A mouse-adapted model of SARS-CoV-2 to test COVID-19 countermeasures.
Kenneth H. Dinnon,Sarah R. Leist,Alexandra Schäfer,Caitlin E. Edwards,David R. Martinez,Stephanie A. Montgomery,Ande West,Boyd Yount,Yixuan J. Hou,Lily E. Adams,Kendra Gully,Ariane J. Brown,Emily Huang,Matthew D. Bryant,Ingrid Choong,Jeffrey S. Glenn,Jeffrey S. Glenn,Lisa E. Gralinski,Timothy P. Sheahan,Ralph S. Baric +19 more
TLDR
A model in mouse using a species-adapted virus recapitulates features of SARS-CoV-2 infection and age-related disease pathogenesis in humans, and provides a model system for rapid evaluation of medical countermeasures against coronavirus disease 2019 (COVID-19).Abstract:
Coronaviruses are prone to transmission to new host species, as recently demonstrated by the spread to humans of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic1. Small animal models that recapitulate SARS-CoV-2 disease are needed urgently for rapid evaluation of medical countermeasures2,3. SARS-CoV-2 cannot infect wild-type laboratory mice owing to inefficient interactions between the viral spike protein and the mouse orthologue of the human receptor, angiotensin-converting enzyme 2 (ACE2)4. Here we used reverse genetics5 to remodel the interaction between SARS-CoV-2 spike protein and mouse ACE2 and designed mouse-adapted SARS-CoV-2 (SARS-CoV-2 MA), a recombinant virus that can use mouse ACE2 for entry into cells. SARS-CoV-2 MA was able to replicate in the upper and lower airways of both young adult and aged BALB/c mice. SARS-CoV-2 MA caused more severe disease in aged mice, and exhibited more clinically relevant phenotypes than those seen in Hfh4-ACE2 transgenic mice, which express human ACE2 under the control of the Hfh4 (also known as Foxj1) promoter. We demonstrate the utility of this model using vaccine-challenge studies in immune-competent mice with native expression of mouse ACE2. Finally, we show that the clinical candidate interferon-λ1a (IFN-λ1a) potently inhibits SARS-CoV-2 replication in primary human airway epithelial cells in vitro-both prophylactic and therapeutic administration of IFN-λ1a diminished SARS-CoV-2 replication in mice. In summary, the mouse-adapted SARS-CoV-2 MA model demonstrates age-related disease pathogenesis and supports the clinical use of pegylated IFN-λ1a as a treatment for human COVID-196.read more
Citations
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SARS-CoV-2 vaccines in development.
TL;DR: The development of vaccines against SARS-CoV-2 is reviewed, including an overview of the development process, the different types of vaccine candidate, and data from animal studies as well as phase I and II clinical trials in humans.
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
SARS-CoV-2 D614G variant exhibits efficient replication ex vivo and transmission in vivo
Yixuan J. Hou,Shiho Chiba,Peter Halfmann,Camille Ehre,Makoto Kuroda,Kenneth H. Dinnon,Sarah R. Leist,Alexandra Schäfer,Noriko Nakajima,Kenta Takahashi,Rhianna E. Lee,Teresa M. Mascenik,Rachel L. Graham,Caitlin E. Edwards,Longping V. Tse,Kenichi Okuda,Alena J. Markmann,Luther A. Bartelt,Aravinda M. de Silva,David M. Margolis,Richard C. Boucher,Scott H. Randell,Tadaki Suzuki,Lisa E. Gralinski,Yoshihiro Kawaoka,Yoshihiro Kawaoka,Ralph S. Baric +26 more
TL;DR: The current dominant structural variant of SARS-CoV-2 appears to have evolved from the ancestral form and enhances transmissibility, and the mutation renders the new virus variant more susceptible to neutralizing antisera without altering the efficacy of vaccine candidates currently under development.
Journal ArticleDOI
Mechanisms of SARS-CoV-2 Transmission and Pathogenesis.
TL;DR: Advances in animal models that are important for understanding the pathogenesis of SARS-CoV-2, vaccine development, and therapeutic testing are presented and comparisons are made from studies with SARS to provide further perspectives on COVID-19 and draw inferences for future investigations.
Journal ArticleDOI
Animal models for COVID-19.
