Respiratory syncytial virus fusion nanoparticle vaccine immune responses target multiple neutralizing epitopes that contribute to protection against wild-type and palivizumab-resistant mutant virus challenge |
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| Affiliation: | 1. Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA;2. Novavax, Inc., Gaithersburg, MD, USA;4. Department of Molecular Virology and Microbiology and Pediatrics, Baylor College of Medicine, Houston, TX, USA;1. Sanofi Pasteur, Discovery North America, 38 Sidney Street, Cambridge, MA 02139, USA;2. Sanofi Pasteur, ARD North America, 1755 Steeles Avenue West, Toronto, ON M2R 3T4, Canada;1. Vaxart, Inc., 290 Utah Ave, Suite 200, South San Francisco, CA 94080, USA;2. Division of Infectious Diseases, Allergy & Immunology, Department of Internal Medicine, Saint Louis University, St. Louis, MO, USA;3. Dept. Pharmacology and Therapeutics and School of Pharmacy, University College Cork, Cork, Ireland;1. VIB-UGent Center for Medical Biotechnology, Technologiepark 927, Ghent, B-9052, Belgium;2. Department of Biomedical Molecular Biology, Ghent University, Ghent, B-9052, Belgium;3. Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755-3844, USA;1. VIDO-InterVac, University of Saskatchewan, Saskatoon, SK, S7N 5E3, Canada;2. Microbiology & Immunology, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada;3. Veterinary Microbiology, University of Saskatchewan, Saskatoon, SK, S7N 5B4, Canada;1. Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA;2. Department of Pediatrics, Division of Infectious Disease, Emory University School of Medicine, Atlanta, GA, USA;3. Children’s Healthcare of Atlanta, Atlanta, GA, USA;4. Meissa Vaccines, Inc. South San Francisco, CA, USA |
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| Abstract: | Human respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract infections in newborns, young children, elderly, and immune-compromised. The RSV fusion (F) glycoprotein is a major focus of vaccine development and the target of palivizumab (Synagis®) which is licensed as an immuno-prophylactic for use in newborn children at high risk of infection. However, clinical use of a narrowly targeted monoclonal antibodies leads to the generation of escape mutant strains that are fully resistant to neutralization by the antibody. Herein, we evaluated the RSV F nanoparticle vaccine (RSV F vaccine), produced as near-full-length, pre-fusogenic F trimers that form stable protein-detergent nanoparticles. The RSV F vaccine induces polyclonal antibodies that bind to antigenic site II as well as other epitopes known to be broadly neutralizing. Cotton rats immunized with the RSV F vaccine produced antibodies that were both neutralizing and protected against wild-type RSV infection, as well as against a palivizumab-resistant mutant virus. Use of aluminum phosphate adjuvant with the RSV F vaccine increased site II antibody avidity 100 to 1000-fold, which correlated with enhanced protection against challenge. The breadth of the vaccine-induced antibody response was demonstrated using competitive binding with monoclonal antibodies targeting antigenic sites Ø, II, IV, and VIII found on pre-fusion and post-fusion conformations of RSV F. In summary, we found the RSV F vaccine induced antibodies that bind to conserved epitopes including those defined as pre-fusion F specific; that use of adjuvant increased antibody avidity that correlated with enhanced protection in the cotton rat challenge model; and the polyclonal, high-avidity antibodies neutralized and protected against both wild-type and palivizumab-resistant mutant virus. These data support the ongoing clinical development of the aluminum phosphate adjuvanted RSV F nanoparticle vaccine. |
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| Keywords: | Respiratory syncytial virus Palivizumab-resistant mutant RSV Fusion glycoprotein Nanoparticle vaccine Cotton rat |
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