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

Cell
Anna Z WecZachary A Bornholdt

Abstract

Experimental monoclonal antibody (mAb) therapies have shown promise for treatment of lethal Ebola virus (EBOV) infections, but their species-specific recognition of the viral glycoprotein (GP) has limited their use against other divergent ebolaviruses associated with human disease. Here, we mined the human immune response to natural EBOV infection and identified mAbs with exceptionally potent pan-ebolavirus neutralizing activity and protective efficacy against three virulent ebolaviruses. These mAbs recognize an inter-protomer epitope in the GP fusion loop, a critical and conserved element of the viral membrane fusion machinery, and neutralize viral entry by targeting a proteolytically primed, fusion-competent GP intermediate (GPCL) generated in host cell endosomes. Only a few somatic hypermutations are required for broad antiviral activity, and germline-approximating variants display enhanced GPCL recognition, suggesting that such antibodies could be elicited more efficiently with suitably optimized GP immunogens. Our findings inform the development of both broadly effective immunotherapeutics and vaccines against filoviruses.

References

Apr 16, 1996·Proceedings of the National Academy of Sciences of the United States of America·A SanchezS T Nichol
Feb 7, 1998·Proceedings of the National Academy of Sciences of the United States of America·A TakadaY Kawaoka
Sep 5, 1998·The Journal of Infectious Diseases·M BrayJ Huggins
Jan 1, 1997·ILAR Journal·J. Derrell ClarkDennis F. Kohn
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Apr 16, 2005·Science·Kartik ChandranJames M Cunningham
May 14, 2005·Journal of Structural Biology·Christian SulowayBridget Carragher
Mar 31, 2006·Journal of Virology·Kathryn SchornbergJudith White
Jul 25, 2006·Journal of Structural Biology·Guang TangSteven J Ludtke
Sep 12, 2006·Journal of Structural Biology·Thomas D GoddardThomas E Ferrin
Sep 12, 2007·Bioinformatics·M A LarkinD G Higgins
Nov 22, 2008·PLoS Pathogens·Jonathan S TownerStuart T Nichol
Mar 6, 2009·Journal of Structural Biology·Gabriel C LanderBridget Carragher
Jun 15, 2011·PLoS Neglected Tropical Diseases·Adam MacneilPierre E Rollin
Aug 26, 2011·Nature·Jan E CaretteThijn R Brummelkamp
Nov 22, 2011·Nature Structural & Molecular Biology·João M DiasErica Ollmann Saphire
Mar 8, 2012·The EMBO Journal·Emily Happy MillerKartik Chandran
Mar 27, 2012·Current Opinion in Virology·Emily Happy Miller, Kartik Chandran
Dec 29, 2012·PLoS Pathogens·Gopi S MohanChinglai Yang
Jan 22, 2013·Annual Review of Immunology·Davide Corti, Antonio Lanzavecchia
Aug 30, 2014·Nature·Xiangguo QiuGary P Kobinger
Nov 19, 2014·Proceedings of the National Academy of Sciences of the United States of America·Charles D MurinErica Ollmann Saphire
Feb 28, 2015·Cell·Andrew I FlyakJames E Crowe
May 1, 2015·PLoS Pathogens·Sven Moller-Tank, Wendy Maury
May 7, 2015·The Journal of Infectious Diseases·Jennifer M BrannanJohn M Dye
May 15, 2015·Clinical Microbiology Reviews·Gary Wong, Gary P Kobinger
Oct 16, 2015·Journal of Virology·James A SimmonsJudith M White
Nov 13, 2015·PLoS Pathogens·Marc-Antoine de La VegaGary P Kobinger

❮ Previous
Next ❯

Citations

Jan 30, 2018·Nature Reviews. Drug Discovery·Robert W CrossThomas W Geisbert
Jan 31, 2018·Nature Reviews. Immunology·Laura M Walker, Dennis R Burton
Mar 4, 2018·The Journal of Biological Chemistry·Elisabeth K NyakaturaJonathan R Lai
Jun 26, 2018·The Journal of Infectious Diseases·Kelly L WarfieldM Javad Aman
Aug 24, 2018·PLoS Pathogens·Philipp A IlinykhAlexander Bukreyev
Sep 27, 2018·Experimental Biology and Medicine·Jenny C Mortimer
Sep 12, 2018·The Journal of Infectious Diseases·Jacob C MilliganErica Ollmann Saphire
Feb 8, 2019·Journal of Virology·Lauren E WilliamsonJames E Crowe
Sep 6, 2019·Proceedings of the National Academy of Sciences of the United States of America·Stylianos BournazosJeffrey V Ravetch
Jul 10, 2018·The Journal of Infectious Diseases·Pavlo GilchukJames E Crowe
Jun 10, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Tony W NgSteven A Porcelli
Jun 12, 2018·The Journal of Infectious Diseases·Andrea MarziAyato Takada
Aug 28, 2018·Frontiers in Immunology·Kuldeep DhamaWanpen Chaicumpa
Oct 5, 2019·Influenza and Other Respiratory Viruses·Julius WongStephen J Kent
Jan 4, 2018·Chemical Communications : Chem Comm·Joshua A RabinowitzChris W Diehnelt
May 28, 2019·F1000Research·Judith OlejnikAdam J Hume
Feb 6, 2020·Proceedings of the National Academy of Sciences of the United States of America·Andrew S HerbertJohn M Dye
Oct 3, 2018·Expert Opinion on Drug Discovery·Robert W CrossThomas W Geisbert
Jun 3, 2020·The American Journal of Tropical Medicine and Hygiene·M Kariuki NjengaEric Osoro
Jun 26, 2018·The Journal of Infectious Diseases·Julie DyallJudith M White
Mar 6, 2019·Nature Structural & Molecular Biology·Brandyn R WestErica Ollmann Saphire
Aug 15, 2018·The Journal of Infectious Diseases·Matthew S BrambleAnne W Rimoin
May 6, 2020·Nature Reviews. Microbiology·Nicholas Di PaolaGustavo Palacios
Mar 27, 2020·Frontiers in Cellular and Infection Microbiology·Muhammed IraqiAngel Porgador

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antivirals (ASM)

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.

Antivirals

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.

Cell eTOC

Cell is a scientific journal publishing research across a broad range of disciplines within the life sciences field. Discover the latest research from Cell here.