IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-50976-9.html
   My bibliography  Save this article

Simulation-driven design of stabilized SARS-CoV-2 spike S2 immunogens

Author

Listed:
  • Xandra Nuqui

    (University of California San Diego)

  • Lorenzo Casalino

    (University of California San Diego)

  • Ling Zhou

    (The University of Texas at Austin)

  • Mohamed Shehata

    (University of California San Diego)

  • Albert Wang

    (Albert Einstein College of Medicine)

  • Alexandra L. Tse

    (Albert Einstein College of Medicine)

  • Anupam A. Ojha

    (University of California San Diego)

  • Fiona L. Kearns

    (University of California San Diego)

  • Mia A. Rosenfeld

    (University of California San Diego
    National Institutes of Health)

  • Emily Happy Miller

    (Albert Einstein College of Medicine
    Albert Einstein College of Medicine)

  • Cory M. Acreman

    (The University of Texas at Austin)

  • Surl-Hee Ahn

    (University of California Davis)

  • Kartik Chandran

    (Albert Einstein College of Medicine)

  • Jason S. McLellan

    (The University of Texas at Austin)

  • Rommie E. Amaro

    (University of California San Diego
    University of California San Diego)

Abstract

The full-length prefusion-stabilized SARS-CoV-2 spike (S) is the principal antigen of COVID-19 vaccines. Vaccine efficacy has been impacted by emerging variants of concern that accumulate most of the sequence modifications in the immunodominant S1 subunit. S2, in contrast, is the most evolutionarily conserved region of the spike and can elicit broadly neutralizing and protective antibodies. Yet, S2’s usage as an alternative vaccine strategy is hampered by its general instability. Here, we use a simulation-driven approach to design S2-only immunogens stabilized in a closed prefusion conformation. Molecular simulations provide a mechanistic characterization of the S2 trimer’s opening, informing the design of tryptophan substitutions that impart kinetic and thermodynamic stabilization. Structural characterization via cryo-EM shows the molecular basis of S2 stabilization in the closed prefusion conformation. Informed by molecular simulations and corroborated by experiments, we report an engineered S2 immunogen that exhibits increased protein expression, superior thermostability, and preserved immunogenicity against sarbecoviruses.

