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ACKNOWLEDGMENTS
Funding:Research was supported by the Office of Naval Research
MURI Program N00014-16-1-2921 (molecular design, STM
spectroscopy, band structure); by the U.S. Department of Energy
(DOE), Office of Science, Basic Energy Sciences (BES), under the
Nanomachine Program award number DE-AC02-05CH11231
(surface growth, image analysis); by the Center for Energy Efficient
Electronics Science NSF Award 0939514 (precursor synthesis);
and by the National Science Foundation under grants DMR-
1508412 (structural relaxation studies) and DMR-1926004 (LSDA
simulations), as well as DMR-1839098 (zero-mode analysis).
Computational resources were provided by the DOE Lawrence
Berkeley National Laboratory’s NERSC facility and by the NSF
through XSEDE resources at NICS.Author contributions:D.J.R.,
G.V., J.J., S.G.L., M.F.C., and F.R.F. initiated and conceived the
research; G.V., R.M., and F.R.F. designed, synthesized, and
characterized the molecular precursors; D.J.R., C.B., T.Ch., and
M.F.C. performed on-surface synthesis and STM characterization
and analysis; J.J., T.Ca., and S.G.L. performed the DFT calculations
and the theoretical analysis that predicted and interpreted the
STM data. All authors contributed to the scientific discussion.
Competing interests:The authors declare no competing
interests.Data and materials availability:The DFT code and
pseudopotentials can be downloaded from the Quantum
Espresso website ( 43 ). For this study, we used version 6.3 for

the theoretical calculations. All data presented in the main text

and the supplementary materials can be found in the

corresponding Zenodo repository ( 44 ).

SUPPLEMENTARY MATERIALS

science.sciencemag.org/content/369/6511/1597/suppl/DC1

Materials and Methods

Supplementary Text

Figs. S1 to S15

References ( 45 – 50 )

12 June 2019; resubmitted 13 December 2019

Accepted 14 July 2020

10.1126/science.aay3588

CORONAVIRUS

Adaptation of SARS-CoV-2 in BALB/c mice for

testing vaccine efficacy

Hongjing Gu^1 *, Qi Chen^1 *, Guan Yang^2 *, Lei He^1 *, Hang Fan^1 *, Yong-Qiang Deng^1 *, Yanxiao Wang^2 ,

Yue Teng^1 , Zhongpeng Zhao^1 , Yujun Cui^1 , Yuchang Li^1 , Xiao-Feng Li^1 , Jiangfan Li^1 , Na-Na Zhang^1 ,

Xiaolan Yang^1 , Shaolong Chen^1 , Yan Guo^1 , Guangyu Zhao^1 , Xiliang Wang^1 , De-Yan Luo^1 , Hui Wang^1 ,

Xiao Yang^2 , Yan Li^3 , Gencheng Han^3 , Yuxian He^4 , Xiaojun Zhou^5 , Shusheng Geng^6 , Xiaoli Sheng^6 ,

Shibo Jiang^7 †‡, Shihui Sun^1 †‡, Cheng-Feng Qin^1 †‡, Yusen Zhou^1 ‡§

The ongoing coronavirus disease 2019 (COVID-19) pandemic has prioritized the development of

small-animal models for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We adapted

a clinical isolate of SARS-CoV-2 by serial passaging in the respiratory tract of aged BALB/c mice. The

resulting mouse-adapted strain at passage 6 (called MASCp6) showed increased infectivity in mouse

lung and led to interstitial pneumonia and inflammatory responses in both young and aged mice

after intranasal inoculation. Deep sequencing revealed a panel of adaptive mutations potentially

associated with the increased virulence. In particular, the N501Y mutation is located at the receptor

binding domain (RBD) of the spike protein. The protective efficacy of a recombinant RBD vaccine

candidate was validated by using this model. Thus, this mouse-adapted strain and associated challenge

model should be of value in evaluating vaccines and antivirals against SARS-CoV-2.

T

he pandemic of coronavirus disease 2019

(COVID-19) caused by the newly em-

erged severe acute respiratory syndrome

coronavirus 2 (SARS-CoV-2) has become

a global health crisis ( 1 – 3 ). In the ab-

sence of protective immunity in the whole

human population ( 4 ), SARS-CoV-2 has exhib-

ited an unprecedented human-to-human trans-

mission capability. Although several vaccine

candidates are being currently tested in cli-

nical trials, no commercial COVID-19 vaccine

is presently available.

SARS-CoV-2 belongs to theBetacoronavirus

genus of theCoronaviridaefamily, along with

two other closely related highly pathogenic

viruses, SARS-CoV and Middle East respiratory

syndrome coronavirus (MERS-CoV). SARS-

CoV-2 has a positive-sense, single-stranded

RNAgenomeof30kbinlength,whichiscoated

by the inner nucleocapsid (N) proteins and an

outerenvelopemadeupofmembrane(M)and

envelope (E) proteins, as well as spike (S) pro-

teins. Like SARS-CoV, the S protein of SARS-

CoV-2 mediates viral entry into host cells by

binding to their shared receptor, angiotensin-

converting enzyme 2 (ACE2), through the

receptor-binding domain (RBD) ( 1 ). Previously,

we and others have demonstrated that the

RBD of SARS-CoV and MERS-CoV contain

major conformation-dependent neutralizing

epitopes and are capable of eliciting potent

neutralizing antibodies in immunized ani-

mals, thus representing promising targets for

vaccine development ( 5 – 8 ).

Small-animal models that recapitulate SARS-

CoV-2 infection are urgently needed. Because

SARS-CoV-2 does not use mouse ACE2 as its

receptor ( 1 ), wild-type mice are thought to be

less susceptible to SARS-CoV-2. Transgenic

mice expressing human ACE2 have been de-

veloped by means of different strategies. Such

mice have been used previously to study SARS-

CoV-2 infection and pathogenesis and to eval-

uate countermeasures against COVID-19 ( 9 – 11 ).

Here, we report the generation of a mouse-

adapted strain of SARS-CoV-2 that can produc-

tively replicate in the respiratory tract and

SCIENCEsciencemag.org 25 SEPTEMBER 2020•VOL 369 ISSUE 6511 1603

(^1) State Key Laboratory of Pathogen and Biosecurity, Beijing
Institute of Microbiology and Epidemiology, Academy of
Military Medical Sciences, Beijing 100071, China.^2 State Key
Laboratory of Proteomics, Beijing Proteome Research
Center, National Center for Protein Sciences (Beijing), Beijing
Institute of Lifeomics, Beijing 102206, China.^3 Institute of
Military Cognition and Brain Sciences, Beijing 100850, China.
(^4) Institute of Pathogen Biology, Chinese Academy of Medical
Sciences and Peking Union Medical College, Beijing 100730,
China.^5 Laboratory Animal Center, Academy of Military Medical
Sciences, Beijing 100071, China.^6 Beijing JOINN Biologics Co.,
Beijing 100176, China.^7 Key Laboratory of Medical Molecular
Virology (MOE/NHC/CAMS), School of Basic Medical Sciences,
Fudan University, Shanghai 200032, China.
*These authors contributed equally to this work.
†Corresponding author. Email: [email protected] (S.J.);
[email protected] (S.S.); [email protected] (C.-F.Q.)
‡These authors contributed equally to this work. §Deceased.
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