI G, PAGNI G, VIVALDI F, IBBA GV, SANNIA L, PEDRAZZINI F, BAGNI E, FABII S, ALVINO A, ANTONIELLI E, DORONZO B, MARTINENGO E, BECCHI G, SALMOIRAGHI A, DIGIOVANNA F, CARAMANNO G, CAPORICCI D, BRUN M, GIANI P, FERRARIO G, PECI P, RONCONI G, SKOUSE D, GIUSTINIANI S, CUCCHI GF, TAVASCI E, SILVERII A, MARCELLINI G, SPECA G, STANISCIA D, CIMINO A, SERAFINI N, DEBONIS P, CERRUTI P, BAZZUCCHI M, DALPRA F, SPEROTTO C, MOLE GD, BARBANO G, POMARI F, GASCHINO G, PARIGI A, GANDOLFO N, RONDONI F, BRUSCA A, DILEO M, GOLZIO PG, ABRATE M, SCLAVO MG, ROCCI R, POGGIO G, GIANI S, CUZZUCREA D, BRASCHI GB, SCIACCA R, SAMMARTANO A, FURLANELLO F, BRAITO G, CUZZATO V, TOTIS O, FAURETTO F, LEO F, GALATI A, PALMA P, CAMERINI F, MORGERA T, BARBIERI L, SLAVICK GA, FRESCO C, CUDA A, SARNICOLA P, ARZILLO P, BINAGHI G, MACCHI G, CALVERI G, DIMARCO G, LEVANTESI G, PANERAI C, CATURELLI G, FACCHIN L, SARTORE G, ZARDINI P, MARINO P, CARBONIERI E, NAVA S, MAZZINI C, NAVA R, SERRA N, SASSARA M, NICROSINI F, GANDOLFI P, BERGOGNONI G, BALLESTRA AM, VIOLO C, VOLPI A, DEVITA C, FRANZOSI MG, GERACI E, MAGGIONI AP, MAURI F, NEGRI E, SANTORO E, TAVAZZI L, TOGNONI G, FERUGLIO GA, LOTTO A, ROVELLI F, SOLINAS P, BRUNO M, CAPPELLO T, COPPINI A, FINCATI F, MANTOVANI G, PANGRAZZI J, POGNA M, TURAZZA FM, ANSELMI M, BARBONAGLIA L, BIGI R, CAVALLI A, FRIGERIO M, GIORDANO A, GUALTIEROTTI C, TORTA D, CAROLA R, GIORDANO F, BARLOTTI R, LOPARCO G, VIGLINO GL, RUGGERI G, GIAMUNDO L, DANESI A, PACIARONI E, GAMBINI C, URBANO G, PURCARO A, FRANCESCONI M, FIGLIOLIA S, CANNONE M, ANTOLINI R, DEVOTI G, CRISTALLINI P, PORCIELLO PI, TEONI P, BURALI A, ZUCCONELLI V, DEMATTEIS C, IERVOGLINI A, SCATASTA M, AMABILI S, CARATTI CA, ZOLA G, FERRAGUTO P, SALICI G, CENTARO A, ROTIROTI D, GENOVESE M, GINEVRINO P, DAMATO N, ALTAMURA CM, COLONNA L, CASTELLANETA G, BOVENZI F, MESSINA D, GALANTINO A, CAMPOREALE N, CUCCHINI F, CAMPOSTELLA L, MALACRIDA R, GENONI M, PELLEGRINI P, BRIDDA A, RIGGI L, ACONE L, MOSCATIELLO G, BRUNO A, INVERNIZZI G, TESPILI M, GUAGLIUMI G, CASARI A, ALBANO T, TOMASSINI B, DIBIASE G, SCARAMUZZINO G, RUGGERO S, BRACCHETTI D, DECASTRO U, FULVI M, BRAITO E, ERLICHER A, OBERLECHNER W, GAGLIARDI RS, BIGHIGNOLI L, BONIZZATO G, RIZZI GM, SCAZZINA L, PERRINI A, STRANEO G, STRANEO U, SCIRE A, VERRIENTI A, GUADALUPI M, STORELLI A, ZUCCA L, DABUSTI M, ALBONICO B, DEPETRA V, TABACCHI GC, SCERVINO R, MEREU D, MAXIA P, BIANCO A, CRABU E, MANGIAMELI S, CENTAMORE G, MALFITANO D, AMICO C, VANCHERI F, SANTOPUOLI G, BALDINI F, PANTALEONI A, CONTESSOTTO F, TERLIZZI R, MERIGHI A, TURCHI E, TEGLIO V, PIGNATTI F, PEZZANA A, GOZZOLINO G, GIGLIO M, PETTINATI G, IEVA M, CIRICUGNO S, CORREALE E, ROMANO S, DIFUCCIA A, CASTELLANO B, NATALE A, CERNETTI C, CELEGON L, CANDELPERGHER G, ARIENZO F, RUSSO F, DEVIVO L, MAY L, ACHILLI G, BLASI A, SORRENTINO F, DATO A, GALLONE P, PALUMBO C, DELLAMONICA R, PAGANO L, ALBERTI A, ORSELLI L, DEPONTI C, PARMIGIANI ML, FERRARI M, ACITO P, BUSI F, DELLAVITTORIA G, BELLET C, BORTOLINI F, ROSSI A, CORONA C, BONDI S, NICCOLINI D, GAMBERI G, ARCURI G, MAIOLINO P, CARROZZA A, DELIO U, CAPRETTI G, MARINONI C, GUASCONI C, SONNINO S, PAGLIEI M, FERRARI G, LOMBARDI R, AGNELLI D, DERINALDIS G, CALCAGNILE A, SIGNORELLI S, BENDINELLI S, LUSETTI L, MOLLAIOLI M, COSMI F, PLASTINA F, VENNERI N, FERACO E, CATELLI P, POLUZZI C, DISTANTE S, BIANCHI C, COPPETTI S, ZAMPAGLIONE G, GATTO C, ZURLO R, USLENGHI E, MARGARIA F, MILANESE U, LOMANTO B, ZIACCHI V, RIVA D, BERTOCCHI P, TIRELLA G, DAULERIO M, SAURO G, BINI A, MAZZONI V, POGGI P, MARESTA A, JACOPI F, PATRONCINI A, PUPITA F, GAGGI S, FRAUSINI G, ANTONIOLI GE, MALACARNE C, CODECA L, CAPPATO R, ANDREOLI L, VARACCA S, BUIO E, FAZZINI PF, PUCCI P, SARRO F, VERGASSOLA R, BARCHIELLI M, DEMATTEIS D, CARRONE M, BRUNOZZI LT, MENICONI L, LIBERATI R, RADOGNA M, TALLONE M, CONTE R, IERI A, ZIPOLI A, SANSONI M, CANZIANI R, GUIDALI P, CRISTALLO E, MARIELLO F, MUZIO L, BENVENUTO MR, BALDINI MR, VECCHIO C, CHIARELLA F, FALCIDIENO M, CECCHI A, GIULIANO G, SEU V, PERUGINI P, TOSELLI A, BASSO F, CORTI E, ROSSI P, DELFINO R, CAPONNETTO S, GNECCO G, GHIGLIOTTI G, PENNESI A, LOMBARDI G, RUGGIERI A, BERTOLO L, SLOMP L, LANZETTA T, MAZZARONE L, CRESTI A, BELLODI G, ZUARINI AM, VENERI L, PARCHI C, GIOVANELLI N, NEGRONI S, DETHOMATIS M, BARGHINI A, MARINO E, RICCI D, LEMME P, DIGIACOMO U, AQUARO G, RONZANI G, OTTELLO B, VONTI V, MORETTI S, PALERMO R, MARSILI P, SIDERI F, RAGAZZINI G, GRAMENZI S, BATTISTINI S, DIODATO T, VALERIO A, TUCCI C, DEPASQUALE B, GELFO PG, BERTULLA A, BOLLINI R, DEMARCHI E, BACCA F, DEGIORGI V, LOCATELLI V, SAVOIA MT, FERRACINI C, BARBARESI F, COTOGNI A, FRANCO G, PASSONI F, DURBANO M, MORETTI G, PEROTTI S, CAPRETTI M, DELBENE P, CASCONE M, BALDINI U, ORLANDI M, ODDONE A, CAIZZI V, MASINI G, LAZZARI M, BALLERINI B, BOZZI L, MOCETTI T, BERTOLINI A, PASOTTI E, SANGUINETTI M, MANTOVANI R, TOGNOLI T, MAGGI A, TUSA M, CAMERONI E, GUERRA GP, REGGIANI A, REDAELLI S, GIUSTI S, TANTALO L, RIZZI A, DIGIOVANNI N, GUZZO V, GABRIELE M, COLOMBO G, ALBERZONI A, SALVIOLI G, GALFETTI F, DOVICO E, BELLUZZI F, GOLA E, CASELLATO F, LECCHI G, CONSOLO F, SACCA CB, CONSOLO A, PICCOLO E, GASPARINI G, MASSA D, BELLI C, DOSSENA MG, CORSINI C, SANNA GP, AZZOLLINI M, TRUAZZA F, NADOR F, DEMARTINI M, BOZZI G, SEREGNI R, PASTINE I, MORPURGO M, CASAZZA F, REGALIA F, MAGGIOLINI S, RIGO R, PANCALDI S, POZZETTI D, PASCOTTO P, FRANCESCHI L, DAINESE F, MELINI L, CAPPELLI C, BERNARDI C, PALMIERI M, BORGIONI L, ZILIO G, SANDRI R, ALITTO F, MASARO G, VALAGUSSA F, SCHIAVINA R, RAVESI D, DANIELLO L, PIANTADOSI FR, BARRA P, ROMEO D, MININNI N, SEVERINO S, MOSTACCI M, CASTELLARI M, BANDA D, ROLANDI R, VILLA WD, CARBONE V, ALLEGRI M, FASCIOLO L, PITTALIS M, MUREDDU V, SORO F, DELEDDA MG, MARRAS E, MARCHI SM, DELUCA C, MANETTA M, VOLTA SD, SPERANDEO V, DONZELLI M, VITRANO MG, PITROLO F, LAMONICA S, BELLANCA G, MESSINA G, MIRTO U, RAINERI A, TRAINA M, DIBENEDETTO A, RIBAUDO E, DIFRANCESCO M, RONCHITELLI R, CARONE M, DIGREGORIO D, DIPAOLO G, PASQUALE M, COREA L, COCCHIERI M, ALUNNI G, PAPI L, CHIRIATTI G, LUPETTI M, GAZZOLA U, ARRUZZOLI S, VILLANI GQ, MELLINI M, MADRUZZA L, PIAZZA R, MICHELI G, FRANCHINI C, BECHI S, MARTINES C, MARCHESE D, GABBIA G, BIGALLI A, CIUTI M, CABANI E, DELCITERNA F, ALFIERI A, CHITI M, LONGHINI J, CODELUPPI P, NEGRELLI M, ZANUTTINI D, NICOLOSI GL, MARTIN G, PETRELLA A, BARDAZZI L, BIANCO GA, CELLAMARE G, GIANNELLI F, LICITRA G, LICITRA R, LETTICA GV, TUMIOTTO G, BELLANTI G, BOSI S, CASALI G, MONDUCCI I, BARONE A, PARENTI F, HEYMAN J, COZZI E, BALDACCI G, BACCOS D, BRIGHI F, DESANCTIS A, BOCK R, ROSSI F, AMATI P, SEMPRINI P, NARDELLI A, BOTTERO G, VARTOLO C, MILAZZOTTO F, DICROCE G, DIMARIO F, ANGRISANI G, AZZOLINI P, NEJA CP, MANZOLI U, ROSSI E, TRANI C, MASINI V, SEBASTIANI F, TOPAI M, BORGIA MC, LUCIANI C, FERRI F, DEPAOLA D, CAPURSO S, TUGNOLI F, VETTA C, ALTIERI T, BORZI M, VISCOMI A, STRIANO U, SALITURI S, ZONZIN P, FIORENCIS R, BADIN A, RAVERA B, BALDI C, SILVESTRI F, ALLEMANO P, REYNAUD S, SANSON A, MILANI L, DESIMONE MV, RUSSO A, VILLELLA A, GRAZINI M, AMIDEI S, ANSELMI L, PICCANICOLINO R, MASCELLI G, TAGLIAMONTE A, MESSINA V, TEDESCHI C, BOSSI M, BISIOLI M, TACCHI G, PAGNI G, VIVALDI F, IBBA GV, SANNIA L, PEDRAZZINI F, BAGNI E, FABII S, ALVINO A, ANTONIELLI E, DORONZO B, MARTINENGO E, BECCHI G, SALMOIRAGHI A, DIGIOVANNA F, CARAMANNO G, CAPORICCI D, BRUN M, GIANI P, FERRARIO G, PECI P, RONCONI G, SKOUSE D, GIUSTINIANI S, CUCCHI GF, TAVASCI E, SILVERII A, MARCELLINI G, SPECA G, STANISCIA D, CIMINO A, SERAFINI N, DEBONIS P, CERRUTI P, BAZZUCCHI M, DALPRA F, SPEROTTO C, MOLE GD, BARBANO G, POMARI F, GASCHINO G, PARIGI A, GANDOLFO N, RONDONI F, BRUSCA A, DILEO M, GOLZIO PG, ABRATE M, SCLAVO MG, ROCCI R, POGGIO G, GIANI S, CUZZUCREA D, BRASCHI GB, SCIACCA R, SAMMARTANO A, FURLANELLO F, BRAITO G, CUZZATO V, TOTIS O, FAURETTO F, LEO F, GALATI A, PALMA P, CAMERINI F, MORGERA T, BARBIERI L, SLAVICK GA, FRESCO C, CUDA A, SARNICOLA P, ARZILLO P, BINAGHI G, MACCHI G, CALVERI G, DIMARCO G, LEVANTESI G, PANERAI C, CATURELLI G, FACCHIN L, SARTORE G, ZARDINI P, MARINO P, CARBONIERI E, NAVA S, MAZZINI C, NAVA R, SERRA N, SASSARA M, NICROSINI F, GANDOLFI P, BERGOGNONI G, BALLESTRA AM, and VIOLO C

