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Citation
Tags
HERO ID
7003131
Reference Type
Journal Article
Title
Design and characterization of a fusion glycoprotein vaccine for Respiratory Syncytial Virus with improved stability
Author(s)
Zhang, Lan; Espeseth, AmyS; Bett, AJ; Durr, E; Galli, JD; Cosmi, S; Cejas, PJ; Luo, Bin; Touch, S; Parmet, P; Fridman, A; ,
Year
2018
Is Peer Reviewed?
1
Journal
Vaccine
ISSN:
0264-410X
EISSN:
1873-2518
Publisher
ELSEVIER SCI LTD
Location
OXFORD
Page Numbers
8119-8130
PMID
30340881
DOI
10.1016/j.vaccine.2018.10.032
Web of Science Id
WOS:000453620100030
Abstract
Respiratory Syncytial Virus (RSV) infection is the leading cause of lower respiratory tract infection in both young children and older adults. Currently, there is no licensed vaccine available, and therapeutic options are limited. The infectious RSV particle is decorated with a type I viral fusion (F) glycoprotein that structurally rearranges from a metastable prefusion form to a highly stable postfusion form. In people naturally infected with RSV, the neutralizing antibodies primarily recognize the prefusion conformation. Therefore, engineered RSV F protein stabilized in its prefusion conformation has been an attractive strategy for developing RSV F vaccine antigens. Long-term stability at 4 degrees C or higher is a desirable attribute for a RSV F subunit vaccine antigen. We have previously shown that a prefusion stabilized RSV F construct, DS-Cavl, undergoes conformational changes and forms intermediate structures upon long-term storage at 4 degrees C. Structure-based design was performed to improve the stability of the RSV F subunit vaccine. We identified additional mutations that further stabilize RSV F protein in its prefusion conformation by using binding to a previously described antigenic site I antibody 4D7 as the screening tool. In addition, we designed and identified variants with increased expression levels, which is another desirable attribute for a subunit vaccine. Our data suggested that an RSV F variant F111 is properly folded, and has improved heat stability as well as stability upon long-term storage at 4 degrees C. A mouse immunogenicity study demonstrated that no compromise in immunogenicity (both binding and neutralizing antibody levels) was observed with the introduction of these additional mutations. (C) 2018 Merck Sharp & Dohme Corp., and the Authors. Published by Elsevier Ltd.
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