Crystal Structure and Immunogenicity of the DS-Cav1-Stabilized Fusion Glycoprotein From Respiratory Syncytial Virus Subtype B

Main Article Content

M. Gordon Joyce
Amy Bao
Man Chen
Ivelin S. Georgiev
Li Ou
Tatsiana Bylund
Aliaksandr Druz
Wing-Pui Kong
Dongjun Peng
Emily J. Rundlet
Joseph G. Van Galen
Shuishu Wang
Yongping Yang
Baoshan Zhang
Gwo-Yu Chuang
Jason S. McLellan
Barney S. Graham
John R. Mascola
Peter D. Kwong


Background: Respiratory syncytial virus (RSV) subtypes, A and B, co-circulate in annual epidemics and alternate in dominance. We have shown that a subtype A RSV fusion (F) glycoprotein, stabilized in its prefusion conformation by DS-Cav1 mutations, is a promising RSV-vaccine immunogen, capable of boosting RSV-neutralizing titers in healthy adults. In both humans and vaccine-tested animals, neutralizing titers elicited by this subtype A DS-Cav1 immunogen were ~ 2- to 3-fold higher against the homologous subtype A virus than against the heterologous subtype B virus.

Methods: To understand the molecular basis for this subtype difference, we introduced DS-Cav1 mutations into RSV strain B18537 F, determined the trimeric crystal structure, and carried out immunogenicity studies.

Results: The B18537 DS-Cav1 F structure at 2-Å resolution afforded a precise delineation of prefusion F characteristics, including those of antigenic site Ø, a key trimer-apex site. Structural comparison with the subtype A prefusion F indicated 11% of surface residues to be different, with an alpha-carbon root-mean-square deviation (RMSD) of 1.2 Å; antigenic site Ø, however, resulted in 23% of its surface residues and had an alpha-carbon RMSD of 2.2 Å. Immunization of vaccine-tested animals with DS-Cav1-stabilized B18537 F induced neutralizing responses ~100-fold higher than with postfusion B18537 F. Notably, elicited responses neutralized RSV subtypes A and B at similar levels and were directed towards both conserved equatorial and diverse apical regions.

Conclusion: We propose that structural differences in apical and equatorial sites–coupled to differently focused immune responses–provide a molecular explanation for observed differences in elicited subtype A and B neutralizing responses.

Keywords: antigenic site; crystal structure; epitope; fusion glycoprotein; immunogenicity; neutralization; RSV subtype; vaccine

Article Details

How to Cite
Joyce MG, Bao A, Chen M, Georgiev IS, Ou L, Bylund T, Druz A, Kong W-P, Peng D, Rundlet EJ, Van Galen JG, Wang S, Yang Y, Zhang B, Chuang G-Y, McLellan JS, Graham BS, Mascola JR, Kwong PD. Crystal Structure and Immunogenicity of the DS-Cav1-Stabilized Fusion Glycoprotein From Respiratory Syncytial Virus Subtype B. PAI [Internet]. 2019 Dec. 11 [cited 2022 Jun. 24];4(2):294-323. Available from:
Author Biographies

Ivelin S. Georgiev, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee Department of Electrical Engineering and Computer Science, Vanderbilt University, Nashville, Tennessee



Peter D. Kwong, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland

Chief, Structural Biology Section


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