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Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract (LRT) infections, with increased severity in high-risk human populations, such as infants, the immunocompromised, and the elderly. Although the virus was identified more than 60 years ago, there is still no licensed vaccine available. Over the years, several vaccine delivery strategies have been evaluated. In this study, we developed two recombinant vesicular stomatitis virus (rVSV) vector-based vaccine candidates expressing the RSV-G (attachment) protein (rVSV-G) or F (fusion) protein (rVSV-F). All vectors were evaluated in the cotton rat animal model for their in vivo immunogenicity and protective efficacy against an RSV-A2 virus challenge. Intranasal (i.n.) delivery of rVSV-G and rVSV-F together completely protected the lower respiratory tract (lungs) at doses as low as 10(3) PFU. In contrast, doses greater than 10(6) PFU were required to protect the upper respiratory tract (URT) completely. Reimmunization of RSV-immune cotton rats was most effective with rVSV-F. In immunized animals, overall antibody responses were sufficient for protection, whereas CD4 and CD8 T cells were not necessary. A prime-boost immunization regimen increased both protection and neutralizing antibody titers. Overall, mucosally delivered rVSV-vector-based RSV vaccine candidates induce protective immunity and therefore represent a promising immunization regimen against RSV infection. IMPORTANCE Even after decades of intensive research efforts, a safe and efficacious RSV vaccine remains elusive. Expression of heterologous antigens from rVSV vectors has demonstrated several practical and safety advantages over other virus vector systems and live attenuated vaccines. In this study, we developed safe and efficacious vaccine candidates by expressing the two major immunogenic RSV surface proteins in rVSV vectors and delivering them mucosally in a prime-boost regimen. The main immune parameter responsible for protection was the antibody response. These vaccine candidates induced complete protection of both the upper and lower respiratory tracts.

The resurgence of several infectious diseases, like measles, has driven the search for new chemotherapeutics to prevent and treat viral infections. Self-assembling antiviral peptides are a promising class of entry inhibitors capable of meeting this need. Fusion inhibitory peptides derived from the heptad repeat of the C-terminal (HRC) of the measles fusion protein, dimerized and conjugated with lipophilic groups, were found to be efficacious against measles virus. The structures of the self-assembled nanoparticles formed by these peptides modulated their activity. Based on the analysis of a L454W mutation in the fusion protein of a naturally occurring measles viral isolate, HRC peptides bearing the tryptophan residue at position 454 (HRC-L454W) were synthesized with the goal of improving membrane anchoring and manipulating self-assembly. Monomeric and dimeric peptides, whether conjugated or not to a single lipophilic group, reduced infection in vivo. Bis-conjugation with lipophilic groups, in contrast, abrogated activity. Based on the physicochemical properties, self-assembly and membrane insertion kinetics of the HRC-L454W peptides we show that bis-conjugation increases the stability and order of the inner core of the spontaneously self-assembled nanoparticles, resulting in their compaction. The presence of the tryptophan residue also increases steric hindrance effects in the nanoparticle of the dimeric peptides, contributing to inter-peptide cluster meshing, but the same level of compaction is not achieved. We propose that the highly ordered packing and stability of molecular clusters forming the inner core of self-assembled nanoparticles prevent efficient dissociation of the peptides in vivo, hindering their release and therefore eliminating their antiviral efficacy.