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

Yi-Zong Lee, Jerome Han, Yi-Nan Zhang, Garrett Ward, Keegan Braz Gomes, Sarah Auclair, Robyn L. Stanfield, Linling He, Ian A. Wilson and Jiang Zhu ()
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Yi-Zong Lee: The Scripps Research Institute
Jerome Han: The Scripps Research Institute
Yi-Nan Zhang: The Scripps Research Institute
Garrett Ward: The Scripps Research Institute
Keegan Braz Gomes: LLC
Sarah Auclair: The Scripps Research Institute
Robyn L. Stanfield: The Scripps Research Institute
Linling He: The Scripps Research Institute
Ian A. Wilson: The Scripps Research Institute
Jiang Zhu: The Scripps Research Institute

Nature Communications, 2024, vol. 15, issue 1, 1-25

Abstract: Abstract 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 F2-F1 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.

Date: 2024
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DOI: 10.1038/s41467-024-54287-x

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