Antibodies from a Human Survivor Define Sites of Vulnerability for Broad Protection against Ebolaviruses

Cell

Volumn 169, Issue 5, 2017, Pages 878-890.e15

  Wec, Anna Z ^a   Herbert, Andrew S ^b   Murin, Charles D ^c   Nyakatura, Elisabeth K ^a   Abelson, Dafna M ^d   Fels, J Maximilian ^a   He, Shihua ^e,f   James, Rebekah M ^b   de La Vega, Marc Antoine ^e,f   Zhu, Wenjun ^e,f   Bakken, Russell R ^b   Goodwin, Eileen ^g   Turner, Hannah L ^c   Jangra, Rohit K ^a   Zeitlin, Larry ^d   Qiu, Xiangguo ^e,f   Lai, Jonathan R ^a   Walker, Laura M ^g   Ward, Andrew B ^c   Dye, John M ^b   Chandran, Kartik ^a   Bornholdt, Zachary A ^d   more..

^a ALBERT EINSTEIN COLLEGE OF MEDICINE   (United States)

^b UNITED STATES ARMY MEDICAL RESEARCH INSTITUTE OF INFECTIOUS DISEASES   (United States)

^c SCRIPPS RESEARCH INSTITUTE   (United States)

^d Mapp Biopharmaceutical   (United States)

^e PUBLIC HEALTH AGENCY OF CANADA   (Canada)

^f UNIVERSITY OF MANITOBA   (Canada)

^g Adimab LLC   (United States)

Author keywords

15878; Ebola virus; ebolavirus; EBOV; ferret; human broadly neutralizing antibodies; infection; mouse; neutralization; protection

Indexed keywords

CROSS REACTING ANTIBODY; EPITOPE; MONOCLONAL ANTIBODY; EBOLA VACCINE; NEUTRALIZING ANTIBODY; VIRUS ANTIBODY;

ANTIVIRAL ACTIVITY; ARTICLE; BINDING AFFINITY; BUNDIBUGYO VIRUS; CONTROLLED STUDY; CROSS REACTION; EBOLA HEMORRHAGIC FEVER; EBOLAVIRUS; ELECTRON MICROSCOPY; ENDOSOME; ENZYME LINKED IMMUNOSORBENT ASSAY; EPITOPE MAPPING; FOLLOW UP; HOST CELL; HUMAN; IMMUNE RESPONSE; IN VITRO STUDY; MEMBRANE FUSION; NONHUMAN; POST EXPOSURE PROPHYLAXIS; PRIORITY JOURNAL; SOMATIC HYPERMUTATION; SUDAN VIRUS; SURVIVOR; VIRUS ENTRY; VIRUS INFECTIVITY; VIRUS NEUTRALIZATION; VIRUS RESISTANCE; AMINO ACID SEQUENCE; ANIMAL; BAGG ALBINO MOUSE; CHEMISTRY; CHLOROCEBUS AETHIOPS; CLASSIFICATION; FEMALE; IMMUNOLOGY; ISOLATION AND PURIFICATION; KINETICS; MOLECULAR MODEL; MOUSE; MUSTELA PUTORIUS FURO; SEQUENCE ALIGNMENT; VERO CELL LINE; VIROLOGY;

AMINO ACID SEQUENCE; ANIMALS; ANTIBODIES, MONOCLONAL; ANTIBODIES, NEUTRALIZING; ANTIBODIES, VIRAL; CERCOPITHECUS AETHIOPS; CROSS REACTIONS; EBOLA VACCINES; EBOLAVIRUS; FEMALE; FERRETS; HEMORRHAGIC FEVER, EBOLA; HUMANS; KINETICS; MICE; MICE, INBRED BALB C; MODELS, MOLECULAR; SEQUENCE ALIGNMENT; SURVIVORS; VERO CELLS;

EID: 85019578866     PISSN: 00928674     EISSN: 10974172     Source Type: Journal    
DOI: 10.1016/j.cell.2017.04.037     Document Type: Article

References (68)

