Newcastle disease virus is a safe and immunogenic respiratory-delivered vaccine against SARS-CoV-2 in a ferret model

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused close to 800 million infections and over 7 million deaths worldwide. In addition to its impact on human health, the virus has shown cross-species transmission, including spillover into mustelids such as mink. Here, we evaluated the safety, immunogenicity, and efficacy of a live attenuated Newcastle disease virus (NDV) vaccine expressing a prefusion-stabilized (PFS) SARS-CoV-2 spike protein (pS), delivered intranasally in domestic ferrets, included in the study as a well-established model of upper respiratory infection in humans, and a representative mustelid species. The vaccine (NDV-PFS) was safe and immunogenic, promoting a systemic antibody response and plasma neutralizing activity against the Ancestral, Delta, and, to a lesser degree, Omicron variant. Upon intranasal challenge with the Ancestral strain, vaccination conferred protection against virus replication, reducing SARS-CoV-2 RNA in the nasal turbinates by approximately five orders of magnitude, and eliminating detectable virus antigen in turbinates by immunohistochemistry. Importantly, both single- and double-dose regimens reduced SARS-CoV-2 replication to a similar extent, indicating that this vaccine platform may be amenable to single-dose administration. Overall, NDV-PFS proved to be a safe, immunogenic, and protective intranasal vaccine against SARS-CoV-2 in ferrets. As the first study to evaluate an NDV-vectored vaccine in this species, this study expands the range of animals in which this platform has proven effective, and supports further development of NDV-based mucosal vaccines for respiratory pathogens in multiple species.