title: Novel Respiratory Syncytial Virus-Like Particle Vaccine Composed of the Postfusion and Prefusion Conformations of the F Glycoprotein.
abstract: Respiratory syncytial virus (RSV) is the leading cause of severe respiratory disease in infants and children and represents an important global health burden for the elderly and the immunocompromised. Despite decades of research efforts, no licensed vaccine for RSV is available. We have developed virus-like particle (VLP)-based RSV vaccines assembled with the human metapneumovirus (hMPV) matrix protein (M) as the structural scaffold and the RSV fusion glycoprotein (F) in either the postfusion or prefusion conformation as its prime surface immunogen. Vaccines were composed of postfusion F, prefusion F, or a combination of the two conformations and formulated with a squalene-based oil emulsion as adjuvant. Immunization with these VLP vaccines afforded full protection against RSV infection and prevented detectable viral replication in the mouse lung after challenge. Analyses of lung cytokines and chemokines showed that VLP vaccination mostly induced the production of gamma interferon (IFN-γ), a marker of the Th1-mediated immune response, which is predominantly required for viral protection. Conversely, immunization with a formalin-inactivated RSV (FI-RSV) vaccine induced high levels of inflammatory chemokines and cytokines of the Th2- and Th17-mediated types of immune responses, as well as severe lung inflammation and histopathology. The VLP vaccines showed restricted production of these immune mediators and did not induce severe bronchiolitis or perivascular infiltration as seen with the FI-RSV vaccine. Remarkably, analysis of the serum from immunized mice showed that the VLP vaccine formulated using a combination of postfusion and prefusion F elicited the highest level of neutralizing antibody and enhanced the Th1-mediated immune response.
authors.affiliation: TechnoVax, Inc., Tarrytown, New York, USA.
authors.forename: Velasco
authors.identifier: 0000-0001-7489-3145
authors.initials: V
authors.lastname: Cimica
authors.affiliation: TechnoVax, Inc., Tarrytown, New York, USA.
authors.forename: Hélène
authors.initials: H
authors.lastname: Boigard
authors.affiliation: EMD-Millipore Corporation, Billerica, Massachusetts, USA.
authors.forename: Bipin
authors.initials: B
authors.lastname: Bhatia
authors.affiliation: Department of Pathology, New York Medical College, Westchester Medical Center, Valhalla, New York, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Fallon
authors.affiliation: Department of Pathobiology, Sophie Davis School of Biomedical Education, City College of New York, New York, New York, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Alimova
authors.affiliation: Department of Pathobiology, Sophie Davis School of Biomedical Education, City College of New York, New York, New York, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Gottlieb
authors.affiliation: TechnoVax, Inc., Tarrytown, New York, USA jmgalarza@technovax.com.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Galarza
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D016207:Cytokines / Q000276:immunology; D006801:Humans; D007114:Immunization; D007371:Interferon-gamma / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000821:virology; D029121:Metapneumovirus / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D011487:Protein Conformation; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology / Q000517:prevention & control*; D022261:Respiratory Syncytial Virus Vaccines / Q000008:administration & dosage / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D012136:Respiratory Syncytial Viruses / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D015164:Vaccines, Inactivated / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D058425:Vaccines, Virus-Like Particle / Q000008:administration & dosage / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D014760:Viral Fusion Proteins / Q000009:adverse effects / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D019562:Viral Load; D014763:Viral Matrix Proteins / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D016207:Cytokines; C526850:F protein, human respiratory syncytial virus; D022261:Respiratory Syncytial Virus Vaccines; D015164:Vaccines, Inactivated; D058425:Vaccines, Virus-Like Particle; D014760:Viral Fusion Proteins; D014763:Viral Matrix Proteins; D007371:Interferon-gamma