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ACKNOWLEDGMENTS
We thank J. Stein and M. Young for technology transfer and
administrative support, respectively; members of the National
Institutes of Health (NIH) National Institute of Allergy and
Infectious Diseases (NIAID) Vaccine Research Center (VRC)
Translational Research Program, including H. Bao, E. McCarthy,
J. Noor, A. Taylor, and R. Woodward, for technical and
administrative assistance with animal experiments; H. Mu and
M. Farzan for the ACE2-overexpressing 293 cells; B. Zhang for the
production and purification of published mAbs; T. Ruckwardt,
E. Phung, I.-T. Teng, A. Olia, O. Abiona, and A. DiPiazza for
contributions to probe production and validation; and M. Brunner
and M. Whitt for kind support on recombinant VSV-based SARS-
CoV-2 pseudovirus production.Funding:This work was supported
by the Intramural Research Program of the VRC, NIAID, and NIH;
the Department of Health and Human Services, Office of the
Assistant Secretary for Preparedness and Response, Biomedical
Advanced Research and Development Authority (contract no.
75A50120C00034); the Undergraduate Scholarship Program,
Office of Intramural Training and Education, Office of the Director,
NIH (K.S.C.); an Emory Executive Vice President for Health Affairs
Synergy Fund Award (M.S.S.); the Pediatric Research Alliance
Center for Childhood Infections and Vaccines and Children’s
Healthcare of Atlanta (M.S.S.); and the Woodruff Health Sciences
Center 2020 COVID-19 CURE Award (M.S.S.).Author
contributions:K.S.C., M.G., D.W., S.O., S.R.N., D.R.F., S.F.A.,
R.L.D., B.F., T.S.J., C.D.S., L.L., D.V., A.V.R., Z.F., A.P.W., J.I.M.,
M.S., S.O., S.D.S, C.T., A.C., M.K., K.W.B., M.M., B.M.N., G.S.A.,
A.R.H., F.L., C.A.S., E.S.Y., L.W., E.L., S.T.N., S.J.P., M.M.D., J.M.,
J-P.M.T., A.C., A.D., N.D., A.P., L.P., H.A., K.E.F., J.M., K.W., D.K.E.,
M.C.N., J.M., I.N.M., A.C., M.G.L., M.S.S., M.R., A.M., D.C.D., N.J.S.,
B.S.G., and R.A.S. designed, completed, analyzed, and/or
supervised experiments. Y.Z., L.W., S.B-B., M.C., W.S., A.P., and
E.B. provided critical published reagents and analytic tools. K.S.C.,
M.C.N., N.J.S., M.R., B.S.G, and R.A.S. wrote the manuscript.
K.S.C., D.W., M.S., K.E.F., S.F.A., and G.A. prepared the figures
and tables. All authors contributed to discussions about and
editing of the manuscript.Competing interests:K.S.C. and B.S.G.
are inventors on US Patent 10,960,070 B2 and International Patent
Application WO/2018/081318 entitled“Prefusion Coronavirus
Spike Proteins and Their Use.”K.S.C. and B.S.G. are inventors on
US Patent Application 62/972,886 entitled“2019-nCoV Vaccine.”
J.M., L.W., C.A.S., J.R.M, D.D, N.J.S., A.R.H., W.S., Y.Z., and M.R.
are inventors on US Patent Application 63/147,419 entitled
“Antibodies Targeting the Spike Protein of Coronaviruses.”
K.S.C., B.S.G, L.W., W.S., and Y.Z. are inventors on multiple
US Patent applications entitled“Anti-Coronavirus Antibodies and
Methods of Use.”A.C., M.K., A.C., and D.K.E. are employees of
Moderna. M.S.S. serves on the scientific board of advisors for
Moderna. D.V., A.V.R., Z.F., A.C., L.P., H.A., and M.G.L. are
employees of BIOQUAL Inc.Data and materials availability:
All data are available in the main text or the supplementary
materials. This work is licensed under a Creative Commons
Attribution 4.0 International (CC BY 4.0) license, which permits
unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited. To view a copy of this
license, visit https://creativecommons.org/licenses/by/4.0/.
