A Respiratory Syncytial Virus Vaccine Vectored by a Stable Chimeric and Replication-Deficient Sendai Virus Protects Mice without Inducing Enhanced Disease

Respiratory syncytial virus (RSV) is a major cause of severe respiratory infections in children and elderly people and no marketed vaccine exists. In this study, we generated and analyzed a subunit vaccine against RSV based on a novel genome replication-deficient Sendai virus (SeV) vector. We inserted the RSV F protein, known as a genetically stable antigen, into our vector in a specific way to optimize the vaccine features. Exchanging the ectodomain of the SeV F protein with its counterpart from RSV, we created a chimeric vectored vaccine that contains the RSV F protein as an essential structural component. In this way, the antigen is actively expressed, on the surface of vaccine particles, in its prefusion conformation and, as recently reported for other vectored vaccines, the occurrence of silencing mutations of the transgene in the vaccine genome can be prevented. In addition, its active gene expression contributes to a further stimulation of the immune response. In order to understand the best route of immunization, we compared vaccine efficacy after intranasal (i.n.) or intramuscular (i.m.) immunization of BALB/c mice. Via both routes, substantial RSV-specific immune responses were induced, consisting in serum IgG and neutralizing antibodies, as well as cytotoxic T-cells. Moreover, i.n. immunization was also able to stimulate specific mucosal IgA in the upper and lower respiratory tract. In virus challenge experiments, animals were protected against RSV infection after both i.n. and i.m. immunization, without inducing vaccine-enhanced disease. Above all, the administration of the replication-deficient SeV appeared to be safe and well tolerated.IMPORTANCE Respiratory syncytial virus (RSV) is a major cause of respiratory diseases in young children and elderly people worldwide. There is a great demand for a licensed vaccine. Promising existing vaccine approaches based on live-attenuated vaccines or viral vectors have suffered from unforeseen drawbacks related to immunogenicity and attenuation. We provide a novel RSV vaccine concept based on a genome-replication deficient Sendai vector that has many favorable vaccine characteristics. Specific vaccine design guarantees genetic stability of the transgene, furthermore, it supports a favorable presentation of the antigen, activating the adaptive response - features that other vectored vaccine approaches often had often difficulties with. Wide immunological and pathological analyses in mice confirmed the validity and efficacy of this approach after both parenteral and mucosal administration. Above all, this concept is suitable for initiating clinical studies and it could also be applied to other infectious diseases.