Cotton rat immune responses to virus-like particles containing the pre-fusion form of respiratory syncytial virus fusion protein

Abstract

BackgroundVirus-like particles (VLPs) based on Newcastle disease virus (NDV) core proteins, M and NP, and containing two chimera proteins, F/F and H/G, composed of the respiratory syncytial virus (RSV) fusion protein (F) and glycoprotein (G) ectodomains fused to the transmembrane and cytoplasmic domains of the NDV F and HN proteins, respectively, stimulate durable, protective anti-RSV neutralizing antibodies in mice. Furthermore, immunization of mice with a VLP containing a F/F chimera protein with modifications previously reported to stabilize the pre-fusion form of the RSV F protein resulted in significantly improved neutralizing antibody titers over VLPs containing the wild type F protein. The goal of this study was to determine if VLPs containing the pre-fusion form of the RSV F protein stimulated protective immune responses in cotton rats, a more RSV permissive animal model than mice.MethodsCotton rats were immunized intramuscularly with VLPs containing stabilized pre-fusion F/F chimera protein as well as the H/G chimera protein. The anti-RSV F and RSV G antibody responses were determined by ELISA. Neutralizing antibody titers in sera of immunized animals were determined in plaque reduction assays. Protection of the animals from RSV challenge was assessed. The safety of the VLP vaccine was determined by monitoring lung pathology upon RSV challenge of immunized animals.ResultsThe Pre-F/F VLP induced neutralizing titers that were well above minimum levels previously proposed to be required for a successful vaccine and titers significantly higher than those stimulated by RSV infection. In addition, Pre-F/F VLP immunization stimulated higher IgG titers to the soluble pre-fusion F protein than RSV infection. Cotton rats immunized with Pre-F/F VLPs were protected from RSV challenge, and, importantly, the VLP immunization did not result in enhanced respiratory disease upon RSV challenge.ConclusionsVLPs containing the pre-fusion RSV F protein have characteristics required for a safe, effective RSV vaccine.

Novel chimeric virus-like particles vaccine displaying MERS-CoV receptor-binding domain induce specific humoral and cellular immune response in mice

“…and Anderson, 2006). VLP derived from hepatitis B virus (Ye et al, 2013), Newcastle disease virus (Schmidt et al, 2014;Cullen et al, 2015), and parvovirus (Gilbert et al, 2004(Gilbert et al, , 2006 have been shown to be suitable candidates for the expression of foreign epitopes. In the present study, we demonstrated that the recombinant CPV VP2 linked to MERS RBD results in self-assembly into sVLP which display the RBD on the surface, and showed that this vaccine candidate is able to induce robust B-and T-cell responses in mice.…”

Structural, antigenic and immunogenic features of respiratory syncytial virus glycoproteins relevant for vaccine development

“…The purified VLPs were inoculated i.m. in either mice [87] or cotton rats [88], and these animals elicited a serum neutralizing antibody response and were protected against an hRSV challenge. Thus, immunization with pre-fusion F, either as a subunit vaccine or incorporated to recombinant viruses or VLPs, seems to be a promising approach for hRSV vaccine development.…”

Comparative models for human nasal infections and immunity

“…Interestingly, animals previously infected and then challenged with RSV had undetectable viral loads in the nose. Hence, intranasal immunization with VLPs may lead to better stimulation of mucosal immune responses and greater protection, compared to other routes of immunization (Cullen et al, 2015).…”