This license does not apply to figures/photos/artwork or other
content included in the article that is credited to a third party; obtain
authorization from the rights holder before using such material.SUPPLEMENTARY MATERIALS
science.org/doi/10.1126/science.abl8912
Figs. S1 to S10Tables S1 to S5
MDAR Reproducibility Checklist11 August 2021; accepted 15 October 2021
Published online 21 October 2021
10.1126/science.abl8912CORONAVIRUSMembrane fusion and immune evasion by the spike
protein of SARS-CoV-2 Delta variant
Jun Zhang1,2†, Tianshu Xiao1,2†, Yongfei Cai1,2, Christy L. Lavine^3 , Hanqin Peng^1 , Haisun Zhu^4 ,
Krishna Anand^4 , Pei Tong5,6, Avneesh Gautam5,6, Megan L. Mayer7,8, Richard M. Walsh Jr.7,8,
Sophia Rits-Volloch^1 , Duane R. Wesemann5,6, Wei Yang^4 ‡, Michael S. Seaman^3 ,
Jianming Lu9,10, Bing Chen1,2*The Delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has outcompeted
previously prevalent variants and become a dominant strain worldwide. We report the structure,
function, and antigenicity of its full-length spike (S) trimer as well as those of the Gamma and Kappa
variants, and compare their characteristics with the G614, Alpha, and Beta variants. Delta S can fuse
membranes more efficiently at low levels of cellular receptor angiotensin converting enzyme 2 (ACE2),
and its pseudotyped viruses infect target cells substantially faster than the other five variants,
possibly accounting for its heightened transmissibility. Each variant shows different rearrangement of
the antigenic surface of the amino-terminal domain of the S protein but only makes produces changes
in the receptor binding domain (RBD), making the RBD a better target for therapeutic antibodies.S
evere acute respiratory syndrome coro-
navirus 2 (SARS-CoV-2) is the causative
agent of the COVID-19 pandemic ( 1 ).
The strain responsible for the initial
outbreak, Wuhan-Hu-1 ( 1 ), was the basis
for first-generation vaccine development. We
previously characterized two early variants of
concern (VOC): Alpha and Beta ( 2 ). The Delta
variant ( 3 ) (also known as lineage B.1.617.2) was
first detected in India and was quickly charac-
terized as a VOC and has since outcompeted
other variants to become a globally dominantstrain within several months. It is estimated
to be about twice as transmissible as Wuhan-
Hu-1 ( 4 , 5 ). Infection by the Delta variant
appears to have a shorter incubation period
with a viral load ~1000 times greater in the
first positive Polymerase Chain Reaction (PCR)
test than earlier variants ( 6 ). It remains un-
certain whether it causes more severe disease
( 7 , 8 ),butitdoeshavesomeresistancetoim-
munity elicited by first-generation vaccines
( 9 – 12 ). Another VOC, Gamma (lineage B.1.1.28
or P.1), has spread in Brazil and some other
countries ( 13 , 14 ). A third variant, Kappa (line-
age B.1.617.1), also first reported in India, re-
mains a variant of interest (VOI) but had only
a limited surge ( 15 , 16 ). It is critical to under-
stand the molecular mechanisms of the in-
creased transmissibility and immune evasion
of variants to guide intervention strategies.
SARS-CoV-2 is an enveloped, positive-stranded
RNA virus that enters a host cell by fusing its
lipid bilayer with the target cell membrane.
The fusion reaction is facilitated by the virus-
encoded trimeric spike (S) protein after it binds
to the host angiotensin converting enzyme 2
(ACE2). The S protein is produced as a single-
chain precursor, and processed by a host furin-
like protease into the receptor-binding fragment
S1 and the fusion fragment S2 (fig. S1) ( 17 ).
After engaging with ACE2 on the host cell
surface, the S protein is cleaved by a second
cellular protease in S2 (S2’site; fig. S1) ( 18 ),
initiating S1 dissociation and a cascade of S2SCIENCEscience.org 10 DECEMBER 2021•VOL 374 ISSUE 6573 1353
(^1) Division of Molecular Medicine, Boston Children’s Hospital,
Harvard Medical School, 3 Blackfan Street, Boston, MA
02115, USA.^2 Department of Pediatrics, Harvard Medical
School, 3 Blackfan Street, Boston, MA 02115, USA.^3 Center
for Virology and Vaccine Research, Beth Israel Deaconess
Medical Center, 330 Brookline Avenue, Boston, MA, 02215,
USA.^4 Institute for Protein Innovation, Harvard Institutes of
Medicine, 4 Blackfan Circle, Boston, MA 02115, USA.
(^5) Division of Allergy and Clinical Immunology, Department of
Medicine, Brigham and Women’s Hospital, Boston, MA
02115, USA.^6 Ragon Institute of MGH, MIT, and Harvard,
Boston, MA 02115, USA.^7 The Harvard Cryo-EM Center for
Structural Biology, Harvard Medical School, 250 Longwood
Avenue, Boston, MA 02115, USA.^8 Department of
Biological Chemistry and Molecular Pharmacology, Blavatnik
Institute, Harvard Medical School, 240 Longwood Avenue,
Boston, MA 02115, USA.^9 Codex BioSolutions, Inc., 401
Professional Drive, Gaithersburg, MD 20879, USA.
(^10) Department of Biochemistry and Molecular and Cellular
Biology, Georgetown University School of Medicine, 3900
Reservoir Road, N.W., Washington, D.C. 20057, USA.
*Corresponding author. Email: [email protected]
†These authors contributed equally to this work.‡Present address.
GV20 Therapeutics LLC, 1 Broadway Floor 14, Cambridge, MA
02142, USA.
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