Subjects
cardiovascular diseases
Abstract

Background. Current knowledge of risk assessment in survivors of myocardial infarction is largely based on data gathered before the advent of thrombolysis. It must be determined whether and to what extent available information and proposed criteria of prognostication are applicable in the thrombolytic era. Methods and Results. We reassessed risk prediction in the 10 219 survivors of myocardial infarction with follow-up data available (ie, 98% of the total) who had been enrolled in the GISSI-2 trial, relying on a set of prespecified variables. The 3.5% 6-month all-cause mortality rate of these patients compared with the higher value of 4.6% found in the corresponding GISSI-1 cohort, originally allocated to streptokinase therapy, indicates a 24% reduction in postdischarge 6-month mortality. On multivariate analysis (Cox model), the following variables were predictors of 6-month all-cause mortality: ineligibility for exercise test for both cardiac (relative risk [RR], 3.30; 95% confidence interval [CI], 2.36-4.62) and noncardiac reasons (RR, 3.28; 95% CI, 2.23-4.72), early left ventricular failure (RR, 2.41; 95% Cl, 1.87-3.09), echocardiographic evidence of recovery phase left ventricular dysfunction (RR, 2.30; 95% CI, 1.78-2.98), advanced (more than 70 years) age (RR, 1.81; 95% Cl, 1.43 -2.30), electrical instability (ie, frequent and/or complex ventricular arrhythmias) (RR, 1.70; 95% Cl, 1.32-2.19), late left ventricular failure (RR, 1.54; 95% Cl, 1.17-2.03), previous myocardial infarction (RR, 1.47; 95% CI, 1.14-1.89), and a history of treated hypertension (RR, 1.32; 95% Cl, 1.05-1.65). Early post-myocardial infarction angina, a positive exercise test, female sex, history of angina, history of insulin-dependent diabetes, and anterior site of myocardial infarction were not risk predictors. On further multivariate analysis, performed on 8315 patients with the echocardiographic indicator of left ventricular dysfunction available, only previous myocardial infarction was not retained as an independent risk predictor. Conclusions. A decline in 6-month mortality of myocardial infarction survivors, seen within 6 hours of symptom onset, has been observed in recent years. Ineligibility for exercise test, early left ventricular failure, and recovery-phase left ventricular dysfunction are the most powerful (RR, >2) predictors of 6-month mortality among patients recovering from myocardial infarction after thrombolysis. Qualitative variables reflecting residual myocardial ischemia do not appear to be risk predictors. The lack of an independent adverse influence of early post-myocardial infarction angina on 6-month survival represents a major difference between this study and those of the prethrombolytic era.

15. On the traces of XPD: cell cycle matters - untangling the genotype-phenotype relationship of XPD mutations

Author

Cameroni Elisabetta, Stettler Karin, and Suter Beat

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Cytology, QH573-671
Abstract

Abstract Mutations in the human gene coding for XPD lead to segmental progeria - the premature appearance of some of the phenotypes normally associated with aging - which may or may not be accompanied by increased cancer incidence. XPD is required for at least three different critical cellular functions: in addition to participating in the process of nucleotide excision repair (NER), which removes bulky DNA lesions, XPD also regulates transcription as part of the general transcription factor IIH (TFIIH) and controls cell cycle progression through its interaction with CAK, a pivotal activator of cyclin dependent kinases (CDKs). The study of inherited XPD disorders offers the opportunity to gain insights into the coordination of important cellular events and may shed light on the mechanisms that regulate the delicate equilibrium between cell proliferation and functional senescence, which is notably altered during physiological aging and in cancer. The phenotypic manifestations in the different XPD disorders are the sum of disturbances in the vital processes carried out by TFIIH and CAK. In addition, further TFIIH- and CAK-independent cellular activities of XPD may also play a role. This, added to the complex feedback networks that are in place to guarantee the coordination between cell cycle, DNA repair and transcription, complicates the interpretation of clinical observations. While results obtained from patient cell isolates as well as from murine models have been elementary in revealing such complexity, the Drosophila embryo has proven useful to analyze the role of XPD as a cell cycle regulator independently from its other cellular functions. Together with data from the biochemical and structural analysis of XPD and of the TFIIH complex these results combine into a new picture of the XPD activities that provides ground for a better understanding of the patophysiology of XPD diseases and for future development of diagnostic and therapeutic tools.

Published
2010
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16. Rim15 and the crossroads of nutrient signalling pathways in Saccharomyces cerevisiae

Author

Cameroni Elisabetta, Pedruzzi Ivo, Dubouloz Frédérique, Smets Bart, Roosen Johnny, Wanke Valeria, Swinnen Erwin, De Virgilio Claudio, and Winderickx Joris

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Cytology, QH573-671
Abstract

Abstract In recent years, the general understanding of nutrient sensing and signalling, as well as the knowledge about responses triggered by altered nutrient availability have greatly advanced. While initial studies were directed to top-down elucidation of single nutrient-induced pathways, recent investigations place the individual signalling pathways into signalling networks and pursue the identification of converging effector branches that orchestrate the dynamical responses to nutritional cues. In this review, we focus on Rim15, a protein kinase required in yeast for the proper entry into stationary phase (G0). Recent studies revealed that the activity of Rim15 is regulated by the interplay of at least four intercepting nutrient-responsive pathways.

Published
2006
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17. PET/CT Targeted Tissue Sampling Reveals Intravenously Administered HGN194 IgG1 Affects HIV Distribution after Rectal Exposure.

Author

Taylor RA, Xiao S, Carias AM, McRaven MD, Thakkar DN, Araínga M, Lorenzo-Redondo R, Allen EJ, Rogers KA, Kumarapperuma SC, Gong S, Anderson MR, Thomas Y, Madden PJ, Corti D, Cameroni E, Lanzavecchia A, Goins B, Fox P, Villinger FJ, Ruprecht RM, and Hope TJ

Subjects
Animals, Humans, Administration, Intravenous, Rectum virology, Antibodies, Monoclonal immunology, Antibodies, Monoclonal administration & dosage, Antibodies, Neutralizing immunology, HIV-1 immunology, Mice, Immunoglobulin G, Positron Emission Tomography Computed Tomography methods, HIV Antibodies immunology, HIV Infections virology
Abstract

Neutralizing monoclonal antibodies hold great potential for prevention of human immunodeficiency virus (HIV) acquisition. IgG is the most abundant antibody in human serum, has a long half-life, and potent effector functions, making it a prime candidate for an HIV prevention therapeutic. We combined Positron Emission Tomography imaging and fluorescent microscopy of 64 Cu-labeled, photoactivatable-green fluorescent protein HIV (PA-GFP-BaL) and fluorescently labeled HGN194 IgG1 to determine whether intravenously instilled IgG influences viral interaction with mucosal barriers and viral penetration in colorectal tissue 2 h after rectal viral challenge. Our results show that IgG1 did not alter the number of virions found throughout the colon or viral penetration into the epithelium of the rectum or descending colon. A minor increase in virions was observed in the transverse colon of IgG1 treated animals. Overall, the number of viral particles found in the mesenteric lymph nodes was low. However, IgG1 administration resulted in a significant reduction of virions found in mesenteric lymph nodes. Taken together, our results show that HGN194 IgG1 does not prevent virions from penetrating into the colorectal mucosa but may perturb HIV virion access to the lymphatic system.

Published
2024
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18. A potent pan-sarbecovirus neutralizing antibody resilient to epitope diversification.

Author

Rosen LE, Tortorici MA, De Marco A, Pinto D, Foreman WB, Taylor AL, Park YJ, Bohan D, Rietz T, Errico JM, Hauser K, Dang HV, Chartron JW, Giurdanella M, Cusumano G, Saliba C, Zatta F, Sprouse KR, Addetia A, Zepeda SK, Brown J, Lee J, Dellota E Jr, Rajesh A, Noack J, Tao Q, DaCosta Y, Tsu B, Acosta R, Subramanian S, de Melo GD, Kergoat L, Zhang I, Liu Z, Guarino B, Schmid MA, Schnell G, Miller JL, Lempp FA, Czudnochowski N, Cameroni E, Whelan SPJ, Bourhy H, Purcell LA, Benigni F, di Iulio J, Pizzuto MS, Lanzavecchia A, Telenti A, Snell G, Corti D, Veesler D, and Starr TN

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution has resulted in viral escape from clinically authorized monoclonal antibodies (mAbs), creating a need for mAbs that are resilient to epitope diversification. Broadly neutralizing coronavirus mAbs that are sufficiently potent for clinical development and retain activity despite viral evolution remain elusive. We identified a human mAb, designated VIR-7229, which targets the viral receptor-binding motif (RBM) with unprecedented cross-reactivity to all sarbecovirus clades, including non-ACE2-utilizing bat sarbecoviruses, while potently neutralizing SARS-CoV-2 variants since 2019, including the recent EG.5, BA.2.86, and JN.1. VIR-7229 tolerates extraordinary epitope variability, partly attributed to its high binding affinity, receptor molecular mimicry, and interactions with RBM backbone atoms. Consequently, VIR-7229 features a high barrier for selection of escape mutants, which are rare and associated with reduced viral fitness, underscoring its potential to be resilient to future viral evolution. VIR-7229 is a strong candidate to become a next-generation medicine., Competing Interests: Declaration of interests L.E.R., A.D.M., D.P., D.B., T.R., J.M.E., K.H., H.V.D., M.G., G.C., C.S., F.Z., E.D., A.R., J.N., Q.T., Y.D., B.T., R.A., S.S., B.G., M.A.S., G. Schnell, J.L.M., F.A.L., N.C., E.C., L.A.P., F.B., J.d.I., M.S.P., A.L., A.T., G. Snell, and D.C. are current or previous employees of Vir Biotechnology and may hold shares in Vir Biotechnology. L.E.R., A.D.M., D.P., E.C., F.B., M.S.P., G. Snell, and D.C. are currently listed as inventors on multiple patent applications that disclose the subject matter described in this paper. J.W.C. is an employee and shareholder of ProtaBody. J.W.C. and ProtaBody have received funding from Vir Biotechnology related to the work described in this paper. I.Z., Z.L., S.P.J.W., G.D.d.M., L.K., H.B., and T.N.S. have received funding through sponsored research awards to their respective institutions from Vir Biotechnology related to the work described in this paper. I.Z. is a current employee of Bristol Myers Squibb. L.A.P. is a former employee and shareholder of Regeneron Pharmaceuticals and is a member of the Scientific Advisory Board AI-driven structure-enabled antiviral platform (ASAP). Regeneron provided no funding for this work. L.A.P. is a current employee of Third Rock Ventures. D.V. is named as inventor on patents for coronavirus vaccines filed by the University of Washington. The lab of T.N.S. has received sponsored research agreements unrelated to the present work from Aerium Therapeutics, Inc. and Invivyd, Inc., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2024
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19. Potent broadly neutralizing antibody VIR-3434 controls hepatitis B and D virus infection and reduces HBsAg in humanized mice.

