A highly stable prefusion RSV F vaccine derived from structural analysis of the fusion mechanism

Nature Communications
Anders KrarupJohannes P M Langedijk

Abstract

Respiratory syncytial virus (RSV) causes acute lower respiratory tract infections and is the leading cause of infant hospitalizations. Recently, a promising vaccine antigen based on the RSV fusion protein (RSV F) stabilized in the native prefusion conformation has been described. Here we report alternative strategies to arrest RSV F in the prefusion conformation based on the prevention of hinge movements in the first refolding region and the elimination of proteolytic exposure of the fusion peptide. A limited number of unique mutations are identified that stabilize the prefusion conformation of RSV F and dramatically increase expression levels. This highly stable prefusion RSV F elicits neutralizing antibodies in cotton rats and induces complete protection against viral challenge. Moreover, the structural and biochemical analysis of the prefusion variants suggests a function for p27, the excised segment that precedes the fusion peptide in the polypeptide chain.

References

Jun 1, 1986·American Journal of Diseases of Children·W P GlezenJ A Kasel
Jul 29, 1998·Protein Engineering·K A MiroshnikovV V Mesyanzhinov
Oct 13, 2004·Journal of Structural Biology·C O S SorzanoA Pascual-Montano
Jun 21, 2005·Proceedings of the National Academy of Sciences of the United States of America·Hsien-Sheng YinTheodore S Jardetzky
Feb 7, 2009·The New England Journal of Medicine·Caroline Breese HallPeter Szilagyi
Mar 6, 2009·Journal of Structural Biology·Gabriel C LanderBridget Carragher
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Jan 26, 2010·Nature Structural & Molecular Biology·Jason S McLellanPeter D Kwong
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·T Geoff G BattyeAndrew G W Leslie
May 19, 2011·Proceedings of the National Academy of Sciences of the United States of America·Kurt A SwansonAndrea Carfi
Feb 11, 2012·Proceedings of the National Academy of Sciences of the United States of America·Margarita MagroConcepción Palomo
Apr 13, 2012·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Hong ZhouDavid K Shay
Jun 19, 2013·Proceedings of the National Academy of Sciences of the United States of America·Lassi LiljeroosSarah Jane Butcher
Jun 26, 2013·Acta Crystallographica. Section D, Biological Crystallography·Philip R Evans, Garib N Murshudov
Aug 21, 2013·Nature·Davide CortiAntonio Lanzavecchia
Feb 18, 2014·Current Opinion in Virology·Theodore S Jardetzky, Robert A Lamb

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Citations

Dec 8, 2015·Expert Review of Vaccines·Patricia A JorqueraRalph A Tripp
Dec 8, 2015·Nature Chemical Biology·Michael B BattlesJason S McLellan
Jun 24, 2016·Proceedings of the National Academy of Sciences of the United States of America·Albert S SongRobert A Lamb
Aug 2, 2016·Nature Structural & Molecular Biology·M Gordon JoycePeter D Kwong
Nov 3, 2016·Proceedings of the National Academy of Sciences of the United States of America·Jarrod J MousaJames E Crowe
Dec 22, 2016·Nature Communications·Christopher C StobartMartin L Moore
Sep 30, 2016·Scientific Reports·April M KillikellyBarney S Graham
Mar 16, 2017·Expert Review of Vaccines·Sandra ScheiblhoferJosef Thalhamer
Mar 10, 2017·International Journal of Molecular Sciences·Emma Rey-Jurado, Alexis M Kalergis
Jun 10, 2017·Human Vaccines & Immunotherapeutics·Emma Rey-JuradoAlexis M Kalergis
Jun 3, 2017·Science·Kathryn M HastieErica Ollmann Saphire
Aug 8, 2017·International Journal of Molecular Sciences·Silvia VandiniMarcello Lanari
Aug 12, 2017·International Journal of Molecular Sciences·Nicolás M S GálvezAlexis M Kalergis
Jan 13, 2018·Viral Immunology·Charles J RussellJulia L Hurwitz
Nov 17, 2017·Nature Communications·Michael B BattlesJason S McLellan
May 18, 2018·Antiviral Chemistry & Chemotherapy·M S BoukhvalovaJcg Blanco
Dec 3, 2016·Clinical Microbiology Reviews·Cameron GriffithsDavid J Marchant
Aug 16, 2017·Proceedings of the National Academy of Sciences of the United States of America·Jesper PallesenJason S McLellan
Oct 20, 2018·Minerva pediatrica·Alessandra PierangeliGuido Antonelli
Feb 23, 2018·Infectious Diseases and Therapy·Eric A F SimõesXavier Carbonell-Estrany
Dec 21, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Wei TangFenyong Liu
May 10, 2019·Nature Communications·Morgan S A GilmanJason S McLellan
Jul 16, 2019·PLoS Pathogens·Harrison G JonesJason S McLellan
Dec 9, 2017·EMBO Molecular Medicine·Eduardo OlmedillasVicente Más
Oct 2, 2019·Nature Structural & Molecular Biology·Ha V DangDavid Veesler
Sep 14, 2018·Retrovirology·Alba Torrents de la Peña, Rogier W Sanders

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Datasets Mentioned

BETA
ACO83301.1

Methods Mentioned

BETA
ELISA
electron microscopy
X-ray
size-exclusion chromatography
transfection
light scattering
biosensors
PCR

Software Mentioned

PHASER
COOT
PHENIX
Astra
windows
ForteBio Data Analysis
AIMLESS
GraphPad PRISM
Xmipp )
iMOSFLM

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