Structural basis of respiratory syncytial virus subtype-dependent neutralization by an antibody targeting the fusion glycoprotein

Daiyin Tian, Michael B. Battles, Syed M. Moin, Man Chen, Kayvon Modjarrad, Azad Kumar, Masaru Kanekiyo, Kevin W. Graepel, Noor M. Taher, Anne L. Hotard, Martin L. Moore, Min Zhao, Zi-Zheng Zheng, Ning-Shao Xia (), Jason S. McLellan () and Barney S. Graham ()
Additional contact information
Daiyin Tian: National Institutes of Health
Michael B. Battles: Geisel School of Medicine at Dartmouth
Syed M. Moin: National Institutes of Health
Man Chen: National Institutes of Health
Kayvon Modjarrad: Walter Reed Army Institute of Research
Azad Kumar: National Institutes of Health
Masaru Kanekiyo: National Institutes of Health
Kevin W. Graepel: Vanderbilt University Medical Center
Noor M. Taher: Geisel School of Medicine at Dartmouth
Anne L. Hotard: Emory University
Martin L. Moore: Emory University
Min Zhao: School of Public Health, Xiamen University
Zi-Zheng Zheng: School of Public Health, Xiamen University
Ning-Shao Xia: School of Public Health, Xiamen University
Jason S. McLellan: Geisel School of Medicine at Dartmouth
Barney S. Graham: National Institutes of Health

Nature Communications, 2017, vol. 8, issue 1, 1-7

Abstract: Abstract A licensed vaccine for respiratory syncytial virus (RSV) is unavailable, and passive prophylaxis with the antibody palivizumab is restricted to high-risk infants. Recently isolated antibodies 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 vaccines.

Date: 2017
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DOI: 10.1038/s41467-017-01858-w

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