IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-34571-4.html
   My bibliography  Save this article

Intranasal delivery of a rationally attenuated SARS-CoV-2 is immunogenic and protective in Syrian hamsters

Author

Listed:
  • Shufeng Liu

    (Food and Drug Administration)

  • Charles B. Stauft

    (Food and Drug Administration)

  • Prabhuanand Selvaraj

    (Food and Drug Administration)

  • Prabha Chandrasekaran

    (National Institutes of Health)

  • Felice D’Agnillo

    (Food and Drug Administration)

  • Chao-Kai Chou

    (Food and Drug Administration)

  • Wells W. Wu

    (Food and Drug Administration)

  • Christopher Z. Lien

    (Food and Drug Administration)

  • Clement A. Meseda

    (Food and Drug Administration)

  • Cyntia L. Pedro

    (Food and Drug Administration)

  • Matthew F. Starost

    (National Institutes of Health)

  • Jerry P. Weir

    (Food and Drug Administration)

  • Tony T. Wang

    (Food and Drug Administration)

Abstract

Few live attenuated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are in pre-clinical or clinical development. We seek to attenuate SARS-CoV-2 (isolate WA1/2020) by removing the polybasic insert within the spike protein and the open reading frames (ORFs) 6–8, and by introducing mutations that abolish non-structural protein 1 (Nsp1)-mediated toxicity. The derived virus (WA1-ΔPRRA-ΔORF6-8-Nsp1K164A/H165A) replicates to 100- to 1000-fold-lower titers than the ancestral virus and induces little lung pathology in both K18-human ACE2 (hACE2) transgenic mice and Syrian hamsters. Immunofluorescence and transcriptomic analyses of infected hamsters confirm that three-pronged genetic modifications attenuate the proinflammatory pathways more than the removal of the polybasic cleavage site alone. Finally, intranasal administration of just 100 PFU of the WA1-ΔPRRA-ΔORF6-8-Nsp1K164A/H165A elicits robust antibody responses in Syrian hamsters and protects against SARS-CoV-2-induced weight loss and pneumonia. As a proof-of-concept study, we demonstrate that live but sufficiently attenuated SARS-CoV-2 vaccines may be attainable by rational design.