1. Audet, J., Wong, G., Wang, H., Lu, G., Gao, G.F., Kobinger, G., Qiu, X., Molecular characterization of the monoclonal antibodies composing ZMAb: a protective cocktail against Ebola virus. Sci. Rep., 4, 2014, 6881.
2. Bornholdt, Z.A., Ndungo, E., Fusco, M.L., Bale, S., Flyak, A.I., Crowe, J.E. Jr., Chandran, K., Saphire, E.O., Host-primed Ebola virus GP exposes a hydrophobic NPC1 receptor-binding pocket, revealing a target for broadly neutralizing antibodies. MBio, 7, 2016 e02154–e15.
3. Bornholdt, Z.A., Turner, H.L., Murin, C.D., Li, W., Sok, D., Souders, C.A., Piper, A.E., Goff, A., Shamblin, J.D., Wollen, S.E., et al. Isolation of potent neutralizing antibodies from a survivor of the 2014 Ebola virus outbreak. Science 351 (2016), 1078–1083.
4. Brannan, J.M., Froude, J.W., Prugar, L.I., Bakken, R.R., Zak, S.E., Daye, S.P., Wilhelmsen, C.E., Dye, J.M., Interferon α/β receptor-deficient mice as a model for Ebola virus disease. J. Infect. Dis. 212:Suppl 2 (2015), S282–S294.
5. Bray, M., Davis, K., Geisbert, T., Schmaljohn, C., Huggins, J., A mouse model for evaluation of prophylaxis and therapy of Ebola hemorrhagic fever. J. Infect. Dis. 178 (1998), 651–661.
6. Brecher, M., Schornberg, K.L., Delos, S.E., Fusco, M.L., Saphire, E.O., White, J.M., Cathepsin cleavage potentiates the Ebola virus glycoprotein to undergo a subsequent fusion-relevant conformational change. J. Virol. 86 (2012), 364–372.
7. Burk, R., Bollinger, L., Johnson, J.C., Wada, J., Radoshitzky, S.R., Palacios, G., Bavari, S., Jahrling, P.B., Kuhn, J.H., Neglected filoviruses. FEMS Microbiol. Rev. 40 (2016), 494–519.
8. Carette, J.E., Raaben, M., Wong, A.C., Herbert, A.S., Obernosterer, G., Mulherkar, N., Kuehne, A.I., Kranzusch, P.J., Griffin, A.M., Ruthel, G., et al. Ebola virus entry requires the cholesterol transporter Niemann-Pick C1. Nature 477 (2011), 340–343.
9. Chandran, K., Sullivan, N.J., Felbor, U., Whelan, S.P., Cunningham, J.M., Endosomal proteolysis of the Ebola virus glycoprotein is necessary for infection. Science 308 (2005), 1643–1645.
10. Clark, J.D., Gebhart, G.F., Gonder, J.C., Keeling, M.E., Kohn, D.F., The 1996 Guide for the Care and Use of Laboratory Animals. ILAR J 38 (1997), 41–48.
11. Corti, D., Lanzavecchia, A., Broadly neutralizing antiviral antibodies. Annu. Rev. Immunol. 31 (2013), 705–742.
12. Côté, M., Misasi, J., Ren, T., Bruchez, A., Lee, K., Filone, C.M., Hensley, L., Li, Q., Ory, D., Chandran, K., Cunningham, J., Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection. Nature 477 (2011), 344–348.
13. Cross, R.W., Mire, C.E., Borisevich, V., Geisbert, J.B., Fenton, K.A., Geisbert, T.W., The domestic ferret (Mustela putorius furo) as a lethal infection model for 3 species of Ebolavirus. J. Infect. Dis. 214 (2016), 565–569.
14. Davey, R.T. Jr., Dodd, L., Proschan, M.A., Neaton, J., Neuhaus Nordwall, J., Koopmeiners, J.S., Beigel, J., Tierney, J., Lane, H.C., Fauci, A.S., et al. PREVAIL II Writing Group, Multi-National PREVAIL II Study Team. A randomized, controlled trial of ZMapp for Ebola virus infection. N. Engl. J. Med. 375 (2016), 1448–1456.
