Robust immune response and protection generated by a polyanhydride-based nanoparticle vaccine utilizing the RSV prefusion F protein and/or M protein

Abstract

Abstract Respiratory syncytial virus (RSV) is the leading cause of lower respiratory infections in young children, resulting in 34 million new infections each year. Natural RSV infection is insufficient to establish long-lived and complete protective immunity from reinfection, and there is no licensed vaccine for RSV. We developed a vaccine utilizing a prefusion-stabilized variant of the RSV fusion (F) protein (DS-Cav1) and/or the RSV matrix (M) protein. The vaccine is encapsulated within 20:80 1,8-bis(p-carboxyphenoxy)-3,6-dioxoctane (CPTEG):1,6-bis(p-carboxyphenoxy) hexane (CPH) copolymer nanoparticles with CpG 1668 ODN. The prefusion conformation of RSV F allows for better exposure of the major antigenic site, termed site Ø, a primary target of neutralizing antibody responses found in human serum. The RSV M protein contains epitopes that are known targets of both CD4 and CD8 T cells. To evaluate this vaccine candidate, BALB/c mice were vaccinated intranasally and subsequently boosted intranasally 4 weeks later. Vaccination with the prefusion RSV F nanovaccine significantly ameliorated weight loss and pulmonary dysfunction compared to unvaccinated mice in response to an RSV challenge. This protection remained until at least 100 days post prime vaccination. Additionally, peak viral gene copy numbers in the lung were reduced in vaccinated mice. The prime/boost prefusion RSV F vaccination induced activated lung-localized T cells, as well as tissue-resident memory CD4 and CD8 T cells in the lungs. Vaccination also induced lung tissue-resident B cells. Given the strong immune response generated as well as the protection provided from challenge, this prefusion RSV F nanoparticle formulation may be a promising vaccine candidate.