Structure of RSV Fusion Glycoprotein Trimer Bound to a Prefusion-Specific Neutralizing Antibody
Jason S. McLellan,Man Chen,Sherman Leung,Kevin W. Graepel,Xiulian Du,Yongping Yang,Tongqing Zhou,Ulrich Baxa,Etsuko Yasuda,Tim Beaumont,Azad Kumar,Kayvon Modjarrad,Zizheng Zheng,Min Zhao,Ningshao Xia,Peter D. Kwong,Barney S. Graham +16 more
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TLDR
Preference-specific antibodies that were substantially more potent than the prophylactic antibody palivizumab were identified, which should enable design of improved vaccine antigens and define new targets for passive prevention of RSV-induced disease.Abstract:
The prefusion state of respiratory syncytial virus (RSV) fusion (F) glycoprotein is the target of most RSV-neutralizing activity in human sera, but its metastability has hindered characterization. To overcome this obstacle, we identified prefusion-specific antibodies that were substantially more potent than the prophylactic antibody palivizumab. The cocrystal structure for one of these antibodies, D25, in complex with the F glycoprotein revealed D25 to lock F in its prefusion state by binding to a quaternary epitope at the trimer apex. Electron microscopy showed that two other antibodies, AM22 and 5C4, also bound to the newly identified site of vulnerability, which we named antigenic site O. These studies should enable design of improved vaccine antigens and define new targets for passive prevention of RSV-induced disease.read more
Citations
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Journal ArticleDOI
SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness.
Kizzmekia S. Corbett,Darin K. Edwards,Sarah R. Leist,Olubukola M. Abiona,Seyhan Boyoglu-Barnum,Rebecca A. Gillespie,Sunny Himansu,Alexandra Schäfer,Cynthia T. Ziwawo,Anthony T. DiPiazza,Kenneth H. Dinnon,Sayda Elbashir,Christine A. Shaw,Angela Woods,Ethan J. Fritch,David R. Martinez,Kevin W. Bock,Mahnaz Minai,Bianca M. Nagata,Geoffrey B. Hutchinson,Kai Wu,Carole Henry,Kapil Bahl,Dario Garcia-Dominguez,Ling Zhi Ma,Isabella Renzi,Wing Pui Kong,Stephen D. Schmidt,Lingshu Wang,Yi Zhang,Emily Phung,Emily Phung,Lauren A. Chang,Rebecca J. Loomis,Nedim Emil Altaras,Elisabeth Narayanan,Mihir Metkar,Vlad Presnyak,Cuiping Liu,Mark K. Louder,Wei Shi,Kwanyee Leung,Eun Sung Yang,Ande West,Kendra Gully,Laura J. Stevens,Nianshuang Wang,Daniel Wrapp,Nicole A. Doria-Rose,Guillaume Stewart-Jones,Hamilton Bennett,Gabriela S. Alvarado,Martha Nason,Tracy J. Ruckwardt,Jason S. McLellan,Mark R. Denison,James D. Chappell,Ian N. Moore,Kaitlyn M. Morabito,John R. Mascola,Ralph S. Baric,Andrea Carfi,Barney S. Graham +62 more
TL;DR: In this article, an mRNA vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is proposed, which is used to control the CoVID-19 global pandemic.
Journal ArticleDOI
Crystal structure of a soluble cleaved HIV-1 envelope trimer.
Jean-Philippe Julien,Jean-Philippe Julien,Albert Cupo,Devin Sok,Devin Sok,Robyn L. Stanfield,Robyn L. Stanfield,Dmitry Lyumkis,Marc C. Deller,Per Johan Klasse,Dennis R. Burton,Rogier W. Sanders,John P. Moore,Andrew B. Ward,Andrew B. Ward,Ian A. Wilson +15 more
TL;DR: The crystal structure at 4.7 angstroms of a soluble, cleaved Env trimer that is stabilized and antigenically near-native in complex with a potent broadly neutralizing antibody, PGT122 is described.
Journal ArticleDOI
Structure-Based Design of a Fusion Glycoprotein Vaccine for Respiratory Syncytial Virus
Jason S. McLellan,Man Chen,M. Gordon Joyce,Mallika Sastry,Guillaume Stewart-Jones,Yongping Yang,Baoshan Zhang,Lei Chen,Sanjay Srivatsan,Anqi Zheng,Tongqing Zhou,Kevin W. Graepel,Azad Kumar,Syed M. Moin,Jeffrey C. Boyington,Gwo-Yu Chuang,Cinque Soto,Ulrich Baxa,Arjen Q. Bakker,Hergen Spits,Tim Beaumont,Zizheng Zheng,Ningshao Xia,Sung Youl Ko,John Paul Todd,Srinivas S. Rao,Barney S. Graham,Peter D. Kwong +27 more
TL;DR: A viral antigen is sought that provides greater protection than currently available vaccines and focused on antigenic site Ø, a metastable site specific to the prefusion state of the RSV fusion (F) glycoprotein, as this site is targeted by extremely potent RSV-neutralizing antibodies.
Journal ArticleDOI
Cryo-EM Structure of a Fully Glycosylated Soluble Cleaved HIV-1 Envelope Trimer
Dmitry Lyumkis,Jean-Philippe Julien,Natalia de Val,Albert Cupo,Clinton S. Potter,Per Johan Klasse,Dennis R. Burton,Rogier W. Sanders,Rogier W. Sanders,John P. Moore,Bridget Carragher,Ian A. Wilson,Andrew B. Ward,Andrew B. Ward +13 more
TL;DR: A cryo–electron microscopy reconstruction and structural model of a cleaved, soluble Env trimer in complex with a CD4 binding site bnAb, PGV04 is presented, which reveals the spatial arrangement of Env components, including the V1/V2, V3, HR1, and HR2 domains, as well as shielding glycans.
Journal ArticleDOI
Structure and immune recognition of trimeric pre-fusion HIV-1 Env
Marie Pancera,Tongqing Zhou,Aliaksandr Druz,Ivelin S. Georgiev,Cinque Soto,Jason Gorman,Jinghe Huang,Priyamvada Acharya,Gwo-Yu Chuang,Gilad Ofek,Guillaume Stewart-Jones,Jonathan Stuckey,Robert T. Bailer,M. Gordon Joyce,Mark K. Louder,Nancy Tumba,Yongping Yang,Baoshan Zhang,Myron S. Cohen,Barton F. Haynes,John R. Mascola,Lynn Morris,James B. Munro,Scott C. Blanchard,Walther Mothes,Mark Connors,Peter D. Kwong +26 more
TL;DR: The structure at 3.5 Å resolution for an HIV-1 Env trimer captured in a mature closed state by antibodies PGT122 and 35O22 is reported, revealing the pre-fusion conformation of gp41, rearrangements needed for fusion activation, and defines parameters of immune evasion and immune recognition.
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