Author

Lempp FA, Volz T, Cameroni E, Benigni F, Zhou J, Rosen LE, Noack J, Zatta F, Kaiser H, Bianchi S, Lombardo G, Jaconi S, Vincenzetti L, Imam H, Soriaga LB, Passini N, Belnap DM, Schulze A, Lütgehetmann M, Telenti A, Cathcart AL, Snell G, Purcell LA, Hebner CM, Urban S, Dandri M, Corti D, and Schmid MA

Abstract

Background & Aims: Chronic hepatitis B is a global public health problem, and coinfection with hepatitis delta virus (HDV) worsens disease outcome. Here, we describe a hepatitis B virus (HBV) surface antigen (HBsAg)-targeting monoclonal antibody (mAb) with the potential to treat chronic hepatitis B and chronic hepatitis D., Methods: HBsAg-specific mAbs were isolated from memory B cells of HBV vaccinated individuals. In vitro neutralization was determined against HBV and HDV enveloped with HBsAg representing eight HBV genotypes. Human liver-chimeric mice were treated twice weekly with a candidate mAb starting 3 weeks post HBV inoculation (spreading phase) or during stable HBV or HBV/HDV coinfection (chronic phase)., Results: From a panel of human anti-HBs mAbs, VIR-3434 was selected and engineered for pre-clinical development. VIR-3434 targets a conserved, conformational epitope within the antigenic loop of HBsAg and neutralized HBV and HDV infection with higher potency than hepatitis B immunoglobulins in vitro. Neutralization was pan-genotypic against strains representative of HBV genotypes A-H. In the spreading phase of HBV infection in human liver-chimeric mice, a parental mAb of VIR-3434 (HBC34) prevented HBV dissemination and the increase in intrahepatic HBV RNA and covalently closed circular DNA. In the chronic phase of HBV infection or co-infection with HDV, HBC34 treatment decreased circulating HBsAg by >1 log and HDV RNA by >2 logs., Conclusions: The potently neutralizing anti-HBs mAb VIR-3434 reduces circulating HBsAg and HBV/HDV viremia in human liver-chimeric mice. VIR-3434 is currently in clinical development for treatment of patients with chronic hepatitis B or D., Impact and Implications: Chronic infection with hepatitis B virus and co-infection with hepatitis D virus place approximately 290 million individuals worldwide at risk of severe liver disease and cancer. Available treatments result in low rates of functional cure or require lifelong therapy that does not eliminate the risk of liver disease. We isolated and characterized a potent human antibody that neutralizes hepatitis B and D viruses and reduces infection in a mouse model. This antibody could provide a new treatment for patients with chronic hepatitis B and D., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2023
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20. Neutralization, effector function and immune imprinting of Omicron variants.

Author

Addetia A, Piccoli L, Case JB, Park YJ, Beltramello M, Guarino B, Dang H, de Melo GD, Pinto D, Sprouse K, Scheaffer SM, Bassi J, Silacci-Fregni C, Muoio F, Dini M, Vincenzetti L, Acosta R, Johnson D, Subramanian S, Saliba C, Giurdanella M, Lombardo G, Leoni G, Culap K, McAlister C, Rajesh A, Dellota E Jr, Zhou J, Farhat N, Bohan D, Noack J, Chen A, Lempp FA, Quispe J, Kergoat L, Larrous F, Cameroni E, Whitener B, Giannini O, Cippà P, Ceschi A, Ferrari P, Franzetti-Pellanda A, Biggiogero M, Garzoni C, Zappi S, Bernasconi L, Kim MJ, Rosen LE, Schnell G, Czudnochowski N, Benigni F, Franko N, Logue JK, Yoshiyama C, Stewart C, Chu H, Bourhy H, Schmid MA, Purcell LA, Snell G, Lanzavecchia A, Diamond MS, Corti D, and Veesler D

Subjects
Animals, Cricetinae, Humans, Mice, Angiotensin-Converting Enzyme 2 immunology, Angiotensin-Converting Enzyme 2 metabolism, Antibodies, Monoclonal chemistry, Antibodies, Monoclonal immunology, Cross Reactions, Immune Evasion, Membrane Fusion, Neutralization Tests, Mutation, Memory B Cells immunology, COVID-19 Vaccines immunology, Antibodies, Neutralizing chemistry, Antibodies, Neutralizing immunology, COVID-19 immunology, COVID-19 prevention & control, COVID-19 virology, SARS-CoV-2 classification, SARS-CoV-2 genetics, SARS-CoV-2 immunology
Abstract

Currently circulating SARS-CoV-2 variants have acquired convergent mutations at hot spots in the receptor-binding domain 1 (RBD) of the spike protein. The effects of these mutations on viral infection and transmission and the efficacy of vaccines and therapies remains poorly understood. Here we demonstrate that recently emerged BQ.1.1 and XBB.1.5 variants bind host ACE2 with high affinity and promote membrane fusion more efficiently than earlier Omicron variants. Structures of the BQ.1.1, XBB.1 and BN.1 RBDs bound to the fragment antigen-binding region of the S309 antibody (the parent antibody for sotrovimab) and human ACE2 explain the preservation of antibody binding through conformational selection, altered ACE2 recognition and immune evasion. We show that sotrovimab binds avidly to all Omicron variants, promotes Fc-dependent effector functions and protects mice challenged with BQ.1.1 and hamsters challenged with XBB.1.5. Vaccine-elicited human plasma antibodies cross-react with and trigger effector functions against current Omicron variants, despite a reduced neutralizing activity, suggesting a mechanism of protection against disease, exemplified by S309. Cross-reactive RBD-directed human memory B cells remained dominant even after two exposures to Omicron spikes, underscoring the role of persistent immune imprinting., (© 2023. The Author(s).)

Published
2023
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21. Author Correction: A pan-influenza antibody inhibiting neuraminidase via receptor mimicry.

Author

Momont C, Dang HV, Zatta F, Hauser K, Wang C, di Iulio J, Minola A, Czudnochowski N, De Marco A, Branch K, Donermeyer D, Vyas S, Chen A, Ferri E, Guarino B, Powell AE, Spreafico R, Yim SS, Balce DR, Bartha I, Meury M, Croll TI, Belnap DM, Schmid MA, Schaiff WT, Miller JL, Cameroni E, Telenti A, Virgin HW, Rosen LE, Purcell LA, Lanzavecchia A, Snell G, Corti D, and Pizzuto MS

Published
2023
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22. A pan-influenza antibody inhibiting neuraminidase via receptor mimicry.

Author

Momont C, Dang HV, Zatta F, Hauser K, Wang C, di Iulio J, Minola A, Czudnochowski N, De Marco A, Branch K, Donermeyer D, Vyas S, Chen A, Ferri E, Guarino B, Powell AE, Spreafico R, Yim SS, Balce DR, Bartha I, Meury M, Croll TI, Belnap DM, Schmid MA, Schaiff WT, Miller JL, Cameroni E, Telenti A, Virgin HW, Rosen LE, Purcell LA, Lanzavecchia A, Snell G, Corti D, and Pizzuto MS

Subjects
Animals, Humans, Mice, Antibodies, Monoclonal chemistry, Antibodies, Monoclonal immunology, Antibodies, Monoclonal therapeutic use, Arginine chemistry, Catalytic Domain, Hemagglutinins, Viral immunology, Influenza A Virus, H3N2 Subtype enzymology, Influenza A Virus, H3N2 Subtype immunology, Orthomyxoviridae Infections immunology, Orthomyxoviridae Infections prevention & control, Seasons, Sialic Acids chemistry, Antibodies, Viral chemistry, Antibodies, Viral immunology, Antibodies, Viral therapeutic use, Antibody Specificity immunology, Influenza A virus classification, Influenza A virus enzymology, Influenza A virus immunology, Influenza B virus classification, Influenza B virus enzymology, Influenza B virus immunology, Influenza Vaccines chemistry, Influenza Vaccines immunology, Influenza Vaccines therapeutic use, Influenza, Human immunology, Influenza, Human prevention & control, Neuraminidase antagonists & inhibitors, Neuraminidase chemistry, Neuraminidase immunology, Molecular Mimicry
Abstract

Rapidly evolving influenza A viruses (IAVs) and influenza B viruses (IBVs) are major causes of recurrent lower respiratory tract infections. Current influenza vaccines elicit antibodies predominantly to the highly variable head region of haemagglutinin and their effectiveness is limited by viral drift 1 and suboptimal immune responses 2 . Here we describe a neuraminidase-targeting monoclonal antibody, FNI9, that potently inhibits the enzymatic activity of all group 1 and group 2 IAVs, as well as Victoria/2/87-like, Yamagata/16/88-like and ancestral IBVs. FNI9 broadly neutralizes seasonal IAVs and IBVs, including the immune-evading H3N2 strains bearing an N-glycan at position 245, and shows synergistic activity when combined with anti-haemagglutinin stem-directed antibodies. Structural analysis reveals that D107 in the FNI9 heavy chain complementarity-determinant region 3 mimics the interaction of the sialic acid carboxyl group with the three highly conserved arginine residues (R118, R292 and R371) of the neuraminidase catalytic site. FNI9 demonstrates potent prophylactic activity against lethal IAV and IBV infections in mice. The unprecedented breadth and potency of the FNI9 monoclonal antibody supports its development for the prevention of influenza illness by seasonal and pandemic viruses., (© 2023. The Author(s).)

Published
2023
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23. Therapeutic and vaccine-induced cross-reactive antibodies with effector function against emerging Omicron variants.

Author

Addetia A, Piccoli L, Case JB, Park YJ, Beltramello M, Guarino B, Dang H, Pinto D, Scheaffer S, Sprouse K, Bassi J, Silacci-Fregni C, Muoio F, Dini M, Vincenzetti L, Acosta R, Johnson D, Subramanian S, Saliba C, Giurdanella M, Lombardo G, Leoni G, Culap K, McAlister C, Rajesh A, Dellota E, Zhou J, Farhat N, Bohan D, Noack J, Lempp FA, Cameroni E, Whitener B, Giannini O, Ceschi A, Ferrari P, Franzetti-Pellanda A, Biggiogero M, Garzoni C, Zappi S, Bernasconi L, Kim MJ, Schnell G, Czudnochowski N, Franko N, Logue JK, Yoshiyama C, Stewart C, Chu H, Schmid MA, Purcell LA, Snell G, Lanzavecchia A, Diamond M, Corti D, and Veesler D

Abstract

Currently circulating SARS-CoV-2 variants acquired convergent mutations at receptor-binding domain (RBD) hot spots. Their impact on viral infection, transmission, and efficacy of vaccines and therapeutics remains poorly understood. Here, we demonstrate that recently emerged BQ.1.1. and XBB.1 variants bind ACE2 with high affinity and promote membrane fusion more efficiently than earlier Omicron variants. Structures of the BQ.1.1 and XBB.1 RBDs bound to human ACE2 and S309 Fab (sotrovimab parent) explain the altered ACE2 recognition and preserved antibody binding through conformational selection. We show that sotrovimab binds avidly to all Omicron variants, promotes Fc-dependent effector functions and protects mice challenged with BQ.1.1, the variant displaying the greatest loss of neutralization. Moreover, in several donors vaccine-elicited plasma antibodies cross-react with and trigger effector functions against Omicron variants despite reduced neutralizing activity. Cross-reactive RBD-directed human memory B cells remained dominant even after two exposures to Omicron spikes, underscoring persistent immune imprinting. Our findings suggest that this previously overlooked class of cross-reactive antibodies, exemplified by S309, may contribute to protection against disease caused by emerging variants through elicitation of effector functions.

Published
2023
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24. Maturation of SARS-CoV-2 Spike-specific memory B cells drives resilience to viral escape.

Author

Marzi R, Bassi J, Silacci-Fregni C, Bartha I, Muoio F, Culap K, Sprugasci N, Lombardo G, Saliba C, Cameroni E, Cassotta A, Low JS, Walls AC, McCallum M, Tortorici MA, Bowen JE, Dellota EA Jr, Dillen JR, Czudnochowski N, Pertusini L, Terrot T, Lepori V, Tarkowski M, Riva A, Biggiogero M, Franzetti-Pellanda A, Garzoni C, Ferrari P, Ceschi A, Giannini O, Havenar-Daughton C, Telenti A, Arvin A, Virgin HW, Sallusto F, Veesler D, Lanzavecchia A, Corti D, and Piccoli L

Abstract

Memory B cells (MBCs) generate rapid antibody responses upon secondary encounter with a pathogen. Here, we investigated the kinetics, avidity, and cross-reactivity of serum antibodies and MBCs in 155 SARS-CoV-2 infected and vaccinated individuals over a 16-month time frame. SARS-CoV-2-specific MBCs and serum antibodies reached steady-state titers with comparable kinetics in infected and vaccinated individuals. Whereas MBCs of infected individuals targeted both prefusion and postfusion Spike (S), most vaccine-elicited MBCs were specific for prefusion S, consistent with the use of prefusion-stabilized S in mRNA vaccines. Furthermore, a large fraction of MBCs recognizing postfusion S cross-reacted with human betacoronaviruses. The avidity of MBC-derived and serum antibodies increased over time resulting in enhanced resilience to viral escape by SARS-CoV-2 variants, including Omicron BA.1 and BA.2 sublineages, albeit only partially for BA.4 and BA.5 sublineages. Overall, the maturation of high-affinity and broadly reactive MBCs provides the basis for effective recall responses to future SARS-CoV-2 variants., Competing Interests: R.M., J.B., C.S.-F., I.B., F.M., K.C., N.S., G.L., C.S., E.C., E.A.D.J., J.R.D., N.C., C.H.-D., A.T., A.A., H.W.V., A.L., D.C., and L.Pi. are or were employees of Vir Biotechnology Inc. and may hold shares in Vir Biotechnology Inc. C.G. is an external scientific consultant to Humabs BioMed SA. The other authors declare no competing interests., (© 2022 The Authors.)

