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
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TLDR
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.Abstract:
Respiratory syncytial virus (RSV) is the leading cause of hospitalization for children under 5 years of age. We sought to engineer a viral antigen that provides greater protection than currently available vaccines and focused on antigenic site O, 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. Structure-based design yielded stabilized versions of RSV F that maintained antigenic site O when exposed to extremes of pH, osmolality, and temperature. Six RSV F crystal structures provided atomic-level data on how introduced cysteine residues and filled hydrophobic cavities improved stability. Immunization with site O–stabilized variants of RSV F in mice and macaques elicited levels of RSV-specific neutralizing activity many times the protective threshold.read more
Citations
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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
Distinct conformational states of SARS-CoV-2 spike protein
Yongfei Cai,Yongfei Cai,Jun Zhang,Jun Zhang,Tianshu Xiao,Tianshu Xiao,Hanqin Peng,Sarah M. Sterling,Richard M. Walsh,Shaun Rawson,Sophia Rits-Volloch,Bing Chen,Bing Chen +12 more
TL;DR: Two cryo–electron microscopy structures derived from a preparation of the full-length S protein, representing its prefusion and postfusion conformations, are reported, advancing the understanding of SARS-CoV-2 entry and may guide the development of vaccines and therapeutics.
Journal ArticleDOI
Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen
Jesper Pallesen,Nianshuang Wang,Kizzmekia S. Corbett,Daniel Wrapp,Robert N. Kirchdoerfer,Hannah L. Turner,Christopher A. Cottrell,Michelle M. Becker,Lingshu Wang,Wei Shi,Wing-Pui Kong,Erica L. Andres,Arminja N. Kettenbach,Mark R. Denison,Mark R. Denison,James D. Chappell,Barney S. Graham,Andrew B. Ward,Jason S. McLellan +18 more
TL;DR: An engineering strategy for stabilization of soluble S proteins in the prefusion conformation is described, which results in greatly increased expression, conformational homogeneity, and elicitation of potent antibody responses, and an engineered immunogen is able to elicit high neutralizing antibody titers against MERS-CoV.
Journal ArticleDOI
Structure-based design of prefusion-stabilized SARS-CoV-2 spikes
Ching-Lin Hsieh,Jory A. Goldsmith,Jeffrey M. Schaub,Andrea M. DiVenere,Hung-Che Kuo,Kamyab Javanmardi,Kevin C. Le,Daniel Wrapp,Alison Gene-Wei Lee,Yutong Liu,Chia Wei Chou,Patrick O. Byrne,Christy K. Hjorth,Nicole V. Johnson,John Ludes-Meyers,Annalee W. Nguyen,Juyeon Park,Nianshuang Wang,Dzifa Amengor,Jason J. Lavinder,Gregory C. Ippolito,Jennifer A. Maynard,Ilya J. Finkelstein,Jason S. McLellan +23 more
TL;DR: High-yield production of a stabilized prefusion spike protein will accelerate the development of vaccines and serological diagnostics for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
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.
References
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