title: A Respiratory Syncytial Virus Vaccine Vectored by a Stable Chimeric and Replication-Deficient Sendai Virus Protects Mice without Inducing Enhanced Disease.
abstract: Respiratory syncytial virus (RSV) is a major cause of severe respiratory infections in children and elderly people, and no marketed vaccine exists. In this study, we generated and analyzed a subunit vaccine against RSV based on a novel genome replication-deficient Sendai virus (SeV) vector. We inserted the RSV F protein, known to be a genetically stable antigen, into our vector in a specific way to optimize the vaccine features. By exchanging the ectodomain of the SeV F protein for its counterpart from RSV, we created a chimeric vectored vaccine that contains the RSV F protein as an essential structural component. In this way, the antigen is actively expressed on the surfaces of vaccine particles in its prefusion conformation, and as recently reported for other vectored vaccines, the occurrence of silencing mutations of the transgene in the vaccine genome can be prevented. In addition, its active gene expression contributes to further stimulation of the immune response. In order to understand the best route of immunization, we compared vaccine efficacies after intranasal (i.n.) or intramuscular (i.m.) immunization of BALB/c mice. Via both routes, substantial RSV-specific immune responses were induced, consisting of serum IgG and neutralizing antibodies, as well as cytotoxic T cells. Moreover, i.n. immunization was also able to stimulate specific mucosal IgA in the upper and lower respiratory tract. In virus challenge experiments, animals were protected against RSV infection after both i.n. and i.m. immunization without inducing vaccine-enhanced disease. Above all, the replication-deficient SeV appeared to be safe and well tolerated.IMPORTANCERespiratory syncytial virus (RSV) is a major cause of respiratory diseases in young children and elderly people worldwide. There is a great demand for a licensed vaccine. Promising existing vaccine approaches based on live-attenuated vaccines or viral vectors have suffered from unforeseen drawbacks related to immunogenicity and attenuation. We provide a novel RSV vaccine concept based on a genome replication-deficient Sendai vector that has many favorable vaccine characteristics. The specific vaccine design guarantees genetic stability of the transgene; furthermore, it supports a favorable presentation of the antigen, activating the adaptive response, features that other vectored vaccine approaches have often had difficulties with. Wide immunological and pathological analyses in mice confirmed the validity and efficacy of this approach after both parenteral and mucosal administration. Above all, this concept is suitable for initiating clinical studies, and it could also be applied to other infectious diseases.
authors.affiliation: AmVac Research GmbH, Martinsried, Germany.
authors.forename: Marian Alexander
authors.initials: MA
authors.lastname: Wiegand
authors.affiliation: Department of Medical Biotechnologies, Microbiology Section, University of Siena, Siena, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Gori-Savellini
authors.affiliation: Department of Medical Biotechnologies, Microbiology Section, University of Siena, Siena, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Gandolfo
authors.affiliation: Department of Medical Biotechnologies, Microbiology Section, University of Siena, Siena, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Papa
authors.affiliation: AmVac Research GmbH, Martinsried, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Kaufmann
authors.affiliation: AmVac Research GmbH, Martinsried, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Felder
authors.affiliation: Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ginori
authors.affiliation: Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.
authors.forename: Maria Giulia
authors.initials: MG
authors.lastname: Disanto
authors.affiliation: Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Spina
authors.affiliation: Department of Medical Biotechnologies, Microbiology Section, University of Siena, Siena, Italy mariagrazia.cusi@unisi.it.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Cusi
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology; D005260:Female; D005822:Genetic Vectors; D007114:Immunization; D007070:Immunoglobulin A / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood; D051379:Mice; D008807:Mice, Inbred BALB C; D018357:Respiratory Syncytial Virus Infections / Q000517:prevention & control* / Q000821:virology; D022261:Respiratory Syncytial Virus Vaccines / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D018113:Respiratory Syncytial Virus, Human / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D029082:Sendai virus / Q000235:genetics* / Q000276:immunology; D014613:Vaccines, Attenuated; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D014760:Viral Fusion Proteins / Q000235:genetics / Q000276:immunology*; D014779:Virus Replication
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; C526850:F protein, human respiratory syncytial virus; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D022261:Respiratory Syncytial Virus Vaccines; D014613:Vaccines, Attenuated; D022223:Vaccines, Subunit; D014760:Viral Fusion Proteins
keywords: RSV F protein; Sendai vector; Sendai virus (SeV); genetic stability; live vectors; paramyxovirus; replication deficient; respiratory syncytial virus; vaccine; viral vector