Published
2023
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25. Maturation of SARS-CoV-2 Spike-specific memory B cells drives resilience to viral escape.

Author

Marzi R, Bassi J, Silacci-Fregni C, Bartha I, Muoio F, Culap K, Sprugasci N, Lombardo G, Saliba C, Cameroni E, Cassotta A, Low JS, Walls AC, McCallum M, Tortorici MA, Bowen JE, Dellota EA Jr, Dillen JR, Czudnochowski N, Pertusini L, Terrot T, Lepori V, Tarkowski M, Riva A, Biggiogero M, Pellanda AF, Garzoni C, Ferrari P, Ceschi A, Giannini O, Havenar-Daughton C, Telenti A, Arvin A, Virgin HW, Sallusto F, Veesler D, Lanzavecchia A, Corti D, and Piccoli L

Abstract

Memory B cells (MBCs) generate rapid antibody responses upon secondary encounter with a pathogen. Here, we investigated the kinetics, avidity and cross-reactivity of serum antibodies and MBCs in 155 SARS-CoV-2 infected and vaccinated individuals over a 16-month timeframe. SARS-CoV-2-specific MBCs and serum antibodies reached steady-state titers with comparable kinetics in infected and vaccinated individuals. Whereas MBCs of infected individuals targeted both pre- and postfusion Spike (S), most vaccine-elicited MBCs were specific for prefusion S, consistent with the use of prefusion-stabilized S in mRNA vaccines. Furthermore, a large fraction of MBCs recognizing postfusion S cross-reacted with human betacoronaviruses. The avidity of MBC-derived and serum antibodies increased over time resulting in enhanced resilience to viral escape by SARS-CoV-2 variants, including Omicron BA.1 and BA.2 sub-lineages, albeit only partially for BA.4 and BA.5 sublineages. Overall, the maturation of high-affinity and broadly-reactive MBCs provides the basis for effective recall responses to future SARS-CoV-2 variants.

Published
2022
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26. Omicron spike function and neutralizing activity elicited by a comprehensive panel of vaccines.

Author

Bowen JE, Addetia A, Dang HV, Stewart C, Brown JT, Sharkey WK, Sprouse KR, Walls AC, Mazzitelli IG, Logue JK, Franko NM, Czudnochowski N, Powell AE, Dellota E Jr, Ahmed K, Ansari AS, Cameroni E, Gori A, Bandera A, Posavad CM, Dan JM, Zhang Z, Weiskopf D, Sette A, Crotty S, Iqbal NT, Corti D, Geffner J, Snell G, Grifantini R, Chu HY, and Veesler D

Subjects
Humans, Immunization, Secondary, Antibodies, Neutralizing blood, Antibodies, Neutralizing immunology, Antibodies, Viral blood, Antibodies, Viral immunology, COVID-19 blood, COVID-19 prevention & control, COVID-19 Vaccines immunology, SARS-CoV-2 immunology, Spike Glycoprotein, Coronavirus genetics, Spike Glycoprotein, Coronavirus immunology
Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern comprises several sublineages, with BA.2 and BA.2.12.1 having replaced the previously dominant BA.1 and with BA.4 and BA.5 increasing in prevalence worldwide. We show that the large number of Omicron sublineage spike mutations leads to enhanced angiotensin-converting enzyme 2 (ACE2) binding, reduced fusogenicity, and severe dampening of plasma neutralizing activity elicited by infection or seven clinical vaccines relative to the ancestral virus. Administration of a homologous or heterologous booster based on the Wuhan-Hu-1 spike sequence markedly increased neutralizing antibody titers and breadth against BA.1, BA.2, BA.2.12.1, BA.4, and BA.5 across all vaccines evaluated. Our data suggest that although Omicron sublineages evade polyclonal neutralizing antibody responses elicited by primary vaccine series, vaccine boosters may provide sufficient protection against Omicron-induced severe disease.

Published
2022
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27. Author Correction: Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies.

Author

Collier DA, De Marco A, Ferreira IATM, Meng B, Datir RP, Walls AC, Kemp SA, Bassi J, Pinto D, Silacci-Fregni C, Bianchi S, Tortorici MA, Bowen J, Culap K, Jaconi S, Cameroni E, Snell G, Pizzuto MS, Pellanda AF, Garzoni C, Riva A, Elmer A, Kingston N, Graves B, McCoy LE, Smith KGC, Bradley JR, Temperton N, Ceron-Gutierrez L, Barcenas-Morales G, Harvey W, Virgin HW, Lanzavecchia A, Piccoli L, Doffinger R, Wills M, Veesler D, Corti D, and Gupta RK

Published
2022
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28. Omicron BA.1 and BA.2 neutralizing activity elicited by a comprehensive panel of human vaccines.

Author

Bowen JE, Sprouse KR, Walls AC, Mazzitelli IG, Logue JK, Franko NM, Ahmed K, Shariq A, Cameroni E, Gori A, Bandera A, Posavad CM, Dan JM, Zhang Z, Weiskopf D, Sette A, Crotty S, Iqbal NT, Corti D, Geffner J, Grifantini R, Chu HY, and Veesler D

Abstract

The SARS-CoV-2 Omicron variant of concern comprises three sublineages designated BA.1, BA.2, and BA.3, with BA.2 steadily replacing the globally dominant BA.1. We show that the large number of BA.1 and BA.2 spike mutations severely dampen plasma neutralizing activity elicited by infection or seven clinical vaccines, with cross-neutralization of BA.2 being consistently more potent than that of BA.1, independent of the vaccine platform and number of doses. Although mRNA vaccines induced the greatest magnitude of Omicron BA.1 and BA.2 plasma neutralizing activity, administration of a booster based on the Wuhan-Hu-1 spike sequence markedly increased neutralizing antibody titers and breadth against BA.1 and BA.2 across all vaccines evaluated. Our data suggest that although BA.1 and BA.2 evade polyclonal neutralizing antibody responses, current vaccine boosting regimens may provide sufficient protection against Omicron-induced disease.

Published
2022
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29. SARS-CoV-2 breakthrough infections elicit potent, broad, and durable neutralizing antibody responses.

Author

Walls AC, Sprouse KR, Bowen JE, Joshi A, Franko N, Navarro MJ, Stewart C, Cameroni E, McCallum M, Goecker EA, Degli-Angeli EJ, Logue J, Greninger A, Corti D, Chu HY, and Veesler D

Abstract

Although infections among vaccinated individuals lead to milder COVID-19 symptoms relative to those in unvaccinated subjects, the specificity and durability of antibody responses elicited by breakthrough cases remain unknown. Here, we demonstrate that breakthrough infections induce serum-binding and -neutralizing antibody responses that are markedly more potent, durable, and resilient to spike mutations observed in variants than those in subjects who received only 2 doses of vaccine. However, we show that breakthrough cases, subjects who were vaccinated after infection, and individuals vaccinated three times have serum-neutralizing activity of comparable magnitude and breadth, indicating that an increased number of exposures to SARS-CoV-2 antigen(s) enhance the quality of antibody responses. Neutralization of SARS-CoV was moderate, however, underscoring the importance of developing vaccines eliciting broad sarbecovirus immunity for pandemic preparedness., Competing Interests: Declaration of interests The Veesler laboratory has received an unrelated sponsored research agreement from Vir Biotechnology. A.C.W. and D.V. are named as inventors on patent applications filed by the University of Washington for SARS-CoV-2 and sarbecovirus receptor-binding domain nanoparticle vaccines. E.C. and D.C. are employees of Vir Biotechnology and may hold shares in Vir Biotechnology. H.Y.C. is a consultant for Merck, Pfizer, Ellume, and the Bill and Melinda Gates Foundation and has received support from Cepheid and Sanofi-Pasteur. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Published
2022
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30. Poor neutralization and rapid decay of antibodies to SARS-CoV-2 variants in vaccinated dialysis patients.

Author

Bassi J, Giannini O, Silacci-Fregni C, Pertusini L, Hitz P, Terrot T, Franzosi Y, Muoio F, Saliba C, Meury M, Dellota EA Jr, Dillen JR, Hernandez P, Czudnochowski N, Cameroni E, Beria N, Ventresca M, Badellino A, Lavorato-Hadjeres S, Lecchi E, Bonora T, Mattiolo M, Trinci G, Garzoni D, Bonforte G, Forni-Ogna V, Giunzioni D, Berwert L, Gupta RK, Ferrari P, Ceschi A, Cippà P, Corti D, Lanzavecchia A, and Piccoli L

Subjects
Animals, Antibodies, Neutralizing blood, Antibody Affinity, CHO Cells, COVID-19 Vaccines immunology, Case-Control Studies, Cricetulus, Dose-Response Relationship, Immunologic, Follow-Up Studies, HEK293 Cells, Humans, Immunoglobulin G blood, Risk Factors, mRNA Vaccines immunology, Antibodies, Neutralizing immunology, Neutralization Tests, Renal Dialysis, SARS-CoV-2 immunology, Vaccination
Abstract

Patients on dialysis are at risk of severe course of SARS-CoV-2 infection. Understanding the neutralizing activity and coverage of SARS-CoV-2 variants of vaccine-elicited antibodies is required to guide prophylactic and therapeutic COVID-19 interventions in this frail population. By analyzing plasma samples from 130 hemodialysis and 13 peritoneal dialysis patients after two doses of BNT162b2 or mRNA-1273 vaccines, we found that 35% of the patients had low-level or undetectable IgG antibodies to SARS-CoV-2 Spike (S). Neutralizing antibodies against the vaccine-matched SARS-CoV-2 and Delta variant were low or undetectable in 49% and 77% of patients, respectively, and were further reduced against other emerging variants. The fraction of non-responding patients was higher in SARS-CoV-2-naïve hemodialysis patients immunized with BNT162b2 (66%) than those immunized with mRNA-1273 (23%). The reduced neutralizing activity correlated with low antibody avidity. Patients followed up to 7 months after vaccination showed a rapid decay of the antibody response with an average 21- and 10-fold reduction of neutralizing antibodies to vaccine-matched SARS-CoV-2 and Delta variant, which increased the fraction of non-responders to 84% and 90%, respectively. These data indicate that dialysis patients should be prioritized for additional vaccination boosts. Nevertheless, their antibody response to SARS-CoV-2 must be continuously monitored to adopt the best prophylactic and therapeutic strategy., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: J.B., C.S.-F., F.M., C.S., M.Me., E.A.D.J., N.C., E.C., D.C. A.L., and L.Pi. are employees of Vir Biotechnology Inc. and may hold shares in Vir Biotechnology Inc. R.K.G. has received consulting fees from Johnson and Johnson and GlaxoSmithKline for educational activities. The other authors declare no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Published
2022
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31. Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift.

