(603d) Mucosal Polyanhydride Nanovaccine Against Respiratory Syncytial Virus Infection in the Neonatal Calf

Authors: 
Kelly, S., Iowa State University
Mcgill, J., Kansas State University
Kumar, P., Kansas State University
Speckhart, S., University of Tennessee, Knoxville
Haughney, S., Iowa State University
Henningson, J., Kansas State University
Narasimhan, B., Iowa State University
Sacco, R., National Animal Disease Center
Human respiratory syncytial virus is a leading cause of lower respiratory tract disease in infants and young children worldwide, with an estimated 33 million new cases annually in children under five years of age and more than 100,000 resultant deaths. Bovine RSV (BRSV) is closely related to HRSV and a significant cause of morbidity in young cattle. BRSV infection in calves displays many similarities to RSV infection in humans, including similar age dependency and disease pathogenesis, making it an attractive animal model for vaccine studies with HRSV. BRSV is an enveloped, negative-stranded RNA virus that whose viral envelope is lipid derived from the host plasma membrane, but also contains three virally encoded transmembrane surface glycoproteins, namely the large major attachment glycoprotein G, the type I viral fusion protein F, and small hydrophobic protein SH, the former two playing a critical role in viral replication. Current vaccination strategies incorporate the F and G proteins, as these antigens contain dominant epitopes that can induce neutralizing antibodies, thus inhibiting viral attachment.

Polyanhydride nanoparticle-based vaccines (i.e., nanovaccines) represent a safe and efficacious platform technology with the capability to enhance immune responses against pathogens such as BRSV. These materials are biocompatible, providing mild inflammation at the injection site. Due to their hydrophobic properties, they provide sustained release of encapsulated proteins, which allows for dose sparing, and display chemistry-dependent internalization and activation by antigen presenting cells, which allows for the ability to modulate immune responses. In the current study, the efficacy of a polyanhydride nanovaccine encapsulating the BRSV F and G glycoproteins was evaluated in the neonatal calf. The nanovaccine released immunologically active antigen, evidenced by the ability of BRSV immune serum to bind the released proteins, as well as stimulate CD4+ T cells from BRSV-immune cows. The nanovaccine demonstrated the ability to activate bovine monocyte-derived dendritic cells and alveolar macrophages through the secretion of IFN-Ɣ, TNF-α, IL-6, and IL-1β. Following intranasal administration to calves, the nanovaccine allowed for reduced gross pathology and histopathology in the lungs as well as viral burden in the lungs. Nasal fluid and bronchoalveolar lavage fluid showed statistically significantly higher levels of IgA compared to unvaccinated controls, as well as higher viral neutralization titer six days post-challenge. Peripheral blood mononuclear cells from the nanovaccine-immunized calves stimulated with the F and G proteins demonstrated enhanced T cell responses compared to unvaccinated calves, with a significantly higher degree of dividing T cells, as well as secreted IFN-Ɣ and IL-17. These results demonstrate that a single intranasal dose of a polyanhydride nanovaccine encapsulating the BRSV F and G glycoproteins was an effective vaccine platform that allowed for robust adaptive immune responses against BRSV.