Suggested Citation

  • Xandra Nuqui & Lorenzo Casalino & Ling Zhou & Mohamed Shehata & Albert Wang & Alexandra L. Tse & Anupam A. Ojha & Fiona L. Kearns & Mia A. Rosenfeld & Emily Happy Miller & Cory M. Acreman & Surl-Hee A, 2024. "Simulation-driven design of stabilized SARS-CoV-2 spike S2 immunogens," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50976-9
    DOI: 10.1038/s41467-024-50976-9
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-50976-9
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-50976-9?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Ching-Lin Hsieh & Sarah R. Leist & Emily Happy Miller & Ling Zhou & John M. Powers & Alexandra L. Tse & Albert Wang & Ande West & Mark R. Zweigart & Jonathan C. Schisler & Rohit K. Jangra & Kartik Cha, 2024. "Prefusion-stabilized SARS-CoV-2 S2-only antigen provides protection against SARS-CoV-2 challenge," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Chunyan Wang & Rien Haperen & Javier Gutiérrez-Álvarez & Wentao Li & Nisreen M. A. Okba & Irina Albulescu & Ivy Widjaja & Brenda Dieren & Raul Fernandez-Delgado & Isabel Sola & Daniel L. Hurdiss & Ola, 2021. "A conserved immunogenic and vulnerable site on the coronavirus spike protein delineated by cross-reactive monoclonal antibodies," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    3. Maolin Lu & Xiaochu Ma & Luis R. Castillo-Menendez & Jason Gorman & Nirmin Alsahafi & Utz Ermel & Daniel S. Terry & Michael Chambers & Dongjun Peng & Baoshan Zhang & Tongqing Zhou & Nick Reichard & Ke, 2019. "Associating HIV-1 envelope glycoprotein structures with states on the virus observed by smFRET," Nature, Nature, vol. 568(7752), pages 415-419, April.
    4. Gabriel Ozorowski & Jesper Pallesen & Natalia de Val & Dmitry Lyumkis & Christopher A. Cottrell & Jonathan L. Torres & Jeffrey Copps & Robyn L. Stanfield & Albert Cupo & Pavel Pugach & John P. Moore &, 2017. "Open and closed structures reveal allostery and pliability in the HIV-1 envelope spike," Nature, Nature, vol. 547(7663), pages 360-363, July.
    5. Lihong Liu & Pengfei Wang & Manoj S. Nair & Jian Yu & Micah Rapp & Qian Wang & Yang Luo & Jasper F.-W. Chan & Vincent Sahi & Amir Figueroa & Xinzheng V. Guo & Gabriele Cerutti & Jude Bimela & Jason Go, 2020. "Potent neutralizing antibodies against multiple epitopes on SARS-CoV-2 spike," Nature, Nature, vol. 584(7821), pages 450-456, August.
    6. Mathieu Claireaux & Tom G. Caniels & Marlon Gast & Julianna Han & Denise Guerra & Gius Kerster & Barbera D. C. Schaik & Aldo Jongejan & Angela I. Schriek & Marloes Grobben & Philip J. M. Brouwer & Kar, 2022. "A public antibody class recognizes an S2 epitope exposed on open conformations of SARS-CoV-2 spike," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    7. Christopher O. Barnes & Claudia A. Jette & Morgan E. Abernathy & Kim-Marie A. Dam & Shannon R. Esswein & Harry B. Gristick & Andrey G. Malyutin & Naima G. Sharaf & Kathryn E. Huey-Tubman & Yu E. Lee &, 2020. "SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies," Nature, Nature, vol. 588(7839), pages 682-687, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Timothy J. C. Tan & Zongjun Mou & Ruipeng Lei & Wenhao O. Ouyang & Meng Yuan & Ge Song & Raiees Andrabi & Ian A. Wilson & Collin Kieffer & Xinghong Dai & Kenneth A. Matreyek & Nicholas C. Wu, 2023. "High-throughput identification of prefusion-stabilizing mutations in SARS-CoV-2 spike," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Seoryeong Park & Jaewon Choi & Yonghee Lee & Jinsung Noh & Namphil Kim & JinAh Lee & Geummi Cho & Sujeong Kim & Duck Kyun Yoo & Chang Kyung Kang & Pyoeng Gyun Choe & Nam Joong Kim & Wan Beom Park & Se, 2024. "An ancestral SARS-CoV-2 vaccine induces anti-Omicron variants antibodies by hypermutation," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
    3. Ching-Lin Hsieh & Sarah R. Leist & Emily Happy Miller & Ling Zhou & John M. Powers & Alexandra L. Tse & Albert Wang & Ande West & Mark R. Zweigart & Jonathan C. Schisler & Rohit K. Jangra & Kartik Cha, 2024. "Prefusion-stabilized SARS-CoV-2 S2-only antigen provides protection against SARS-CoV-2 challenge," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    4. Rajeshwer S. Sankhala & Kerri G. Lal & Jaime L. Jensen & Vincent Dussupt & Letzibeth Mendez-Rivera & Hongjun Bai & Lindsay Wieczorek & Sandra V. Mayer & Michelle Zemil & Danielle A. Wagner & Samantha , 2024. "Diverse array of neutralizing antibodies elicited upon Spike Ferritin Nanoparticle vaccination in rhesus macaques," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    5. Tingting Li & Xiaojian Han & Chenjian Gu & Hangtian Guo & Huajun Zhang & Yingming Wang & Chao Hu & Kai Wang & Fengjiang Liu & Feiyang Luo & Yanan Zhang & Jie Hu & Wang Wang & Shenglong Li & Yanan Hao , 2021. "Potent SARS-CoV-2 neutralizing antibodies with protective efficacy against newly emerged mutational variants," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    6. Chunyan Wang & Emma L. Hesketh & Tatiana M. Shamorkina & Wentao Li & Peter J. Franken & Dubravka Drabek & Rien Haperen & Sarah Townend & Frank J. M. Kuppeveld & Frank Grosveld & Neil A. Ranson & Joost, 2022. "Antigenic structure of the human coronavirus OC43 spike reveals exposed and occluded neutralizing epitopes," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    