Author

Cameroni E, Bowen JE, Rosen LE, Saliba C, Zepeda SK, Culap K, Pinto D, VanBlargan LA, De Marco A, di Iulio J, Zatta F, Kaiser H, Noack J, Farhat N, Czudnochowski N, Havenar-Daughton C, Sprouse KR, Dillen JR, Powell AE, Chen A, Maher C, Yin L, Sun D, Soriaga L, Bassi J, Silacci-Fregni C, Gustafsson C, Franko NM, Logue J, Iqbal NT, Mazzitelli I, Geffner J, Grifantini R, Chu H, Gori A, Riva A, Giannini O, Ceschi A, Ferrari P, Cippà PE, Franzetti-Pellanda A, Garzoni C, Halfmann PJ, Kawaoka Y, Hebner C, Purcell LA, Piccoli L, Pizzuto MS, Walls AC, Diamond MS, Telenti A, Virgin HW, Lanzavecchia A, Snell G, Veesler D, and Corti D

Subjects
Angiotensin-Converting Enzyme 2 metabolism, Animals, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal, Humanized immunology, Antibodies, Neutralizing immunology, Antibodies, Viral blood, Antigenic Drift and Shift genetics, COVID-19 Vaccines immunology, Cell Line, Convalescence, Epitopes, B-Lymphocyte immunology, Humans, Immune Evasion, Mice, SARS-CoV-2 chemistry, SARS-CoV-2 classification, SARS-CoV-2 genetics, Spike Glycoprotein, Coronavirus chemistry, Spike Glycoprotein, Coronavirus genetics, Spike Glycoprotein, Coronavirus immunology, Spike Glycoprotein, Coronavirus metabolism, Vesiculovirus genetics, Antibodies, Monoclonal immunology, Antibodies, Viral immunology, Antigenic Drift and Shift immunology, Broadly Neutralizing Antibodies immunology, Neutralization Tests, SARS-CoV-2 immunology
Abstract

The recently emerged SARS-CoV-2 Omicron variant encodes 37 amino acid substitutions in the spike protein, 15 of which are in the receptor-binding domain (RBD), thereby raising concerns about the effectiveness of available vaccines and antibody-based therapeutics. Here we show that the Omicron RBD binds to human ACE2 with enhanced affinity, relative to the Wuhan-Hu-1 RBD, and binds to mouse ACE2. Marked reductions in neutralizing activity were observed against Omicron compared to the ancestral pseudovirus in plasma from convalescent individuals and from individuals who had been vaccinated against SARS-CoV-2, but this loss was less pronounced after a third dose of vaccine. Most monoclonal antibodies that are directed against the receptor-binding motif lost in vitro neutralizing activity against Omicron, with only 3 out of 29 monoclonal antibodies retaining unaltered potency, including the ACE2-mimicking S2K146 antibody 1 . Furthermore, a fraction of broadly neutralizing sarbecovirus monoclonal antibodies neutralized Omicron through recognition of antigenic sites outside the receptor-binding motif, including sotrovimab 2 , S2X259 3 and S2H97 4 . The magnitude of Omicron-mediated immune evasion marks a major antigenic shift in SARS-CoV-2. Broadly neutralizing monoclonal antibodies that recognize RBD epitopes that are conserved among SARS-CoV-2 variants and other sarbecoviruses may prove key to controlling the ongoing pandemic and future zoonotic spillovers., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Published
2022
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32. Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift.

Author

Cameroni E, Saliba C, Bowen JE, Rosen LE, Culap K, Pinto D, VanBlargan LA, De Marco A, Zepeda SK, Iulio JD, Zatta F, Kaiser H, Noack J, Farhat N, Czudnochowski N, Havenar-Daughton C, Sprouse KR, Dillen JR, Powell AE, Chen A, Maher C, Yin L, Sun D, Soriaga L, Bassi J, Silacci-Fregni C, Gustafsson C, Franko NM, Logue J, Iqbal NT, Mazzitelli I, Geffner J, Grifantini R, Chu H, Gori A, Riva A, Giannini O, Ceschi A, Ferrari P, Cippà P, Franzetti-Pellanda A, Garzoni C, Halfmann PJ, Kawaoka Y, Hebner C, Purcell LA, Piccoli L, Pizzuto MS, Walls AC, Diamond MS, Telenti A, Virgin HW, Lanzavecchia A, Veesler D, Snell G, and Corti D

Abstract

The recently emerged SARS-CoV-2 Omicron variant harbors 37 amino acid substitutions in the spike (S) protein, 15 of which are in the receptor-binding domain (RBD), thereby raising concerns about the effectiveness of available vaccines and antibody therapeutics. Here, we show that the Omicron RBD binds to human ACE2 with enhanced affinity relative to the Wuhan-Hu-1 RBD and acquires binding to mouse ACE2. Severe reductions of plasma neutralizing activity were observed against Omicron compared to the ancestral pseudovirus for vaccinated and convalescent individuals. Most (26 out of 29) receptor-binding motif (RBM)-directed monoclonal antibodies (mAbs) lost in vitro neutralizing activity against Omicron, with only three mAbs, including the ACE2-mimicking S2K146 mAb 1 , retaining unaltered potency. Furthermore, a fraction of broadly neutralizing sarbecovirus mAbs recognizing antigenic sites outside the RBM, including sotrovimab 2 , S2X259 3 and S2H97 4 , neutralized Omicron. The magnitude of Omicron-mediated immune evasion and the acquisition of binding to mouse ACE2 mark a major SARS-CoV-2 mutational shift. Broadly neutralizing sarbecovirus mAbs recognizing epitopes conserved among SARS-CoV-2 variants and other sarbecoviruses may prove key to controlling the ongoing pandemic and future zoonotic spillovers.

Published
2021
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33. Lectins enhance SARS-CoV-2 infection and influence neutralizing antibodies.

Author

Lempp FA, Soriaga LB, Montiel-Ruiz M, Benigni F, Noack J, Park YJ, Bianchi S, Walls AC, Bowen JE, Zhou J, Kaiser H, Joshi A, Agostini M, Meury M, Dellota E Jr, Jaconi S, Cameroni E, Martinez-Picado J, Vergara-Alert J, Izquierdo-Useros N, Virgin HW, Lanzavecchia A, Veesler D, Purcell LA, Telenti A, and Corti D

Subjects
Angiotensin-Converting Enzyme 2 metabolism, Animals, Cell Adhesion Molecules metabolism, Cell Fusion, Cell Line, Cricetinae, Female, Humans, Lectins immunology, Lectins, C-Type metabolism, Membrane Fusion, Receptors, Cell Surface metabolism, SARS-CoV-2 immunology, Sialic Acid Binding Ig-like Lectin 1 metabolism, Spike Glycoprotein, Coronavirus immunology, Spike Glycoprotein, Coronavirus metabolism, Antibodies, Neutralizing immunology, Lectins metabolism, SARS-CoV-2 metabolism, SARS-CoV-2 pathogenicity
Abstract

SARS-CoV-2 infection-which involves both cell attachment and membrane fusion-relies on the angiotensin-converting enzyme 2 (ACE2) receptor, which is paradoxically found at low levels in the respiratory tract 1-3 , suggesting that there may be additional mechanisms facilitating infection. Here we show that C-type lectin receptors, DC-SIGN, L-SIGN and the sialic acid-binding immunoglobulin-like lectin 1 (SIGLEC1) function as attachment receptors by enhancing ACE2-mediated infection and modulating the neutralizing activity of different classes of spike-specific antibodies. Antibodies to the amino-terminal domain or to the conserved site at the base of the receptor-binding domain, while poorly neutralizing infection of ACE2-overexpressing cells, effectively block lectin-facilitated infection. Conversely, antibodies to the receptor binding motif, while potently neutralizing infection of ACE2-overexpressing cells, poorly neutralize infection of cells expressing DC-SIGN or L-SIGN and trigger fusogenic rearrangement of the spike, promoting cell-to-cell fusion. Collectively, these findings identify a lectin-dependent pathway that enhances ACE2-dependent infection by SARS-CoV-2 and reveal distinct mechanisms of neutralization by different classes of spike-specific antibodies., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Published
2021
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34. Broad betacoronavirus neutralization by a stem helix-specific human antibody.

Author

Pinto D, Sauer MM, Czudnochowski N, Low JS, Tortorici MA, 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

Subjects
Animals, Antibodies, Monoclonal isolation & purification, Antibodies, Neutralizing isolation & purification, Convalescence, Cricetinae, Cross Reactions, Humans, Immunoglobulin Fab Fragments immunology, Immunoglobulin Fc Fragments immunology, Jurkat Cells, Lung immunology, Membrane Fusion immunology, Neutralization Tests, Peptide Mapping, Protein Conformation, alpha-Helical, SARS-CoV-2 immunology, Spike Glycoprotein, Coronavirus genetics, Viral Load immunology, Antibodies, Monoclonal immunology, Antibodies, Neutralizing immunology, Betacoronavirus immunology, Spike Glycoprotein, Coronavirus chemistry, Spike Glycoprotein, Coronavirus immunology, Viral Vaccines immunology, Virus Internalization
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
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35. Broad sarbecovirus neutralization by a human monoclonal antibody.

Author

Tortorici MA, Czudnochowski N, Starr TN, Marzi R, Walls AC, Zatta F, Bowen JE, Jaconi S, Di Iulio J, Wang Z, De Marco A, Zepeda SK, Pinto D, Liu Z, Beltramello M, Bartha I, Housley MP, Lempp FA, Rosen LE, Dellota E Jr, Kaiser H, Montiel-Ruiz M, Zhou J, Addetia A, Guarino B, Culap K, Sprugasci N, Saliba C, Vetti E, Giacchetto-Sasselli I, Fregni CS, Abdelnabi R, Foo SC, Havenar-Daughton C, Schmid MA, Benigni F, Cameroni E, Neyts J, Telenti A, Virgin HW, Whelan SPJ, Snell G, Bloom JD, Corti D, Veesler D, and Pizzuto MS

Subjects
Animals, Antibodies, Monoclonal chemistry, Antibodies, Viral chemistry, Antibodies, Viral therapeutic use, Broadly Neutralizing Antibodies chemistry, COVID-19 immunology, COVID-19 virology, Cross Reactions immunology, Disease Models, Animal, Female, Humans, Immune Evasion genetics, Immune Evasion immunology, Mesocricetus immunology, Mesocricetus virology, Mutation, Neutralization Tests, SARS-CoV-2 chemistry, SARS-CoV-2 genetics, Viral Zoonoses immunology, Viral Zoonoses prevention & control, Viral Zoonoses virology, Antibodies, Monoclonal immunology, Antibodies, Monoclonal therapeutic use, Antibodies, Viral immunology, Broadly Neutralizing Antibodies immunology, Broadly Neutralizing Antibodies therapeutic use, COVID-19 prevention & control, SARS-CoV-2 classification, SARS-CoV-2 immunology
Abstract

The recent emergence of SARS-CoV-2 variants of concern 1-10 and the recurrent spillovers of coronaviruses 11,12 into the human population highlight the need for broadly neutralizing antibodies that are not affected by the ongoing antigenic drift and that can prevent or treat future zoonotic infections. Here we describe a human monoclonal antibody designated S2X259, which recognizes a highly conserved cryptic epitope of the receptor-binding domain and cross-reacts with spikes from all clades of sarbecovirus. S2X259 broadly neutralizes spike-mediated cell entry of SARS-CoV-2, including variants of concern (B.1.1.7, B.1.351, P.1, and B.1.427/B.1.429), as well as a wide spectrum of human and potentially zoonotic sarbecoviruses through inhibition of angiotensin-converting enzyme 2 (ACE2) binding to the receptor-binding domain. Furthermore, deep-mutational scanning and in vitro escape selection experiments demonstrate that S2X259 possesses an escape profile that is limited to a single substitution, G504D. We show that prophylactic and therapeutic administration of S2X259 protects Syrian hamsters (Mesocricetus auratus) against challenge with the prototypic SARS-CoV-2 and the B.1.351 variant of concern, which suggests that this monoclonal antibody is a promising candidate for the prevention and treatment of emergent variants and zoonotic infections. Our data reveal a key antigenic site that is targeted by broadly neutralizing antibodies and will guide the design of vaccines that are effective against all sarbecoviruses., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Published
2021
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36. SARS-CoV-2 RBD antibodies that maximize breadth and resistance to escape.