15. de La Vega, M.A., Stein, D., Kobinger, G.P., Ebolavirus evolution: past and present. PLoS Pathog., 11, 2015, e1005221.
16. Dejnirattisai, W., Wongwiwat, W., Supasa, S., Zhang, X., Dai, X., Rouvinski, A., Jumnainsong, A., Edwards, C., Quyen, N.T., Duangchinda, T., et al. A new class of highly potent, broadly neutralizing antibodies isolated from viremic patients infected with dengue virus. Nat. Immunol. 16 (2015), 170–177.
17. Dias, J.M., Kuehne, A.I., Abelson, D.M., Bale, S., Wong, A.C., Halfmann, P., Muhammad, M.A., Fusco, M.L., Zak, S.E., Kang, E., et al. A shared structural solution for neutralizing ebolaviruses. Nat. Struct. Mol. Biol. 18 (2011), 1424–1427.
18. Dube, D., Brecher, M.B., Delos, S.E., Rose, S.C., Park, E.W., Schornberg, K.L., Kuhn, J.H., White, J.M., The primed ebolavirus glycoprotein (19-kilodalton GP1,2): sequence and residues critical for host cell binding. J. Virol. 83 (2009), 2883–2891.
19. WHO International Study Team. Ebola haemorrhagic fever in Sudan, 1976. Bull. World Health Organ. 56 (1978), 247–270.
20. Flyak, A.I., Ilinykh, P.A., Murin, C.D., Garron, T., Shen, X., Fusco, M.L., Hashiguchi, T., Bornholdt, Z.A., Slaughter, J.C., Sapparapu, G., et al. Mechanism of human antibody-mediated neutralization of Marburg virus. Cell 160 (2015), 893–903.
21. Flyak, A.I., Shen, X., Murin, C.D., Turner, H.L., David, J.A., Fusco, M.L., Lampley, R., Kose, N., Ilinykh, P.A., Kuzmina, N., et al. Cross-reactive and potent neutralizing antibody responses in human survivors of natural Ebolavirus infection. Cell 164 (2016), 392–405.
22. Frei, J.C., Nyakatura, E.K., Zak, S.E., Bakken, R.R., Chandran, K., Dye, J.M., Lai, J.R., Bispecific antibody affords complete post-exposure protection of mice from both Ebola (Zaire) and Sudan viruses. Sci. Rep., 6, 2016, 19193.
23. Furuyama, W., Marzi, A., Nanbo, A., Haddock, E., Maruyama, J., Miyamoto, H., Igarashi, M., Yoshida, R., Noyori, O., Feldmann, H., Takada, A., Discovery of an antibody for pan-ebolavirus therapy. Sci. Rep., 6, 2016, 20514.
24. Goddard, T.D., Huang, C.C., Ferrin, T.E., Visualizing density maps with UCSF Chimera. J. Struct. Biol. 157 (2007), 281–287.
25. Holtsberg, F.W., Shulenin, S., Vu, H., Howell, K.A., Patel, S.J., Gunn, B., Karim, M., Lai, J.R., Frei, J.C., Nyakatura, E.K., et al. Pan-ebolavirus and Pan-filovirus mouse monoclonal antibodies: protection against Ebola and Sudan viruses. J. Virol. 90 (2015), 266–278.
26. Howell, K.A., Qiu, X., Brannan, J.M., Bryan, C., Davidson, E., Holtsberg, F.W., Wec, A.Z., Shulenin, S., Biggins, J.E., Douglas, R., et al. Antibody treatment of Ebola and Sudan virus infection via a uniquely exposed epitope within the glycoprotein receptor-binding site. Cell Rep. 15 (2016), 1514–1526.
27. Jahrling, P.B., Geisbert, T.W., Geisbert, J.B., Swearengen, J.R., Bray, M., Jaax, N.K., Huggins, J.W., LeDuc, J.W., Peters, C.J., Evaluation of immune globulin and recombinant interferon-alpha2b for treatment of experimental Ebola virus infections. J. Infect. Dis. 179:Suppl 1 (1999), S224–S234.