Suggested Citation

  • Shufeng Liu & Charles B. Stauft & Prabhuanand Selvaraj & Prabha Chandrasekaran & Felice D’Agnillo & Chao-Kai Chou & Wells W. Wu & Christopher Z. Lien & Clement A. Meseda & Cyntia L. Pedro & Matthew F., 2022. "Intranasal delivery of a rationally attenuated SARS-CoV-2 is immunogenic and protective in Syrian hamsters," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34571-4
    DOI: 10.1038/s41467-022-34571-4
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-34571-4
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-34571-4?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. Sandile Cele & Laurelle Jackson & David S. Khoury & Khadija Khan & Thandeka Moyo-Gwete & Houriiyah Tegally & James Emmanuel San & Deborah Cromer & Cathrine Scheepers & Daniel G. Amoako & Farina Karim , 2022. "Omicron extensively but incompletely escapes Pfizer BNT162b2 neutralization," Nature, Nature, vol. 602(7898), pages 654-656, February.
    2. Pui Wang & Siu-Ying Lau & Shaofeng Deng & Pin Chen & Bobo Wing-Yee Mok & Anna Jinxia Zhang & Andrew Chak-Yiu Lee & Kwok-Hung Chan & Rachel Chun-Yee Tam & Haoran Xu & Runhong Zhou & Wenjun Song & Li Li, 2021. "Characterization of an attenuated SARS-CoV-2 variant with a deletion at the S1/S2 junction of the spike protein," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    3. Bryan A. Johnson & Xuping Xie & Adam L. Bailey & Birte Kalveram & Kumari G. Lokugamage & Antonio Muruato & Jing Zou & Xianwen Zhang & Terry Juelich & Jennifer K. Smith & Lihong Zhang & Nathen Bopp & C, 2021. "Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis," Nature, Nature, vol. 591(7849), pages 293-299, March.
    4. Fatai S. Oladunni & Jun-Gyu Park & Paula A. Pino & Olga Gonzalez & Anwari Akhter & Anna Allué-Guardia & Angélica Olmo-Fontánez & Shalini Gautam & Andreu Garcia-Vilanova & Chengjin Ye & Kevin Chiem & C, 2020. "Lethality of SARS-CoV-2 infection in K18 human angiotensin-converting enzyme 2 transgenic mice," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    5. Jinyan Liu & Abishek Chandrashekar & Daniel Sellers & Julia Barrett & Catherine Jacob-Dolan & Michelle Lifton & Katherine McMahan & Michaela Sciacca & Haley VanWyk & Cindy Wu & Jingyou Yu & Ai-ris Y. , 2022. "Vaccines elicit highly conserved cellular immunity to SARS-CoV-2 Omicron," Nature, Nature, vol. 603(7901), pages 493-496, March.
    6. Peng Zhou & Xing-Lou Yang & Xian-Guang Wang & Ben Hu & Lei Zhang & Wei Zhang & Hao-Rui Si & Yan Zhu & Bei Li & Chao-Lin Huang & Hui-Dong Chen & Jing Chen & Yun Luo & Hua Guo & Ren-Di Jiang & Mei-Qin L, 2020. "Addendum: A pneumonia outbreak associated with a new coronavirus of probable bat origin," Nature, Nature, vol. 588(7836), pages 6-6, December.
    7. Markus Hoffmann & Kirstin Mösbauer & Heike Hofmann-Winkler & Artur Kaul & Hannah Kleine-Weber & Nadine Krüger & Nils C. Gassen & Marcel A. Müller & Christian Drosten & Stefan Pöhlmann, 2020. "Chloroquine does not inhibit infection of human lung cells with SARS-CoV-2," Nature, Nature, vol. 585(7826), pages 588-590, September.
    8. Peng Zhou & Xing-Lou Yang & Xian-Guang Wang & Ben Hu & Lei Zhang & Wei Zhang & Hao-Rui Si & Yan Zhu & Bei Li & Chao-Lin Huang & Hui-Dong Chen & Jing Chen & Yun Luo & Hua Guo & Ren-Di Jiang & Mei-Qin L, 2020. "A pneumonia outbreak associated with a new coronavirus of probable bat origin," Nature, Nature, vol. 579(7798), pages 270-273, March.
    9. Yaara Finkel & Avi Gluck & Aharon Nachshon & Roni Winkler & Tal Fisher & Batsheva Rozman & Orel Mizrahi & Yoav Lubelsky & Binyamin Zuckerman & Boris Slobodin & Yfat Yahalom-Ronen & Hadas Tamir & Igor , 2021. "SARS-CoV-2 uses a multipronged strategy to impede host protein synthesis," Nature, Nature, vol. 594(7862), pages 240-245, June.
    10. Florian Krammer, 2020. "SARS-CoV-2 vaccines in development," Nature, Nature, vol. 586(7830), pages 516-527, October.
    11. Linlin Bao & Wei Deng & Baoying Huang & Hong Gao & Jiangning Liu & Lili Ren & Qiang Wei & Pin Yu & Yanfeng Xu & Feifei Qi & Yajin Qu & Fengdi Li & Qi Lv & Wenling Wang & Jing Xue & Shuran Gong & Mingy, 2020. "The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice," Nature, Nature, vol. 583(7818), pages 830-833, July.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Charles B. Stauft & Prabhuanand Selvaraj & Felice D’Agnillo & Clement A. Meseda & Shufeng Liu & Cyntia L. Pedro & Kotou Sangare & Christopher Z. Lien & Jerry P. Weir & Matthew F. Starost & Tony T. Wan, 2023. "Intranasal or airborne transmission-mediated delivery of an attenuated SARS-CoV-2 protects Syrian hamsters against new variants," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