Author

Starr TN, Czudnochowski N, Liu Z, Zatta F, Park YJ, Addetia A, Pinto D, Beltramello M, Hernandez P, Greaney AJ, Marzi R, Glass WG, Zhang I, Dingens AS, Bowen JE, Tortorici MA, Walls AC, Wojcechowskyj JA, De Marco A, Rosen LE, Zhou J, Montiel-Ruiz M, Kaiser H, Dillen JR, Tucker H, Bassi J, Silacci-Fregni C, Housley MP, di Iulio J, Lombardo G, Agostini M, Sprugasci N, Culap K, Jaconi S, Meury M, Dellota E Jr, Abdelnabi R, Foo SC, Cameroni E, Stumpf S, Croll TI, Nix JC, Havenar-Daughton C, Piccoli L, Benigni F, Neyts J, Telenti A, Lempp FA, Pizzuto MS, Chodera JD, Hebner CM, Virgin HW, Whelan SPJ, Veesler D, Corti D, Bloom JD, and Snell G

Subjects
Adult, Aged, Animals, Antibodies, Monoclonal chemistry, Antibodies, Monoclonal immunology, Antibodies, Viral chemistry, Antibodies, Viral immunology, Antibody Affinity, Broadly Neutralizing Antibodies chemistry, COVID-19 immunology, COVID-19 Vaccines chemistry, COVID-19 Vaccines immunology, Cell Line, Cricetinae, Epitopes, B-Lymphocyte chemistry, Epitopes, B-Lymphocyte genetics, Epitopes, B-Lymphocyte immunology, Female, Humans, Male, Mesocricetus, Middle Aged, Models, Molecular, SARS-CoV-2 chemistry, SARS-CoV-2 genetics, Spike Glycoprotein, Coronavirus genetics, Vaccinology, COVID-19 Drug Treatment, Broadly Neutralizing Antibodies immunology, COVID-19 virology, Cross Reactions immunology, Immune Evasion genetics, Immune Evasion immunology, SARS-CoV-2 classification, SARS-CoV-2 immunology, Spike Glycoprotein, Coronavirus chemistry, Spike Glycoprotein, Coronavirus immunology
Abstract

An ideal therapeutic anti-SARS-CoV-2 antibody would resist viral escape 1-3 , have activity against diverse sarbecoviruses 4-7 , and be highly protective through viral neutralization 8-11 and effector functions 12,13 . Understanding how these properties relate to each other and vary across epitopes would aid the development of therapeutic antibodies and guide vaccine design. Here we comprehensively characterize escape, breadth and potency across a panel of SARS-CoV-2 antibodies targeting the receptor-binding domain (RBD). Despite a trade-off between in vitro neutralization potency and breadth of sarbecovirus binding, we identify neutralizing antibodies with exceptional sarbecovirus breadth and a corresponding resistance to SARS-CoV-2 escape. One of these antibodies, S2H97, binds with high affinity across all sarbecovirus clades to a cryptic epitope and prophylactically protects hamsters from viral challenge. Antibodies that target the angiotensin-converting enzyme 2 (ACE2) receptor-binding motif (RBM) typically have poor breadth and are readily escaped by mutations despite high neutralization potency. Nevertheless, we also characterize a potent RBM antibody (S2E12 8 ) with breadth across sarbecoviruses related to SARS-CoV-2 and a high barrier to viral escape. These data highlight principles underlying variation in escape, breadth and potency among antibodies that target the RBD, and identify epitopes and features to prioritize for therapeutic development against the current and potential future pandemics., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Published
2021
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37. SARS-CoV-2 immune evasion by the B.1.427/B.1.429 variant of concern.

Author

McCallum M, Bassi J, De Marco A, Chen A, Walls AC, Di Iulio J, Tortorici MA, Navarro MJ, Silacci-Fregni C, Saliba C, Sprouse KR, Agostini M, Pinto D, Culap K, Bianchi S, Jaconi S, Cameroni E, Bowen JE, Tilles SW, Pizzuto MS, Guastalla SB, Bona G, Pellanda AF, Garzoni C, Van Voorhis WC, Rosen LE, Snell G, Telenti A, Virgin HW, Piccoli L, Corti D, and Veesler D

Subjects
2019-nCoV Vaccine mRNA-1273, Amino Acid Substitution, Antibodies, Monoclonal immunology, Antibodies, Neutralizing blood, Antibodies, Neutralizing immunology, Antibodies, Viral blood, Antibodies, Viral immunology, Antigens, Viral immunology, BNT162 Vaccine, COVID-19 immunology, COVID-19 Vaccines immunology, Cryoelectron Microscopy, Humans, Models, Molecular, Mutation, Neutralization Tests, Protein Conformation, Protein Domains, Protein Interaction Domains and Motifs, Protein Subunits chemistry, SARS-CoV-2 genetics, Spike Glycoprotein, Coronavirus chemistry, COVID-19 virology, Immune Evasion, SARS-CoV-2 immunology, SARS-CoV-2 pathogenicity, Spike Glycoprotein, Coronavirus genetics, Spike Glycoprotein, Coronavirus immunology
Abstract

A novel variant of concern (VOC) named CAL.20C (B.1.427/B.1.429), which was originally detected in California, carries spike glycoprotein mutations S13I in the signal peptide, W152C in the N-terminal domain (NTD), and L452R in the receptor-binding domain (RBD). Plasma from individuals vaccinated with a Wuhan-1 isolate-based messenger RNA vaccine or from convalescent individuals exhibited neutralizing titers that were reduced 2- to 3.5-fold against the B.1.427/B.1.429 variant relative to wild-type pseudoviruses. The L452R mutation reduced neutralizing activity in 14 of 34 RBD-specific monoclonal antibodies (mAbs). The S13I and W152C mutations resulted in total loss of neutralization for 10 of 10 NTD-specific mAbs because the NTD antigenic supersite was remodeled by a shift of the signal peptide cleavage site and the formation of a new disulfide bond, as revealed by mass spectrometry and structural studies., (Copyright © 2021, American Association for the Advancement of Science.)

Published
2021
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38. Cooperation Between Systemic IgG1 and Mucosal Dimeric IgA2 Monoclonal Anti-HIV Env Antibodies: Passive Immunization Protects Indian Rhesus Macaques Against Mucosal SHIV Challenges.

Author

Gong S, Lakhashe SK, Hariraju D, Scinto H, Lanzavecchia A, Cameroni E, Corti D, Ratcliffe SJ, Rogers KA, Xiao P, Fontenot J, Villinger F, and Ruprecht RM

Subjects
Animals, Antibodies, Monoclonal immunology, Antibodies, Neutralizing immunology, HIV Antibodies immunology, Macaca mulatta, Pilot Projects, Antibodies, Monoclonal pharmacology, Antibodies, Neutralizing pharmacology, HIV Antibodies pharmacology, HIV-1 immunology, Immunity, Mucosal drug effects, Immunization, Passive, Simian Acquired Immunodeficiency Syndrome immunology, Simian Acquired Immunodeficiency Syndrome prevention & control, Simian Immunodeficiency Virus immunology
Abstract

Understanding the interplay between systemic and mucosal anti-HIV antibodies can provide important insights to develop new prevention strategies. We used passive immunization via systemic and/or mucosal routes to establish cause-and-effect between well-characterized monoclonal antibodies and protection against intrarectal (i.r.) SHIV challenge. In a pilot study, for which we re-used animals previously exposed to SHIV but completely protected from viremia by different classes of anti-HIV neutralizing monoclonal antibodies (mAbs), we made a surprise finding: low-dose intravenous (i.v.) HGN194-IgG1, a human neutralizing mAb against the conserved V3-loop crown, was ineffective when given alone but protected 100% of animals when combined with i.r. applied HGN194-dIgA2 that by itself had only protected 17% of the animals. Here we sought to confirm the unexpected synergy between systemically administered IgG1 and mucosally applied dIgA HGN194 forms using six groups of naïve macaques (n=6/group). Animals received i.v. HGN194-IgG1 alone or combined with i.r.-administered dIgA forms; controls remained untreated. HGN194-IgG1 i.v. doses were given 24 hours before - and all i.r. dIgA doses 30 min before - i.r. exposure to a single high-dose of SHIV-1157ipEL-p. All controls became viremic. Among passively immunized animals, the combination of IgG1+dIgA2 again protected 100% of the animals. In contrast, single-agent i.v. IgG1 protected only one of six animals (17%) - consistent with our pilot data. IgG1 combined with dIgA1 or dIgA1+dIgA2 protected 83% (5/6) of the animals. The dIgA1+dIgA2 combination without the systemically administered dose of IgG1 protected 67% (4/6) of the macaques. We conclude that combining suboptimal antibody defenses at systemic and mucosal levels can yield synergy and completely prevent virus acquisition., Competing Interests: AL, DC and EC are employees of Vir Biotechnology Inc. and may hold shares in Vir Biotechnology Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gong, Lakhashe, Hariraju, Scinto, Lanzavecchia, Cameroni, Corti, Ratcliffe, Rogers, Xiao, Fontenot, Villinger and Ruprecht.)

Published
2021
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39. Recurrent emergence of SARS-CoV-2 spike deletion H69/V70 and its role in the Alpha variant B.1.1.7.

Author

Meng B, Kemp SA, Papa G, Datir R, Ferreira IATM, Marelli S, Harvey WT, Lytras S, Mohamed A, Gallo G, Thakur N, Collier DA, Mlcochova P, Duncan LM, Carabelli AM, Kenyon JC, Lever AM, De Marco A, Saliba C, Culap K, Cameroni E, Matheson NJ, Piccoli L, Corti D, James LC, Robertson DL, Bailey D, and Gupta RK

Subjects
Animals, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, Cell Line, Chlorocebus aethiops, HEK293 Cells, Humans, Immune Evasion, Mutation, Pandemics, Phylogeny, Protein Binding, Recurrence, SARS-CoV-2 immunology, Vero Cells, COVID-19 immunology, COVID-19 virology, SARS-CoV-2 genetics, Spike Glycoprotein, Coronavirus genetics, Spike Glycoprotein, Coronavirus immunology
Abstract

We report severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike ΔH69/V70 in multiple independent lineages, often occurring after acquisition of receptor binding motif replacements such as N439K and Y453F, known to increase binding affinity to the ACE2 receptor and confer antibody escape. In vitro, we show that, although ΔH69/V70 itself is not an antibody evasion mechanism, it increases infectivity associated with enhanced incorporation of cleaved spike into virions. ΔH69/V70 is able to partially rescue infectivity of spike proteins that have acquired N439K and Y453F escape mutations by increased spike incorporation. In addition, replacement of the H69 and V70 residues in the Alpha variant B.1.1.7 spike (where ΔH69/V70 occurs naturally) impairs spike incorporation and entry efficiency of the B.1.1.7 spike pseudotyped virus. Alpha variant B.1.1.7 spike mediates faster kinetics of cell-cell fusion than wild-type Wuhan-1 D614G, dependent on ΔH69/V70. Therefore, as ΔH69/V70 compensates for immune escape mutations that impair infectivity, continued surveillance for deletions with functional effects is warranted., Competing Interests: Declaration of interests A.D.M., C.S., K.C., E.C., L.P., and D.A.C. are employees of Vir Biotechnology and may hold shares in Vir Biotechnology. R.K.G. has received consulting fees from UMOVIS lab, Gilead Sciences, and ViiV Healthcare and a research grant from InvisiSmart Technologies., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2021
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40. N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2.

Author

McCallum M, De Marco A, Lempp FA, Tortorici MA, Pinto D, Walls AC, Beltramello M, Chen A, Liu Z, Zatta F, Zepeda S, di Iulio J, Bowen JE, Montiel-Ruiz M, Zhou J, Rosen LE, Bianchi S, Guarino B, Fregni CS, Abdelnabi R, Foo SC, Rothlauf PW, Bloyet LM, Benigni F, Cameroni E, Neyts J, Riva A, Snell G, Telenti A, Whelan SPJ, Virgin HW, Corti D, Pizzuto MS, and Veesler D

Subjects
Animals, Antibodies, Monoclonal chemistry, Antibodies, Monoclonal immunology, Antibodies, Neutralizing immunology, COVID-19 immunology, COVID-19 virology, Cricetinae, Epitope Mapping, Genetic Variation, Models, Molecular, Mutation genetics, Neutralization Tests, Protein Domains, RNA, Viral genetics, SARS-CoV-2 isolation & purification, SARS-CoV-2 ultrastructure, Antigens, Viral immunology, SARS-CoV-2 immunology
Abstract

The SARS-CoV-2 spike (S) glycoprotein contains an immunodominant receptor-binding domain (RBD) targeted by most neutralizing antibodies (Abs) in COVID-19 patient plasma. Little is known about neutralizing Abs binding to epitopes outside the RBD and their contribution to protection. Here, we describe 41 human monoclonal Abs (mAbs) derived from memory B cells, which recognize the SARS-CoV-2 S N-terminal domain (NTD) and show that a subset of them neutralize SARS-CoV-2 ultrapotently. We define an antigenic map of the SARS-CoV-2 NTD and identify a supersite (designated site i) recognized by all known NTD-specific neutralizing mAbs. These mAbs inhibit cell-to-cell fusion, activate effector functions, and protect Syrian hamsters from SARS-CoV-2 challenge, albeit selecting escape mutants in some animals. Indeed, several SARS-CoV-2 variants, including the B.1.1.7, B.1.351, and P.1 lineages, harbor frequent mutations within the NTD supersite, suggesting ongoing selective pressure and the importance of NTD-specific neutralizing mAbs for protective immunity and vaccine design., Competing Interests: Declaration of interests A.D.M., F.A.L., D.P., M.B., F.Z., J.d.I., M.M.-R., J.Z., L.E.R., S.B., B.G., C.S.F., F.B., E.C., G.S., A.T., H.W.V., D.C., and M.S.P. are employees of Vir Biotechnology Inc. and may hold shares in Vir Biotechnology Inc. D.C. is currently listed as an inventor on multiple patent applications, which disclose the subject matter described in this manuscript. The Neyts laboratories have received sponsored research agreements from Vir Biotechnology Inc. H.W.V. is a founder of PierianDx and Casma Therapeutics. Neither company provided funding for this work or is performing related work. D.V. is a consultant for Vir Biotechnology Inc. The Veesler laboratory has received a sponsored research agreement from Vir Biotechnology Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Published
2021
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41. Structural basis for broad sarbecovirus neutralization by a human monoclonal antibody.