28. Keck, Z.Y., Enterlein, S.G., Howell, K.A., Vu, H., Shulenin, S., Warfield, K.L., Froude, J.W., Araghi, N., Douglas, R., Biggins, J., et al. Macaque monoclonal antibodies targeting novel conserved epitopes within filovirus glycoprotein. J. Virol. 90 (2015), 279–291.
29. Kozak, R., He, S., Kroeker, A., de La Vega, M.A., Audet, J., Wong, G., Urfano, C., Antonation, K., Embury-Hyatt, C., Kobinger, G.P., Qiu, X., Ferrets infected with Bundibugyo virus or Ebola virus recapitulate important aspects of human filovirus disease. J. Virol. 90 (2016), 9209–9223.
30. Kuhn, J.H., Andersen, K.G., Baize, S., Bào, Y., Bavari, S., Berthet, N., Blinkova, O., Brister, J.R., Clawson, A.N., Fair, J., et al. Nomenclature- and database-compatible names for the two Ebola virus variants that emerged in Guinea and the Democratic Republic of the Congo in 2014. Viruses 6 (2014), 4760–4799.
31. Lander, G.C., Stagg, S.M., Voss, N.R., Cheng, A., Fellmann, D., Pulokas, J., Yoshioka, C., Irving, C., Mulder, A., Lau, P.W., et al. Appion: an integrated, database-driven pipeline to facilitate EM image processing. J. Struct. Biol. 166 (2009), 95–102.
32. Larkin, M.A., Blackshields, G., Brown, N.P., Chenna, R., McGettigan, P.A., McWilliam, H., Valentin, F., Wallace, I.M., Wilm, A., Lopez, R., et al. Clustal W and Clustal X version 2.0. Bioinformatics 23 (2007), 2947–2948.
33. Lee, J.E., Fusco, M.L., Hessell, A.J., Oswald, W.B., Burton, D.R., Saphire, E.O., Structure of the Ebola virus glycoprotein bound to an antibody from a human survivor. Nature 454 (2008), 177–182.
34. Lee, J.E., Kuehne, A., Abelson, D.M., Fusco, M.L., Hart, M.K., Saphire, E.O., Complex of a protective antibody with its Ebola virus GP peptide epitope: unusual features of a V lambda x light chain. J. Mol. Biol. 375 (2008), 202–216.
35. Macneil, A., Reed, Z., Rollin, P.E., Serologic cross-reactivity of human IgM and IgG antibodies to five species of Ebola virus. PLoS Negl. Trop. Dis., 5, 2011, e1175.
36. Maruyama, T., Rodriguez, L.L., Jahrling, P.B., Sanchez, A., Khan, A.S., Nichol, S.T., Peters, C.J., Parren, P.W., Burton, D.R., Ebola virus can be effectively neutralized by antibody produced in natural human infection. J. Virol. 73 (1999), 6024–6030.
37. Miller, E.H., Chandran, K., Filovirus entry into cells - new insights. Curr. Opin. Virol. 2 (2012), 206–214.
38. Miller, E.H., Obernosterer, G., Raaben, M., Herbert, A.S., Deffieu, M.S., Krishnan, A., Ndungo, E., Sandesara, R.G., Carette, J.E., Kuehne, A.I., et al. Ebola virus entry requires the host-programmed recognition of an intracellular receptor. EMBO J. 31 (2012), 1947–1960.
39. Misasi, J., Chandran, K., Yang, J.Y., Considine, B., Filone, C.M., Côté, M., Sullivan, N., Fabozzi, G., Hensley, L., Cunningham, J., Filoviruses require endosomal cysteine proteases for entry but exhibit distinct protease preferences. J. Virol. 86 (2012), 3284–3292.
40. Misasi, J., Gilman, M.S., Kanekiyo, M., Gui, M., Cagigi, A., Mulangu, S., Corti, D., Ledgerwood, J.E., Lanzavecchia, A., Cunningham, J., et al. Structural and molecular basis for Ebola virus neutralization by protective human antibodies. Science 351 (2016), 1343–1346.