    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. Meriem Bekliz & Kenneth Adea & Pauline Vetter & Christiane S. Eberhardt & Krisztina Hosszu-Fellous & Diem-Lan Vu & Olha Puhach & Manel Essaidi-Laziosi & Sophie Waldvogel-Abramowski & Caroline Stephan , 2022. "Neutralization capacity of antibodies elicited through homologous or heterologous infection or vaccination against SARS-CoV-2 VOCs," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    2. Xiaoming Hu & Shuang Wang & Shaotong Fu & Meng Qin & Chengliang Lyu & Zhaowen Ding & Yan Wang & Yishu Wang & Dongshu Wang & Li Zhu & Tao Jiang & Jing Sun & Hui Ding & Jie Wu & Lingqian Chang & Yimin C, 2023. "Intranasal mask for protecting the respiratory tract against viral aerosols," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    3. Phanramphoei N. Frantz & Aleksandr Barinov & Claude Ruffié & Chantal Combredet & Valérie Najburg & Guilherme Dias de Melo & Florence Larrous & Lauriane Kergoat & Samaporn Teeravechyan & Anan Jongkaeww, 2021. "A live measles-vectored COVID-19 vaccine induces strong immunity and protection from SARS-CoV-2 challenge in mice and hamsters," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    4. Davida S. Smyth & Monica Trujillo & Devon A. Gregory & Kristen Cheung & Anna Gao & Maddie Graham & Yue Guan & Caitlyn Guldenpfennig & Irene Hoxie & Sherin Kannoly & Nanami Kubota & Terri D. Lyddon & M, 2022. "Tracking cryptic SARS-CoV-2 lineages detected in NYC wastewater," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    5. Marziah Hashimi & T. Andrew Sebrell & Jodi F. Hedges & Deann Snyder & Katrina N. Lyon & Stephanie D. Byrum & Samuel G. Mackintosh & Dan Crowley & Michelle D. Cherne & David Skwarchuk & Amanda Robison , 2023. "Antiviral responses in a Jamaican fruit bat intestinal organoid model of SARS-CoV-2 infection," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    6. Mark P. Khurana & Jacob Curran-Sebastian & Neil Scheidwasser & Christian Morgenstern & Morten Rasmussen & Jannik Fonager & Marc Stegger & Man-Hung Eric Tang & Jonas L. Juul & Leandro Andrés Escobar-He, 2024. "High-resolution epidemiological landscape from ~290,000 SARS-CoV-2 genomes from Denmark," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    7. Ma’ayan Israeli & Yaara Finkel & Yfat Yahalom-Ronen & Nir Paran & Theodor Chitlaru & Ofir Israeli & Inbar Cohen-Gihon & Moshe Aftalion & Reut Falach & Shahar Rotem & Uri Elia & Ital Nemet & Limor Klik, 2022. "Genome-wide CRISPR screens identify GATA6 as a proviral host factor for SARS-CoV-2 via modulation of ACE2," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    8. Lei Peng & Yingxia Hu & Madeleine C. Mankowski & Ping Ren & Rita E. Chen & Jin Wei & Min Zhao & Tongqing Li & Therese Tripler & Lupeng Ye & Ryan D. Chow & Zhenhao Fang & Chunxiang Wu & Matthew B. Dong, 2022. "Monospecific and bispecific monoclonal SARS-CoV-2 neutralizing antibodies that maintain potency against B.1.617," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    9. Gang Ye & Bin Liu & Fang Li, 2022. "Cryo-EM structure of a SARS-CoV-2 omicron spike protein ectodomain," Nature Communications, Nature, vol. 13(1), pages 1-7, December.
    10. 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.
