Structural basis of respiratory syncytial virus
subtype-dependent neutralization by an antibody
targeting the fusion glycoprotein
, Michael B. Battles
, Syed M. Moin
, Man Chen
, Kayvon Modjarrad
, Azad Kumar
, Kevin W. Graepel
, Noor M. Taher
, Anne L. Hotard
, Martin L. Moore
, Min Zhao
, Ning-Shao Xia
, Jason S. McLellan
& Barney S. Graham
A licensed vaccine for respiratory syncytial virus (RSV) is unavailable, and passive prophy-
laxis with the antibody palivizumab is restricted to high-risk infants. Recently isolated anti-
bodies 5C4 and D25 are substantially more potent than palivizumab, and a derivative of D25
is in clinical trials. Here we show that unlike D25, 5C4 preferentially neutralizes subtype A
viruses. The crystal structure of 5C4 bound to the RSV fusion (F) protein reveals that the
overall binding mode of 5C4 is similar to that of D25, but their angles of approach are
substantially different. Mutagenesis and virological studies demonstrate that RSV F residue
201 is largely responsible for the subtype speciﬁcity of 5C4. These results improve our
understanding of subtype-speciﬁc immunity and the neutralization breadth requirements of
next-generation antibodies, and thereby contribute to the design of broadly protective RSV
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Pulmonology, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China.
Department of Biochemistry and Cell Biology, Geisel School
of Medicine at Dartmouth, Hanover, NH 03755, USA.
Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
Henry M. Jackson
Foundation, Bethesda, MD 20817, USA.
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37208, USA.
Pediatrics, Emory University, Atlanta, GA 30322, USA.
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health,
Xiamen University, Xiamen, Fujian 361005, China.
National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life
Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Present address: Division of Select Agents and Toxins, Centers for Disease Control and
Prevention, Atlanta, GA 30333, USA.
Present address: Meissa Vaccines, Inc South, San Francisco, CA 94080, USA. Daiyin Tian and Michael B. Battles
contributed equally to this work. Correspondence and requests for materials should be addressed to N.-S.X. (email: firstname.lastname@example.org)
or to J.S.M. (email: Jason.S.McLellan@Dartmouth.edu) or to B.S.G. (email: email@example.com)