César Muñoz-Fontela,William E. Dowling,Simon G. P. Funnell,Pierre Stéphane Gsell,A. Ximena Riveros-Balta,Randy A. Albrecht,Hanne Leth Andersen,Ralph S. Baric,Miles W. Carroll,Marco Cavaleri,Chuan Qin,Ian Crozier,Kai Dallmeier,Leon de Waal,Emmie de Wit,Leen Delang,Erik D. Dohm,W. Paul Duprex,Darryl Falzarano,Courtney L. Finch,Matthew B. Frieman,Barney S. Graham,Lisa E. Gralinski,Kate Guilfoyle,Bart L. Haagmans,Geraldine A. Hamilton,Amy L. Hartman,Sander Herfst,Suzanne J.F. Kaptein,William B. Klimstra,Ivana Knezevic,Philip R. Krause,Jens H. Kuhn,Roger Le Grand,Mark G. Lewis,Wen-Chun Liu,Pauline Maisonnasse,Anita K. McElroy,Vincent J. Munster,Nadia Oreshkova,Angela L. Rasmussen,Joana Rocha-Pereira,Barry Rockx,Estefanía Rodríguez,Thomas F. Rogers,Francisco J. Salguero,Michael Schotsaert,Koert J. Stittelaar,Hendrik Jan Thibaut,Chien Te K. Tseng,Júlia Vergara-Alert,Martin Beer,Trevor Brasel,Jasper Fuk-Woo Chan,Adolfo García-Sastre,Johan Neyts,Stanley Perlman,Douglas S. Reed,Juergen A. Richt,Chad J. Roy,Joaquim Segalés,Seshadri S. Vasan,Seshadri S. Vasan,Ana Maria Henao-Restrepo,Dan H. Barouch +64 more
TL;DR: The findings of a World Health Organization expert working group that is developing animal models to test vaccines and therapeutic agents for the treatment of COVID-19, and their relevance for preclinical testing, are reviewed.
References
More filters
Journal ArticleDOI
A pneumonia outbreak associated with a new coronavirus of probable bat origin
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,Meiqin Liu,Ying Chen,Xu Rui Shen,Xi Wang,Xiao Shuang Zheng,Kai Zhao,Quanjiao Chen,Fei Deng,Lin Lin Liu,Bing Yan,Fa Xian Zhan,Yan-Yi Wang,Gengfu Xiao,Zhengli Shi +28 more
TL;DR: Identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China, and it is shown that this virus belongs to the species of SARSr-CoV, indicates that the virus is related to a bat coronav virus.
Journal ArticleDOI
Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China.
Dawei Wang,Bo Hu,Chang Hu,Fangfang Zhu,Xing Liu,Jing Zhang,Binbin Wang,Hui Xiang,Zhenshun Cheng,Yong Xiong,Yan Zhao,Yirong Li,Xinghuan Wang,Zhiyong Peng +13 more
TL;DR: The epidemiological and clinical characteristics of novel coronavirus (2019-nCoV)-infected pneumonia in Wuhan, China, and hospital-associated transmission as the presumed mechanism of infection for affected health professionals and hospitalized patients are described.
Journal ArticleDOI
Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia.
Qun Li,Xuhua Guan,Peng Wu,Xiaoye Wang,Lei Zhou,Yeqing Tong,Ruiqi Ren,Kathy Leung,Eric H. Y. Lau,Jessica Y. Wong,Xuesen Xing,Nijuan Xiang,Yang Wu,Chao Li,Chen Qi,Dan Li,Tian Liu,Jing Zhao,Man Liu,Wenxiao Tu,Chuding Chen,Lianmei Jin,Rui Yang,Qi Wang,Suhua Zhou,Rui Wang,Hui Liu,Yingbo Luo,Yuan Liu,Ge Shao,Huan Li,Zhongfa Tao,Yang Yang,Yang Yang,Zhiqiang Deng,Boxi Liu,Zhitao Ma,Yanping Zhang,Guoqing Shi,Tommy Tsan-Yuk Lam,Joseph T. Wu,George F. Gao,George F. Gao,Benjamin J. Cowling,Bo Yang,Gabriel M. Leung,Zijian Feng +46 more
TL;DR: There is evidence that human-to-human transmission has occurred among close contacts since the middle of December 2019 and considerable efforts to reduce transmission will be required to control outbreaks if similar dynamics apply elsewhere.
Journal ArticleDOI
Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor.
Jun Lan,Jiwan Ge,Jinfang Yu,Sisi Shan,Huan Zhou,Shilong Fan,Qi Zhang,Xuanling Shi,Qisheng Wang,Linqi Zhang,Xinquan Wang +10 more
TL;DR: High-resolution crystal structures of the receptor-binding domain of the spike protein of SARS-CoV-2 and SARS -CoV in complex with ACE2 provide insights into the binding mode of these coronaviruses and highlight essential ACE2-interacting residues.
Journal ArticleDOI
Structural basis of receptor recognition by SARS-CoV-2.
Jian Shang,Gang Ye,Ke Shi,Yushun Wan,Chuming Luo,Hideki Aihara,Qibin Geng,Ashley Auerbach,Fang Li +8 more
TL;DR: This study determines the crystal structure of the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 (engineered to facilitate crystallization) in complex with ACE2 and sheds light on the structural features that increase its binding affinity to ACE2.
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