    11. Tomokazu Yamaguchi & Midori Hoshizaki & Takafumi Minato & Satoru Nirasawa & Masamitsu N. Asaka & Mayumi Niiyama & Masaki Imai & Akihiko Uda & Jasper Fuk-Woo Chan & Saori Takahashi & Jianbo An & Akari , 2021. "ACE2-like carboxypeptidase B38-CAP protects from SARS-CoV-2-induced lung injury," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    12. Christopher Cyrus Kuhn & Nirakar Basnet & Satish Bodakuntla & Pelayo Alvarez-Brecht & Scott Nichols & Antonio Martinez-Sanchez & Lorenzo Agostini & Young-Min Soh & Junichi Takagi & Christian Biertümpf, 2023. "Direct Cryo-ET observation of platelet deformation induced by SARS-CoV-2 spike protein," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    13. Jun-Yu Si & Yuan-Mei Chen & Ye-Hui Sun & Meng-Xue Gu & Mei-Ling Huang & Lu-Lu Shi & Xiao Yu & Xiao Yang & Qing Xiong & Cheng-Bao Ma & Peng Liu & Zheng-Li Shi & Huan Yan, 2024. "Sarbecovirus RBD indels and specific residues dictating multi-species ACE2 adaptiveness," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    14. Shahadat Uddin & Arif Khan & Haohui Lu & Fangyu Zhou & Shakir Karim, 2022. "Suburban Road Networks to Explore COVID-19 Vulnerability and Severity," IJERPH, MDPI, vol. 19(4), pages 1-9, February.
    15. Kirsten R.C. Hensgens & Inge H.T. van Rensen & Anita W. Lekx & Frits H.M. van Osch & Lieve H.H. Knarren & Caroline E. Wyers & Joop P. van den Bergh & Dennis G. Barten, 2021. "Sort and Sieve: Pre-Triage Screening of Patients with Suspected COVID-19 in the Emergency Department," IJERPH, MDPI, vol. 18(17), pages 1-11, September.
    16. Quan-Hoang Vuong & Tam-Tri Le & Viet-Phuong La & Huyen Thanh Thanh Nguyen & Manh-Toan Ho & Quy Khuc & Minh-Hoang Nguyen, 2022. "Covid-19 vaccines production and societal immunization under the serendipity-mindsponge-3D knowledge management theory and conceptual framework," Palgrave Communications, Palgrave Macmillan, vol. 9(1), pages 1-12, December.
    17. Hengrui Liu & Sho Iketani & Arie Zask & Nisha Khanizeman & Eva Bednarova & Farhad Forouhar & Brandon Fowler & Seo Jung Hong & Hiroshi Mohri & Manoj S. Nair & Yaoxing Huang & Nicholas E. S. Tay & Sumin, 2022. "Development of optimized drug-like small molecule inhibitors of the SARS-CoV-2 3CL protease for treatment of COVID-19," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    18. Graziella Orrù & Ciro Conversano & Eleonora Malloggi & Francesca Francesconi & Rebecca Ciacchini & Angelo Gemignani, 2020. "Neurological Complications of COVID-19 and Possible Neuroinvasion Pathways: A Systematic Review," IJERPH, MDPI, vol. 17(18), pages 1-18, September.
    19. Hassen Kared & Asia-Sophia Wolf & Amin Alirezaylavasani & Anthony Ravussin & Guri Solum & Trung The Tran & Fridtjof Lund-Johansen & John Torgils Vaage & Lise Sofie Nissen-Meyer & Unni C. Nygaard & Ola, 2022. "Immune responses in Omicron SARS-CoV-2 breakthrough infection in vaccinated adults," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    20. Gleidson Sobreira Leite & Adriano Bessa Albuquerque & Plácido Rogerio Pinheiro, 2021. "Applications of Technological Solutions in Primary Ways of Preventing Transmission of Respiratory Infectious Diseases—A Systematic Literature Review," IJERPH, MDPI, vol. 18(20), pages 1-50, October.

    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:13:y:2022:i:1:d:10.1038_s41467-022-34571-4. 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.