41. Mohan, G.S., Li, W., Ye, L., Compans, R.W., Yang, C., Antigenic subversion: a novel mechanism of host immune evasion by Ebola virus. PLoS Pathog., 8, 2012, e1003065.
42. Moller-Tank, S., Maury, W., Ebola virus entry: a curious and complex series of events. PLoS Pathog., 11, 2015, e1004731.
43. Murin, C.D., Fusco, M.L., Bornholdt, Z.A., Qiu, X., Olinger, G.G., Zeitlin, L., Kobinger, G.P., Ward, A.B., Saphire, E.O., Structures of protective antibodies reveal sites of vulnerability on Ebola virus. Proc. Natl. Acad. Sci. USA 111 (2014), 17182–17187.
44. Natesan, M., Jensen, S.M., Keasey, S.L., Kamata, T., Kuehne, A.I., Stonier, S.W., Lutwama, J.J., Lobel, L., Dye, J.M., Ulrich, R.G., Human survivors of disease outbreaks caused by Ebola or Marburg virus exhibit cross-reactive and long-lived antibody responses. Clin. Vaccine Immunol. 23 (2016), 717–724.
45. National Research Council. Guide for the Care and Use of Laboratory Animals. Eighth Edition, 2011, National Academies Press.
46. Ng, M., Ndungo, E., Jangra, R.K., Cai, Y., Postnikova, E., Radoshitzky, S.R., Dye, J.M., Ramírez de Arellano, E., Negredo, A., Palacios, G., et al. Cell entry by a novel European filovirus requires host endosomal cysteine proteases and Niemann-Pick C1. Virology 468-470 (2014), 637–646.
47. Ogura, T., Iwasaki, K., Sato, C., Topology representing network enables highly accurate classification of protein images taken by cryo electron-microscope without masking. J. Struct. Biol. 143 (2003), 185–200.
48. Pallesen, J., Murin, C.D., de Val, N., Cottrell, C.A., Hastie, K.M., Turner, H.L., Fusco, M.L., Flyak, A.I., Zeitlin, L., Crowe, J.E. Jr., et al. Structures of Ebola virus GP and sGP in complex with therapeutic antibodies. Nat. Microbiol., 1, 2016, 16128.
49. Pei, J., Grishin, N.V., AL2CO: calculation of positional conservation in a protein sequence alignment. Bioinformatics 17 (2001), 700–712.
50. Pettersen, E.F., Goddard, T.D., Huang, C.C., Couch, G.S., Greenblatt, D.M., Meng, E.C., Ferrin, T.E., UCSF Chimera-a visualization system for exploratory research and analysis. J. Comput. Chem. 25 (2004), 1605–1612.
51. Qiu, X., Wong, G., Audet, J., Bello, A., Fernando, L., Alimonti, J.B., Fausther-Bovendo, H., Wei, H., Aviles, J., Hiatt, E., et al. Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Nature 514 (2014), 47–53.
52. Sanchez, A., Trappier, S.G., Mahy, B.W., Peters, C.J., Nichol, S.T., The virion glycoproteins of Ebola viruses are encoded in two reading frames and are expressed through transcriptional editing. Proc. Natl. Acad. Sci. USA 93 (1996), 3602–3607.
53. Schornberg, K., Matsuyama, S., Kabsch, K., Delos, S., Bouton, A., White, J., Role of endosomal cathepsins in entry mediated by the Ebola virus glycoprotein. J. Virol. 80 (2006), 4174–4178.
54. Shedlock, D.J., Bailey, M.A., Popernack, P.M., Cunningham, J.M., Burton, D.R., Sullivan, N.J., Antibody-mediated neutralization of Ebola virus can occur by two distinct mechanisms. Virology 401 (2010), 228–235.
