Rational design of uncleaved prefusion-closed trimer vaccines for human respiratory syncytial virus and metapneumovirus.

Autor: Lee YZ; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA., Han J; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA., Zhang YN; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA., Ward G; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA., Braz Gomes K; Uvax Bio, LLC, Newark, DE, 19702, USA., Auclair S; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA., Stanfield RL; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA., He L; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA., Wilson IA; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA.; Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA., Zhu J; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA. jiang@scripps.edu.; Uvax Bio, LLC, Newark, DE, 19702, USA. jiang@scripps.edu.; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, 92037, USA. jiang@scripps.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Nov 16; Vol. 15 (1), pp. 9939. Date of Electronic Publication: 2024 Nov 16.
DOI: 10.1038/s41467-024-54287-x
Abstrakt: Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) cause human respiratory diseases and are major targets for vaccine development. In this study, we design uncleaved prefusion-closed (UFC) trimers for the fusion protein (F) of both viruses by examining mutations critical to F metastability. For RSV, we assess four previous prefusion F designs, including the first and second generations of DS-Cav1, SC-TM, and 847A. We then identify key mutations that can maintain prefusion F in a native-like, closed trimeric form (up to 76%) without introducing any interprotomer disulfide bond. For hMPV, we develop a stable UFC trimer with a truncated F 2 -F 1 linkage and an interprotomer disulfide bond. Dozens of UFC constructs are characterized by negative-stain electron microscopy (nsEM), x-ray crystallography (11 RSV-F structures and one hMPV-F structure), and antigenic profiling. Using an optimized RSV-F UFC trimer as bait, we identify three potent RSV neutralizing antibodies (NAbs) from a phage-displayed human antibody library, with a public NAb lineage targeting sites Ø and V and two cross-pneumovirus NAbs recognizing site III. In mouse immunization, rationally designed RSV-F and hMPV-F UFC trimers induce robust antibody responses with high neutralizing titers. Our study provides a foundation for future prefusion F-based RSV and hMPV vaccine development.
Competing Interests: Competing interests The authors declare the following competing interests: J.Z. serves as the Co-Founder, Interim Chief Scientific Officer, Consultant, and Scientific Advisory Board member of Uvax Bio, LLC, and holds associated financial interests. Other authors declare that they have no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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