Science - USA (2021-12-24)

mAbs for prophylaxis and for treatments of
unvaccinated individuals or breakthrough
infections in at-risk patients. Moreover, next-
generation vaccine candidates have recently
been described to elicit broad sarbecovirus
immunity ( 32 , 42 , 81 – 83 ), holding the promise
to be resilient to the emergence of SARS-CoV-2
variants and of new zoonotic sarbecoviruses.
Looking forward, the discovery of broadly neu-
tralizing mAbs targeting the fusion machinery
makes tangible the development of a universal
b-coronavirus vaccine ( 27 – 31 ).

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ACKNOWLEDGMENTS

We thank H. Tani (University of Toyama) for providing the reagents

necessary for preparing VSV pseudotyped viruses. We thank

J. L. Mullen, G. Tsueng, A. Abdel Latif, M. Alkuzweny, M. Cano,

E. Haag, J. Zhou, M. Zeller, E. Hufbauer, N. Matteson, K. G. Andersen,

C. Wu, A. I. Su, K. Gangavarapu, L. D. Hughes, and the Center

for Viral Systems Biology outbreak.info (https://outbreak.info/).

Funding:This study was supported by the National

Institute of Allergy and Infectious Diseases (DP1AI158186 and

HHSN272201700059C to D.V.), a Pew Biomedical Scholars

Award (D.V.), an Investigators in the Pathogenesis of Infectious

Disease Award from the Burroughs Wellcome Fund (D.V.),

Fast Grants (D.V.), the Bill and Melinda Gates Foundation

(OPP1156262 to D.V.), the University of Washington Arnold and

Mabel Beckman cryo-EM center and the National Institutes of

Health grant S10OD032290 (to D.V.), and grant U01 AI151698

for the United World Antiviral Research Network (UWARN) as

part of the Centers for Research in Emerging Infectious

Diseases (CREID) Network. D.V. is an investigator of the Howard

Hughes Medical Institute.Author contributions:M.M. and

D.V. conceived of the project. M.M., A.C.W., and D.V. designed

the experiments. M.M. analyzed the incidence of variants.

M.M. and J.E.B. expressed and purified proteins and performed

ELISAs. M.M. carried out cryo-EM sample preparation, data

collection, processing model building, and refinement. A.C.W.

carried out BLI analysis. L.E.R. performed SPR analysis.

A.C.W. and K.R.S. performed pseudovirus neutralization assays

and analysis. H.V.D., A.D.M., S.W.T., M.C.M., L.C., M.S.P., H.Y.C.,

W.C.V.V., and D.C. provided reagents. G.S., D.C., and D.V.

supervised the experiments. M.M. and D.V. wrote the

manuscript, with input from all authors.Competing interests:

L.E.R., A.D.M., G.S., M.S.P., and D.C. are employees of Vir

Biotechnology, Inc., and may hold shares in Vir Biotechnology,

Inc. D.C. is currently listed as an inventor on multiple patent

applications, which disclose the subject matter described in this

manuscript. A.C.W., G.S., D.C., and D.V. are listed as inventors

on patent 49230.03US1 describing the S309 epitope. The

Veesler laboratory has received a sponsored research

agreement from Vir Biotechnology, Inc. H.Y.C. is a consultant

for Merck, Pfizer, Ellume, and the Bill and Melinda Gates

Foundation and has received support from Cepheid and

Sanofi-Pasteur. The remaining authors declare that the research

was conducted in the absence of any commercial or financial

relationships that could be construed as a potential conflict of

SCIENCEscience.org 24 DECEMBER 2021•VOL 374 ISSUE 6575 1625

Fig. 4. S2X303 defines a subclass of site i NTD mAbs cross-reacting with several variants.
(A) Binding of a panel of 11 neutralizing (antigenic site i) and 1 non-neutralizing (S2L20, antigenic site iv)
NTD-specific mAbs to recombinant SARS-CoV-2 S variants analyzed by ELISA displayed as a heatmap
(relative to wild-type Wuhan-Hu-1 binding). (B) Structure of the B.1.617.1 S trimer (surface rendering) bound
to the S2X303 Fab fragment (ribbons) shown in two orthogonal orientations. SARS-CoV-2 S protomers are
colored pink, cyan, and gold, whereas the S2X303 Fab heavy and light chains are colored dark and light
purple, respectively. Only the Fab variable domains are resolved and therefore modeled in the map.
N-linked glycans are rendered as dark blue spheres. (C) Ribbon diagram of the S2X303-bound SARS-CoV-2
B.1.617.1 NTD. (D) Zoomed-in view of the S2X303-bound B.1.617.1 NTD with key residues involved in the
interface shown as sticks. (E) Structure of the S trimer bound to the S2X303 overlaid with S2X333 and
P008-056 antibodies (PDB IDs 7LXW and 7NTC, respectively) shown as a surface rendering. S is colored as
in (B); S2X303, S2X333, and P008-056 are shown in purple, orange, and light gray, respectively.

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