55. Simmons, J.A., D'Souza, R.S., Ruas, M., Galione, A., Casanova, J.E., White, J.M., Ebolavirus glycoprotein directs fusion through NPC1+ endolysosomes. J. Virol. 90 (2015), 605–610.
56. Spence, J.S., Krause, T.B., Mittler, E., Jangra, R.K., Chandran, K., Direct visualization of Ebola virus fusion triggering in the endocytic pathway. MBio, 7, 2016 e01857–e15.
57. Suloway, C., Pulokas, J., Fellmann, D., Cheng, A., Guerra, F., Quispe, J., Stagg, S., Potter, C.S., Carragher, B., Automated molecular microscopy: the new Leginon system. J. Struct. Biol. 151 (2005), 41–60.
58. Takada, A., Robison, C., Goto, H., Sanchez, A., Murti, K.G., Whitt, M.A., Kawaoka, Y., A system for functional analysis of Ebola virus glycoprotein. Proc. Natl. Acad. Sci. USA 94 (1997), 14764–14769.
59. Tang, G., Peng, L., Baldwin, P.R., Mann, D.S., Jiang, W., Rees, I., Ludtke, S.J., EMAN2: an extensible image processing suite for electron microscopy. J. Struct. Biol. 157 (2007), 38–46.
60. Tiller, T., Schuster, I., Deppe, D., Siegers, K., Strohner, R., Herrmann, T., Berenguer, M., Poujol, D., Stehle, J., Stark, Y., et al. A fully synthetic human Fab antibody library based on fixed VH/VL framework pairings with favorable biophysical properties. MAbs 5 (2013), 445–470.
61. Towner, J.S., Sealy, T.K., Khristova, M.L., Albariño, C.G., Conlan, S., Reeder, S.A., Quan, P.L., Lipkin, W.I., Downing, R., Tappero, J.W., et al. Newly discovered ebola virus associated with hemorrhagic fever outbreak in Uganda. PLoS Pathog., 4, 2008, e1000212.
62. Voss, N.R., Yoshioka, C.K., Radermacher, M., Potter, C.S., Carragher, B., DoG Picker and TiltPicker: software tools to facilitate particle selection in single particle electron microscopy. J. Struct. Biol. 166 (2009), 205–213.
63. Wang, H., Shi, Y., Song, J., Qi, J., Lu, G., Yan, J., Gao, G.F., Ebola viral glycoprotein bound to its endosomal receptor Niemann-Pick C1. Cell 164 (2016), 258–268.
64. Wec, A.Z., Nyakatura, E.K., Herbert, A.S., Howell, K.A., Holtsberg, F.W., Bakken, R.R., Mittler, E., Christin, J.R., Shulenin, S., Jangra, R.K., et al. A “Trojan horse” bispecific-antibody strategy for broad protection against ebolaviruses. Science 354 (2016), 350–354.
65. Wong, G., Kobinger, G.P., Backs against the wall: novel and existing strategies used during the 2014-2015 Ebola virus outbreak. Clin. Microbiol. Rev. 28 (2015), 593–601.
66. Wong, A.C., Sandesara, R.G., Mulherkar, N., Whelan, S.P., Chandran, K., A forward genetic strategy reveals destabilizing mutations in the Ebolavirus glycoprotein that alter its protease dependence during cell entry. J. Virol. 84 (2010), 163–175.
67. Zhao, Y., Ren, J., Harlos, K., Jones, D.M., Zeltina, A., Bowden, T.A., Padilla-Parra, S., Fry, E.E., Stuart, D.I., Toremifene interacts with and destabilizes the Ebola virus glycoprotein. Nature 535 (2016), 169–172.
68. Zhao, X., Howell, K.A., He, S., Brannan, J.M., Wec, A.Z., Davidson, E., Turner, H.L., Chiang, C.-I., Lei, L., Fels, J.M., et al. Immunization-elicited broadly protective antibody reveals ebolavirus fusion loop as a site of vulnerability. Cell 169 (2017), 891–904 this issue.