title: Venezuelan equine encephalitis virus replicon particles encoding respiratory syncytial virus surface glycoproteins induce protective mucosal responses in mice and cotton rats.
abstract: Respiratory syncytial virus (RSV) is an important viral pathogen that causes severe lower respiratory tract infection in infants, the elderly, and immunocompromised individuals. There are no licensed RSV vaccines to date. To prevent RSV infection, immune responses in both the upper and lower respiratory tracts are required. Previously, immunization with Venezuelan equine encephalitis virus replicon particles (VRPs) demonstrated effectiveness in inducing mucosal protection against various pathogens. In this study, we developed VRPs encoding RSV fusion (F) or attachment (G) glycoproteins and evaluated the immunogenicity and efficacy of these vaccine candidates in mice and cotton rats. VRPs, when administered intranasally, induced surface glycoprotein-specific virus neutralizing antibodies in serum and immunoglobulin A (IgA) antibodies in secretions at the respiratory mucosa. In addition, fusion protein-encoding VRPs induced gamma interferon (IFN-gamma)-secreting T cells in the lungs and spleen, as measured by reaction with an H-2K(d)-restricted CD8(+) T-cell epitope. In animals vaccinated with F protein VRPs, challenge virus replication was reduced below the level of detection in both the upper and lower respiratory tracts following intranasal RSV challenge, while in those vaccinated with G protein VRPs, challenge virus was detected in the upper but not the lower respiratory tract. Close examination of histopathology of the lungs of vaccinated animals following RSV challenge revealed no enhanced inflammation. Immunization with VRPs induced balanced Th1/Th2 immune responses, as measured by the cytokine profile in the lungs and antibody isotype of the humoral immune response. These results represent an important first step toward the use of VRPs encoding RSV proteins as a prophylactic vaccine for RSV.
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Vanderbilt University, Nashville, Tennessee 37232, USA.
authors.forename: Hoyin
authors.initials: H
authors.lastname: Mok
authors.forename: Sujin
authors.initials: S
authors.lastname: Lee
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Utley
authors.forename: Bryan E
authors.initials: BE
authors.lastname: Shepherd
authors.forename: Vasiliy V
authors.initials: VV
authors.lastname: Polosukhin
authors.forename: Martha L
authors.initials: ML
authors.lastname: Collier
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Davis
authors.forename: Robert E
authors.initials: RE
authors.lastname: Johnston
authors.forename: James E
authors.initials: JE
authors.lastname: Crowe
mesh_terms: D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D004666:Encephalitis Virus, Venezuelan Equine / Q000235:genetics*; D018928:Immunity, Mucosal; D008168:Lung / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D012093:Replicon / Q000235:genetics; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D022261:Respiratory Syncytial Virus Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D018113:Respiratory Syncytial Virus, Human / Q000276:immunology*; D016205:Sigmodontinae; D014611:Vaccination; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014760:Viral Fusion Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014771:Virion / Q000235:genetics
chemical_list: D022261:Respiratory Syncytial Virus Vaccines; D014759:Viral Envelope Proteins; D014760:Viral Fusion Proteins; C116204:attachment protein G