Author

Tortorici MA, Czudnochowski N, Starr TN, Marzi R, Walls AC, Zatta F, Bowen JE, Jaconi S, di Iulio J, Wang Z, De Marco A, Zepeda SK, Pinto D, Liu Z, Beltramello M, Bartha I, Housley MP, Lempp FA, Rosen LE, Dellota E Jr, Kaiser H, Montiel-Ruiz M, Zhou J, Addetia A, Guarino B, Culap K, Sprugasci N, Saliba C, Vetti E, Giacchetto-Sasselli I, Silacci Fregni C, Abdelnabi R, Caroline Foo SY, Havenar-Daughton C, Schmid MA, Benigni F, Cameroni E, Neyts J, Telenti A, Snell G, Virgin HW, Whelan SPJ, Bloom JD, Corti D, Veesler D, and Pizzuto MS

Abstract

The recent emergence of SARS-CoV-2 variants of concern (VOC) and the recurrent spillovers of coronaviruses in the human population highlight the need for broadly neutralizing antibodies that are not affected by the ongoing antigenic drift and that can prevent or treat future zoonotic infections. Here, we describe a human monoclonal antibody (mAb), designated S2X259, recognizing a highly conserved cryptic receptor-binding domain (RBD) epitope and cross-reacting with spikes from all sarbecovirus clades. S2X259 broadly neutralizes spike-mediated entry of SARS-CoV-2 including the B.1.1.7, B.1.351, P.1 and B.1.427/B.1.429 VOC, as well as a wide spectrum of human and zoonotic sarbecoviruses through inhibition of ACE2 binding to the RBD. Furthermore, deep-mutational scanning and in vitro escape selection experiments demonstrate that S2X259 possesses a remarkably high barrier to the emergence of resistance mutants. We show that prophylactic administration of S2X259 protects Syrian hamsters against challenges with the prototypic SARS-CoV-2 and the B.1.351 variant, suggesting this mAb is a promising candidate for the prevention and treatment of emergent VOC and zoonotic infections. Our data unveil a key antigenic site targeted by broadly-neutralizing antibodies and will guide the design of pan-sarbecovirus vaccines.

Published
2021
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42. Antibodies to the SARS-CoV-2 receptor-binding domain that maximize breadth and resistance to viral escape.

Author

Starr TN, Czudnochowski N, Zatta F, Park YJ, Liu Z, Addetia A, Pinto D, Beltramello M, Hernandez P, Greaney AJ, Marzi R, Glass WG, Zhang I, Dingens AS, Bowen JE, Wojcechowskyj JA, De Marco A, Rosen LE, Zhou J, Montiel-Ruiz M, Kaiser H, Tucker H, Housley MP, di Iulio J, Lombardo G, Agostini M, Sprugasci N, Culap K, Jaconi S, Meury M, Dellota E, Cameroni E, Croll TI, Nix JC, Havenar-Daughton C, Telenti A, Lempp FA, Pizzuto MS, Chodera JD, Hebner CM, Whelan SPJ, Virgin HW, Veesler D, Corti D, Bloom JD, and Snell G

Abstract

An ideal anti-SARS-CoV-2 antibody would resist viral escape 1-3 , have activity against diverse SARS-related coronaviruses 4-7 , and be highly protective through viral neutralization 8-11 and effector functions 12,13 . Understanding how these properties relate to each other and vary across epitopes would aid development of antibody therapeutics and guide vaccine design. Here, we comprehensively characterize escape, breadth, and potency across a panel of SARS-CoV-2 antibodies targeting the receptor-binding domain (RBD), including S309 4 , the parental antibody of the late-stage clinical antibody VIR-7831. We observe a tradeoff between SARS-CoV-2 in vitro neutralization potency and breadth of binding across SARS-related coronaviruses. Nevertheless, we identify several neutralizing antibodies with exceptional breadth and resistance to escape, including a new antibody (S2H97) that binds with high affinity to all SARS-related coronavirus clades via a unique RBD epitope centered on residue E516. S2H97 and other escape-resistant antibodies have high binding affinity and target functionally constrained RBD residues. We find that antibodies targeting the ACE2 receptor binding motif (RBM) typically have poor breadth and are readily escaped by mutations despite high neutralization potency, but we identify one potent RBM antibody (S2E12) with breadth across sarbecoviruses closely related to SARS-CoV-2 and with a high barrier to viral escape. These data highlight functional diversity among antibodies targeting the RBD and identify epitopes and features to prioritize for antibody and vaccine development against the current and potential future pandemics.

Published
2021
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43. SARS-CoV-2 immune evasion by variant B.1.427/B.1.429.

Author

McCallum M, Bassi J, Marco A, Chen A, Walls AC, Iulio JD, Tortorici MA, Navarro MJ, Silacci-Fregni C, Saliba C, Agostini M, Pinto D, Culap K, Bianchi S, Jaconi S, Cameroni E, Bowen JE, Tilles SW, Pizzuto MS, Guastalla SB, Bona G, Pellanda AF, Garzoni C, Van Voorhis WC, Rosen LE, Snell G, Telenti A, Virgin HW, Piccoli L, Corti D, and Veesler D

Abstract

SARS-CoV-2 entry is mediated by the spike (S) glycoprotein which contains the receptor-binding domain (RBD) and the N-terminal domain (NTD) as the two main targets of neutralizing antibodies (Abs). A novel variant of concern (VOC) named CAL.20C (B.1.427/B.1.429) was originally detected in California and is currently spreading throughout the US and 29 additional countries. It is unclear whether antibody responses to SARS-CoV-2 infection or to the prototypic Wuhan-1 isolate-based vaccines will be impacted by the three B.1.427/B.1.429 S mutations: S13I, W152C and L452R. Here, we assessed neutralizing Ab responses following natural infection or mRNA vaccination using pseudoviruses expressing the wildtype or the B.1.427/B.1.429 S protein. Plasma from vaccinated or convalescent individuals exhibited neutralizing titers, which were reduced 3-6 fold against the B.1.427/B.1.429 variant relative to wildtype pseudoviruses. The RBD L452R mutation reduced or abolished neutralizing activity of 14 out of 35 RBD-specific monoclonal antibodies (mAbs), including three clinical-stage mAbs. Furthermore, we observed a complete loss of B.1.427/B.1.429 neutralization for a panel of mAbs targeting the N-terminal domain due to a large structural rearrangement of the NTD antigenic supersite involving an S13I-mediated shift of the signal peptide cleavage site. These data warrant closer monitoring of signal peptide variants and their involvement in immune evasion and show that Abs directed to the NTD impose a selection pressure driving SARS-CoV-2 viral evolution through conventional and unconventional escape mechanisms.

Published
2021
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44. Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity.

Author

Thomson EC, Rosen LE, Shepherd JG, Spreafico R, da Silva Filipe A, Wojcechowskyj JA, Davis C, Piccoli L, Pascall DJ, Dillen J, Lytras S, Czudnochowski N, Shah R, Meury M, Jesudason N, De Marco A, Li K, Bassi J, O'Toole A, Pinto D, Colquhoun RM, Culap K, Jackson B, Zatta F, Rambaut A, Jaconi S, Sreenu VB, Nix J, Zhang I, Jarrett RF, Glass WG, Beltramello M, Nomikou K, Pizzuto M, Tong L, Cameroni E, Croll TI, Johnson N, Di Iulio J, Wickenhagen A, Ceschi A, Harbison AM, Mair D, Ferrari P, Smollett K, Sallusto F, Carmichael S, Garzoni C, Nichols J, Galli M, Hughes J, Riva A, Ho A, Schiuma M, Semple MG, Openshaw PJM, Fadda E, Baillie JK, Chodera JD, Rihn SJ, Lycett SJ, Virgin HW, Telenti A, Corti D, Robertson DL, and Snell G

Subjects
Angiotensin-Converting Enzyme 2 chemistry, Antibodies, Neutralizing genetics, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, COVID-19 virology, Humans, Mutation, Phylogeny, SARS-CoV-2 chemistry, SARS-CoV-2 pathogenicity, Spike Glycoprotein, Coronavirus chemistry, Virulence, COVID-19 immunology, Genetic Fitness, Immune Evasion, SARS-CoV-2 genetics, Spike Glycoprotein, Coronavirus genetics
Abstract

SARS-CoV-2 can mutate and evade immunity, with consequences for efficacy of emerging vaccines and antibody therapeutics. Here, we demonstrate that the immunodominant SARS-CoV-2 spike (S) receptor binding motif (RBM) is a highly variable region of S and provide epidemiological, clinical, and molecular characterization of a prevalent, sentinel RBM mutation, N439K. We demonstrate N439K S protein has enhanced binding affinity to the hACE2 receptor, and N439K viruses have similar in vitro replication fitness and cause infections with similar clinical outcomes as compared to wild type. We show the N439K mutation confers resistance against several neutralizing monoclonal antibodies, including one authorized for emergency use by the US Food and Drug Administration (FDA), and reduces the activity of some polyclonal sera from persons recovered from infection. Immune evasion mutations that maintain virulence and fitness such as N439K can emerge within SARS-CoV-2 S, highlighting the need for ongoing molecular surveillance to guide development and usage of vaccines and therapeutics., Competing Interests: Declaration of interests L.E.R., R. Spreafico, J.A.W., L.P., J.D., N.C., M.M., A.D.M., J.B., D.P., K.C., F.Z., S.J., M.B., M.P., E.C., J.D.I., H.W.V., A.T., D.C., and G.S. are or were employees of Vir Biotechnology and may hold shares in Vir Biotechnology. C.G. is an external scientific advisor for Humabs BioMed SA. J. Nix and T.I.C. are consultants with Vir Biotechnology. M.G.S. declares interest in Integrum Scientific, Greensboro, NC, outside the scope of this work. J.D.C. is a current member of the Scientific Advisory Board of OpenEye Scientific Software and is a scientific consultant to Foresite Labs. The Chodera laboratory (I.Z., W.G.G., and J.D.C.) receives or has received funding from multiple sources, including the NIH, the National Science Foundation, the Parker Institute for Cancer Immunotherapy, Relay Therapeutics, Entasis Therapeutics, Silicon Therapeutics, EMD Serono (Merck KGaA), AstraZeneca, Vir Biotechnology, XtalPi, the Molecular Sciences Software Institute, the Starr Cancer Consortium, the Open Force Field Consortium, Cycle for Survival, a Louis V. Gerstner Young Investigator Award, and the Sloan Kettering Institute. A complete funding history for the Chodera lab can be found at https://www.choderalab.org/funding. The other authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2021
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45. SARS-CoV-2 B.1.1.7 sensitivity to mRNA vaccine-elicited, convalescent and monoclonal antibodies.

Author

Collier DA, De Marco A, Ferreira IATM, Meng B, Datir R, Walls AC, Kemp S SA, Bassi J, Pinto D, Fregni CS, Bianchi S, Tortorici MA, Bowen J, Culap K, Jaconi S, Cameroni E, Snell G, Pizzuto MS, Pellanda AF, Garzoni C, Riva A, Elmer A, Kingston N, Graves B, McCoy LE, Smith KG, Bradley JR, Temperton N, Ceron-Gutierrez L L, Barcenas-Morales G, Harvey W, Virgin HW, Lanzavecchia A, Piccoli L, Doffinger R, Wills M, Veesler D, Corti D, and Gupta RK

Abstract

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) transmission is uncontrolled in many parts of the world, compounded in some areas by higher transmission potential of the B1.1.7 variant now seen in 50 countries. It is unclear whether responses to SARS-CoV-2 vaccines based on the prototypic strain will be impacted by mutations found in B.1.1.7. Here we assessed immune responses following vaccination with mRNA-based vaccine BNT162b2. We measured neutralising antibody responses following a single immunization using pseudoviruses expressing the wild-type Spike protein or the 8 amino acid mutations found in the B.1.1.7 spike protein. The vaccine sera exhibited a broad range of neutralising titres against the wild-type pseudoviruses that were modestly reduced against B.1.1.7 variant. This reduction was also evident in sera from some convalescent patients. Decreased B.1.1.7 neutralisation was also observed with monoclonal antibodies targeting the N-terminal domain (9 out of 10), the Receptor Binding Motif (RBM) (5 out of 31), but not in neutralising mAbs binding outside the RBM. Introduction of the E484K mutation in a B.1.1.7 background to reflect newly emerging viruses in the UK led to a more substantial loss of neutralising activity by vaccine-elicited antibodies and mAbs (19 out of 31) over that conferred by the B.1.1.7 mutations alone. E484K emergence on a B.1.1.7 background represents a threat to the vaccine BNT162b., Competing Interests: Competing interests A.D.M., J.B., D.P., C.S.F., S.B., K.C., N.S., E.C., G.S., S.J., A.L., H.W.V., M.S.P., L.P. and D.C. are employees of Vir Biotechnology and may hold shares in Vir Biotechnology. H.W.V. is a founder of PierianDx and Casma Therapeutics. Neither company provided funding for this work or is performing related work. D.V. is a consultant for Vir Biotechnology Inc. The Veesler laboratory has received a sponsored research agreement from Vir Biotechnology Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. RKG has received consulting fees from UMOVIS Lab, Gilead and ViiV.