7. Kuan-Ying A. Huang & Xiaorui Chen & Arpita Mohapatra & Hong Thuy Vy Nguyen & Lisa Schimanski & Tiong Kit Tan & Pramila Rijal & Susan K. Vester & Rory A. Hills & Mark Howarth & Jennifer R. Keeffe & Ale, 2023. "Structural basis for a conserved neutralization epitope on the receptor-binding domain of SARS-CoV-2," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    8. Yingdan Wang & Aihua Hao & Ping Ji & Yunping Ma & Zhaoyong Zhang & Jiali Chen & Qiyu Mao & Xinyi Xiong & Palizhati Rehati & Yajie Wang & Yanqun Wang & Yumei Wen & Lu Lu & Zhenguo Chen & Jincun Zhao & , 2024. "A bispecific antibody exhibits broad neutralization against SARS-CoV-2 Omicron variants XBB.1.16, BQ.1.1 and sarbecoviruses," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    9. Dhiraj Mannar & James W. Saville & Zehua Sun & Xing Zhu & Michelle M. Marti & Shanti S. Srivastava & Alison M. Berezuk & Steven Zhou & Katharine S. Tuttle & Michele D. Sobolewski & Andrew Kim & Benjam, 2022. "SARS-CoV-2 variants of concern: spike protein mutational analysis and epitope for broad neutralization," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    10. Andrew C. Hunt & Bastian Vögeli & Ahmed O. Hassan & Laura Guerrero & Weston Kightlinger & Danielle J. Yoesep & Antje Krüger & Madison DeWinter & Michael S. Diamond & Ashty S. Karim & Michael C. Jewett, 2023. "A rapid cell-free expression and screening platform for antibody discovery," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    11. Wenjuan Du & Oliver Debski-Antoniak & Dubravka Drabek & Rien Haperen & Melissa Dortmondt & Joline Lee & Ieva Drulyte & Frank J. M. Kuppeveld & Frank Grosveld & Daniel L. Hurdiss & Berend-Jan Bosch, 2024. "Neutralizing antibodies reveal cryptic vulnerabilities and interdomain crosstalk in the porcine deltacoronavirus spike protein," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    12. Zhenhao Fang & Lei Peng & Renata Filler & Kazushi Suzuki & Andrew McNamara & Qianqian Lin & Paul A. Renauer & Luojia Yang & Bridget Menasche & Angie Sanchez & Ping Ren & Qiancheng Xiong & Madison Stri, 2022. "Omicron-specific mRNA vaccination alone and as a heterologous booster against SARS-CoV-2," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    13. Mark Chernyshev & Mrunal Sakharkar & Ruth I. Connor & Haley L. Dugan & Daniel J. Sheward & C. G. Rappazzo & Aron Stålmarck & Mattias N. E. Forsell & Peter F. Wright & Martin Corcoran & Ben Murrell & L, 2023. "Vaccination of SARS-CoV-2-infected individuals expands a broad range of clonally diverse affinity-matured B cell lineages," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    14. Daniel Ellis & Julia Lederhofer & Oliver J. Acton & Yaroslav Tsybovsky & Sally Kephart & Christina Yap & Rebecca A. Gillespie & Adrian Creanga & Audrey Olshefsky & Tyler Stephens & Deleah Pettie & Mic, 2022. "Structure-based design of stabilized recombinant influenza neuraminidase tetramers," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    15. Durgadevi Parthasarathy & Karunakar Reddy Pothula & Sneha Ratnapriya & Héctor Cervera Benet & Ruth Parsons & Xiao Huang & Salam Sammour & Katarzyna Janowska & Miranda Harris & Joseph Sodroski & Priyam, 2024. "Conformational flexibility of HIV-1 envelope glycoproteins modulates transmitted/founder sensitivity to broadly neutralizing antibodies," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    16. Haisheng Yu & Banghui Liu & Yudi Zhang & Xijie Gao & Qian Wang & Haitao Xiang & Xiaofang Peng & Caixia Xie & Yaping Wang & Peiyu Hu & Jingrong Shi & Quan Shi & Pingqian Zheng & Chengqian Feng & Guofan, 2023. "Somatically hypermutated antibodies isolated from SARS-CoV-2 Delta infected patients cross-neutralize heterologous variants," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    17. Wenkai Han & Ningning Chen & Xinzhou Xu & Adil Sahil & Juexiao Zhou & Zhongxiao Li & Huawen Zhong & Elva Gao & Ruochi Zhang & Yu Wang & Shiwei Sun & Peter Pak-Hang Cheung & Xin Gao, 2023. "Predicting the antigenic evolution of SARS-COV-2 with deep learning," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    18. X. Tong & R. P. McNamara & M. J. Avendaño & E. F. Serrano & T. García-Salum & C. Pardo-Roa & H. L. Bertera & T. M. Chicz & J. Levican & E. Poblete & E. Salinas & A. Muñoz & A. Riquelme & G. Alter & R., 2023. "Waning and boosting of antibody Fc-effector functions upon SARS-CoV-2 vaccination," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    19. Leire Campos-Mata & Benjamin Trinité & Andrea Modrego & Sonia Tejedor Vaquero & Edwards Pradenas & Anna Pons-Grífols & Natalia Rodrigo Melero & Diego Carlero & Silvia Marfil & César Santiago & Dàlia R, 2024. "A monoclonal antibody targeting a large surface of the receptor binding motif shows pan-neutralizing SARS-CoV-2 activity," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    20. Emanuele Andreano & Ida Paciello & Silvia Marchese & Lorena Donnici & Giulio Pierleoni & Giulia Piccini & Noemi Manganaro & Elisa Pantano & Valentina Abbiento & Piero Pileri & Linda Benincasa & Ginevr, 2022. "Anatomy of Omicron BA.1 and BA.2 neutralizing antibodies in COVID-19 mRNA vaccinees," Nature Communications, Nature, vol. 13(1), pages 1-8, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50976-9. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.