Structure-Based Design and Antigenic Validation of Respiratory Syncytial Virus G Immunogens

Nuñez Castrejon, Ana M.; O’Rourke, Sara M.; Kauvar, Lawrence M.; DuBois, Rebecca M.

doi:10.1128/jvi.02201-21

Structure-Based Design and Antigenic Validation of Respiratory Syncytial Virus G Immunogens

Journal Article · Wed Mar 09 23:00:00 EST 2022 · Journal of Virology

DOI:https://doi.org/10.1128/jvi.02201-21· OSTI ID:1903845

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University of California, Santa Cruz, CA (United States); OSTI
University of California, Santa Cruz, CA (United States)
Trellis Bioscience, Inc., Redwood City, CA (United States)

Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract disease of children, the elderly, and immunocompromised individuals. Currently, there are no FDA-approved RSV vaccines. The RSV G glycoprotein is used for viral attachment to host cells and impairment of host immunity by interacting with the human chemokine receptor CX3CR1. Antibodies that disrupt this interaction are protective against infection and disease. Nevertheless, development of an RSV G vaccine antigen has been hindered by its low immunogenicity and safety concerns. A previous study described three engineered RSV G proteins containing single-point mutations that induce higher levels of IgG antibodies and have improved safety profiles compared to wild-type RSV G. However, it is unclear if the mutations affect RSV G protein folding and display of its conformational epitopes. In this study, we show that the RSV G S177Q protein retains high-affinity binding to protective human and mouse monoclonal antibodies and has equal reactivity as wild-type RSV G protein to human reference immunoglobulin to RSV. Additionally, we determined the high-resolution crystal structure of RSV G S177Q protein in complex with the anti-RSV G antibody 3G12, further validating its antigenic structure. These studies show for the first time that an engineered RSV G protein with increased immunogenicity and safety retains conformational epitopes to high-affinity protective antibodies, supporting its further development as an RSV vaccine immunogen. Respiratory syncytial virus (RSV) causes severe lower respiratory diseases of children, the elderly, and immunocompromised populations. There currently are no FDA-approved RSV vaccines. Most vaccine development efforts have focused on the RSV F protein, and the field has generally overlooked the receptor-binding antigen RSV G due to its poor immunogenicity and safety concerns. However, single-point mutant RSV G proteins have been previously identified that have increased immunogenicity and safety. In this study, we investigate the antibody reactivities of three known RSV G mutant proteins. We show that one mutant RSV G protein retains high-affinity binding to protective monoclonal antibodies, is equally recognized by anti-RSV antibodies in human sera, and forms the same three-dimensional structure as the wild-type RSV G protein. Our study validates the structure-guided design of the RSV G protein as an RSV vaccine antigen.

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Research Organization:: University of California, Santa Cruz, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institute of Allergy and Infectious Diseases (NIAID); Cota Robles Fellowship; National Institutes of Health (NIH)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1903845

Journal Information:: Journal of Virology, Journal Name: Journal of Virology Journal Issue: 7 Vol. 96; ISSN 0022-538X

Publisher:: American Society for MicrobiologyCopyright Statement

Country of Publication:: United States

Language:: English

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