Published
2021
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46. Risk assessment and seroprevalence of SARS-CoV-2 infection in healthcare workers of COVID-19 and non-COVID-19 hospitals in Southern Switzerland.

Author

Piccoli L, Ferrari P, Piumatti G, Jovic S, Rodriguez BF, Mele F, Giacchetto-Sasselli I, Terrot T, Silacci-Fregni C, Cameroni E, Jaconi S, Sprugasci N, Bartha I, Corti D, Uguccioni M, Lanzavecchia A, Garzoni C, Giannini O, Bernasconi E, Elzi L, Albanese E, Sallusto F, and Ceschi A

Abstract

Background: Hospital healthcare workers (HCW), in particular those involved in the clinical care of COVID-19 cases, are presumably exposed to a higher risk of acquiring the disease than the general population., Methods: Between April 16 and 30, 2020 we conducted a prospective, SARS-CoV-2 seroprevalence study in HCWs in Southern Switzerland. Participants were hospital personnel with varying COVID-19 exposure risk depending on job function and working site. They provided personal information (including age, sex, occupation, and medical history) and self-reported COVID-19 symptoms. Odds ratio (OR) of seropositivity to IgG antibodies was estimated by univariate and multivariate logistic regressions., Findings: Among 4726 participants, IgG antibodies to SARS-CoV-2 were detected in 9.6% of the HCWs. Seropositivity was higher among HCWs working on COVID-19 wards (14.1% (11.9-16.5)) compared to other hospital areas at medium (10.7% (7.6-14.6)) or low risk exposure (7.3% (6.4-8.3)). OR for high vs. medium wards risk exposure was 1.42 (0.91-2.22), P  = 0.119, and 1.98 (1.55-2.53), P <0.001 for high vs. low wards risk exposure. The same was for true for doctors and nurses (10.1% (9.0-11.3)) compared to other employees at medium (7.1% (4.8-10.0)) or low risk exposure (6.6% (5.0-8.4)). OR for high vs. medium profession risk exposure was 1.37 (0.89-2.11), P  = 0.149, and 1.75 (1.28-2.40), P  = 0.001 for high vs. low profession risk exposure. Moreover, seropositivity was higher among HCWs who had household exposure to COVID-19 cases compared to those without (18.7% (15.3-22.5) vs. 7.7% (6.9-8.6), OR 2.80 (2.14-3.67), P <0.001)., Interpretation: SARS-CoV-2 antibodies are detectable in up to 10% of HCWs from acute care hospitals in a region with high incidence of COVID-19 in the weeks preceding the study. HCWs with exposure to COVID-19 patients have only a slightly higher absolute risk of seropositivity compared to those without, suggesting that the use of PPE and other measures aiming at reducing nosocomial viral transmission are effective. Household contact with known COVID-19 cases represents the highest risk of seropositivity., Funding: Henry Krenter Foundation, Ente Ospedaliero Cantonale and Vir Biotechnology., Competing Interests: LP, C.S-F and NS report that the work was supported in part by Vir Biotechnology. DC, AL, IB, EC and SJ report that they owns shares of Vir Biotechnology and that the work was supported in part by Vir Biotechnology. FS owns shares of Vir Biotechnology. EB reports other from Gilead Sciences, other from Merck Sharp & Dohme, other from ViiV Healthcare, other from Pfizer, other from Abbvie, other from Sandoz, outside the submitted work. CG reports to be an external scientific consultant of Humabs BioMed SA, outside the submitted work. AC, PF, LE, OG, MU, EA, BFR, IG-S, SJ, FM, GP and TT have nothing to disclose., (© 2020 The Authors.)

Published
2021
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48. Ultrapotent human antibodies protect against SARS-CoV-2 challenge via multiple mechanisms.

Author

Tortorici MA, Beltramello M, Lempp FA, Pinto D, Dang HV, Rosen LE, McCallum M, Bowen J, Minola A, Jaconi S, Zatta F, De Marco A, Guarino B, Bianchi S, Lauron EJ, Tucker H, Zhou J, Peter A, Havenar-Daughton C, Wojcechowskyj JA, Case JB, Chen RE, Kaiser H, Montiel-Ruiz M, Meury M, Czudnochowski N, Spreafico R, Dillen J, Ng C, Sprugasci N, Culap K, Benigni F, Abdelnabi R, Foo SC, Schmid MA, Cameroni E, Riva A, Gabrieli A, Galli M, Pizzuto MS, Neyts J, Diamond MS, Virgin HW, Snell G, Corti D, Fink K, and Veesler D

Subjects
Amino Acid Motifs immunology, Angiotensin-Converting Enzyme 2, Animals, Antibodies, Neutralizing administration & dosage, Antibodies, Neutralizing isolation & purification, Antibodies, Viral administration & dosage, Antibodies, Viral isolation & purification, CHO Cells, COVID-19, Coronavirus Infections therapy, Cricetinae, Cricetulus, Cryoelectron Microscopy, HEK293 Cells, Humans, Immunodominant Epitopes chemistry, Immunodominant Epitopes immunology, Microscopy, Electron, Pneumonia, Viral therapy, Protein Domains immunology, SARS-CoV-2, Spike Glycoprotein, Coronavirus chemistry, Spike Glycoprotein, Coronavirus immunology, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, Betacoronavirus immunology, Coronavirus Infections prevention & control, Pandemics prevention & control, Peptidyl-Dipeptidase A immunology, Pneumonia, Viral prevention & control, Spike Glycoprotein, Coronavirus antagonists & inhibitors
Abstract

Efficient therapeutic options are needed to control the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has caused more than 922,000 fatalities as of 13 September 2020. We report the isolation and characterization of two ultrapotent SARS-CoV-2 human neutralizing antibodies (S2E12 and S2M11) that protect hamsters against SARS-CoV-2 challenge. Cryo-electron microscopy structures show that S2E12 and S2M11 competitively block angiotensin-converting enzyme 2 (ACE2) attachment and that S2M11 also locks the spike in a closed conformation by recognition of a quaternary epitope spanning two adjacent receptor-binding domains. Antibody cocktails that include S2M11, S2E12, or the previously identified S309 antibody broadly neutralize a panel of circulating SARS-CoV-2 isolates and activate effector functions. Our results pave the way to implement antibody cocktails for prophylaxis or therapy, circumventing or limiting the emergence of viral escape mutants., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Published
2020
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49. 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, and Veesler D

Subjects
Angiotensin-Converting Enzyme 2, Antibodies, Monoclonal chemistry, Antibodies, Monoclonal genetics, Antibodies, Monoclonal immunology, Antibodies, Neutralizing blood, Antibodies, Neutralizing chemistry, Antibodies, Viral blood, Antibodies, Viral chemistry, Antibodies, Viral immunology, Antigen-Antibody Reactions, Betacoronavirus immunology, Betacoronavirus isolation & purification, Betacoronavirus metabolism, Binding Sites, COVID-19, Coronavirus Infections pathology, Coronavirus Infections virology, Epitopes chemistry, Epitopes immunology, Humans, Immunoglobulin A blood, Immunoglobulin A immunology, Immunoglobulin G blood, Immunoglobulin G immunology, Immunoglobulin M blood, Immunoglobulin M immunology, Kinetics, Molecular Dynamics Simulation, Pandemics, Peptidyl-Dipeptidase A chemistry, Peptidyl-Dipeptidase A metabolism, Pneumonia, Viral pathology, Pneumonia, Viral virology, Protein Binding, Protein Domains immunology, Protein Structure, Quaternary, SARS-CoV-2, Spike Glycoprotein, Coronavirus chemistry, Spike Glycoprotein, Coronavirus genetics, Spike Glycoprotein, Coronavirus metabolism, Antibodies, Neutralizing immunology, Epitope Mapping methods, Spike Glycoprotein, Coronavirus immunology
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., Competing Interests: Declaration of Interests L.P., N.C., M. Beltramello, C.S.-F., D.P., L.E.R., F.Z., N.S., J.B., A.P., S. Jaconi, B.G., A.M., A.D.M., M.S.P., E.C., S.V.G., F.J., C.H.-D., M.S., D.H., G.S., K.F., H.W.V., A.L., and D.C. are employees of Vir Biotechnology Inc. and may hold shares in Vir Biotechnology Inc. D.C. is currently listed as an inventor on multiple patent applications, which disclose the subject matter described in this manuscript. The Veesler laboratory has received a sponsored research agreement from Vir Biotechnology Inc. The other authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Published
2020
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50. Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody.

Author

Pinto D, Park YJ, Beltramello M, Walls AC, Tortorici MA, Bianchi S, Jaconi S, Culap K, Zatta F, De Marco A, Peter A, Guarino B, Spreafico R, Cameroni E, Case JB, Chen RE, Havenar-Daughton C, Snell G, Telenti A, Virgin HW, Lanzavecchia A, Diamond MS, Fink K, Veesler D, and Corti D

Subjects
Angiotensin-Converting Enzyme 2, Animals, Antibodies, Monoclonal chemistry, Antibodies, Monoclonal pharmacology, Antibodies, Neutralizing chemistry, Antibodies, Neutralizing pharmacology, Antibodies, Viral chemistry, Antibodies, Viral immunology, Antibodies, Viral pharmacology, Antibody-Dependent Cell Cytotoxicity drug effects, Antibody-Dependent Cell Cytotoxicity immunology, B-Lymphocytes immunology, Betacoronavirus chemistry, Betacoronavirus drug effects, COVID-19, Chlorocebus aethiops, Coronavirus Infections immunology, Coronavirus Infections prevention & control, Coronavirus Infections therapy, Coronavirus Infections virology, Cross Reactions drug effects, Cryoelectron Microscopy, Epitopes, B-Lymphocyte chemistry, Epitopes, B-Lymphocyte immunology, HEK293 Cells, Humans, Immune Evasion immunology, Immunoglobulin Fab Fragments chemistry, Immunoglobulin Fab Fragments immunology, Immunoglobulin Fab Fragments pharmacology, Immunologic Memory immunology, Killer Cells, Natural drug effects, Killer Cells, Natural immunology, Models, Molecular, Neutralization Tests, Pandemics prevention & control, Peptidyl-Dipeptidase A chemistry, Peptidyl-Dipeptidase A metabolism, Pneumonia, Viral immunology, Pneumonia, Viral prevention & control, Pneumonia, Viral therapy, Pneumonia, Viral virology, Severe acute respiratory syndrome-related coronavirus chemistry, Severe acute respiratory syndrome-related coronavirus drug effects, SARS-CoV-2, Severe Acute Respiratory Syndrome virology, Spike Glycoprotein, Coronavirus chemistry, Vero Cells, Antibodies, Monoclonal immunology, Antibodies, Neutralizing immunology, Betacoronavirus immunology, Cross Reactions immunology, Severe acute respiratory syndrome-related coronavirus immunology, Severe Acute Respiratory Syndrome immunology, Spike Glycoprotein, Coronavirus immunology
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly emerged coronavirus that is responsible for the current pandemic of coronavirus disease 2019 (COVID-19), which has resulted in more than 3.7 million infections and 260,000 deaths as of 6 May 2020 1,2 . Vaccine and therapeutic discovery efforts are paramount to curb the pandemic spread of this zoonotic virus. The SARS-CoV-2 spike (S) glycoprotein promotes entry into host cells and is the main target of neutralizing antibodies. Here we describe several monoclonal antibodies that target the S glycoprotein of SARS-CoV-2, which we identified from memory B cells of an individual who was infected with severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003. One antibody (named S309) potently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2, by engaging the receptor-binding domain of the S glycoprotein. Using cryo-electron microscopy and binding assays, we show that S309 recognizes an epitope containing a glycan that is conserved within the Sarbecovirus subgenus, without competing with receptor attachment. Antibody cocktails that include S309 in combination with other antibodies that we identified further enhanced SARS-CoV-2 neutralization, and may limit the emergence of neutralization-escape mutants. These results pave the way for using S309 and antibody cocktails containing S309 for prophylaxis in individuals at a high risk of exposure or as a post-exposure therapy to limit or treat severe disease.

Published
2020
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