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

Abstract

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 to be a genetically stable antigen, into our vector in a specific way to optimize the vaccine features. By exchanging the ectodomain of the SeV F protein for 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 surfaces 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 further stimulation of the immune response. In order to understand the best route of immunization, we compared vaccine efficacies after intranasal (i.n.) or intramuscular (i.m.) immunization of BALB/c mice. Via both routes, substantial RSV-specific immune responses were induced, consisting of 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 replication-deficient SeV appeared to be safe and well tolerated. IMPORTANCERespiratory 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. The 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 have often had 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.

Efficient Delivery of Human Cytomegalovirus T Cell Antigens by Attenuated Sendai Virus Vectors

“…At the same time, translation of C, Y1, and Y2 is abrogated entirely since the respective start codons are not present in rdSeV. The lack of these accessory proteins might contribute to the attenuated phenotype of rdSeV, thus further improving its safety profile without abrogating the capability to elicit protective immune responses (26). Further research will be required to determine to what extent the truncation or lack of these accessory proteins impacts the immunogenicity of rdSeV.…”

“…Importantly, it is also considered to be nonpathogenic in humans (22,23). Sendai virus is currently being tested as a Jennerian vaccine for human parainfluenza virus (with the first efforts on this concept dating back to the 1960s [24]) and as a viral vector for the delivery of human respiratory syncytial virus antigens (25)(26)(27). In appreciation of its many favorable characteristics, SeV is also emerging as a vector for the delivery of immunogens (e.g., Gag) from unrelated pathogens, such as HIV-1 (28,29).…”

“…The aim of this study was to explore whether a highly attenuated, replicationdefective Sendai virus strain might be a suitable vector for the delivery of HCMV antigens. SeV strains expressing IE-1 and pp65 were generated, as well as variants that were rendered replication deficient through partial deletion of the viral P gene, thus further contributing to vector safety (26,30,31). These new SeV strains were compared with recombinant MVA viruses expressing the same antigens in a series of ex vivo assays.…”

Respiratory Syncytial Virus Vaccine Approaches: a Current Overview

“…Wiegand et al used a replication deficient SeV as the backbone of their vaccine. Then they removed the F protein of SeV and replaced it with the F protein of RSV [22]. The replication deficient SeV provides a safe vector that carries RSV F protein as an essential structural component.…”

“…The replication deficient SeV provides a safe vector that carries RSV F protein as an essential structural component. The vaccine stimulates a T cell and antibody response through both an intranasal and an intramuscular immunization [22]. …”