Sendai virus-based RSV vaccine protects African green monkeys from RSV infection
Highlights
► SeVRSV, a recombinant Sendai virus expressing RSV F, was tested in AGM. ► SeVRSV elicited antibody responses against SeV and RSV. ► SeVRSV fully protected AGM from lower respiratory tract RSV infection. ► SeVRSV caused no clinically relevant adverse events. ► SeVRSV is an attractive RSV vaccine candidate.
Introduction
RSV causes serious lower respiratory tract infections in infants and is responsible for an estimated 160,000 deaths annually worldwide [1], [2]. Antibody injections can provide effective prophylaxis against RSV disease, but due to high costs and logistical difficulties, these are not available to most infants, particularly in developing countries [3]. Vaccination remains the single best method for prevention of viral disease and yet there is no licensed vaccine despite more than 50 years of dedicated research [2], [4], [5], [6].
Sendai virus (SeV) is a mouse parainfluenza virus type 1 (PIV-1) that has been previously developed as a vaccine for human PIV-1 (hPIV-1) [7], [8]. SeV is an attractive Jennerian (xenogeneic) vaccine candidate, because it is sensitive to human interferon (IFN)-associated innate immunity [9], and there has never been a confirmed case of SeV-associated disease in humans. In non-human primates, it safely induces a protective immune response against hPIV-1 [7].
SeV elicits high-titered antibodies as well as robust CD8+ T cell activities [10], [11] in small animals. Pre-clinical research has also demonstrated that virus-specific antibody forming cells and CD8+ T cells appear in the upper respiratory tract (URT), the site of expected pathogen exposure, within days after a single immunization. Responses are sustained for the lifetime of the animal and are associated with protective immunity [10], [11]. These features emphasize the attraction of SeV-based vaccines for the induction of a protective immune response.
Recently, SeV has been used as a reverse genetics vector to produce recombinant vaccines against a variety of respiratory pathogens. Constructs have expressed genes from pathogens such as human PIV-2, PIV-3, and RSV. In cotton rats, these vaccines can be used individually or in combination to protect against respiratory virus challenge [12], [13], [14], [15], [16]. When three vaccines were combined, expressing foreign genes from PIV-2, PIV-3 and RSV, four different pathogen infections could be prevented (hPIV-1, hPIV-2, hPIV-3 and RSV). For RSV, when the fusion protein F gene was presented in the context of recombinant SeV, protection was elicited against both A and B RSV isolates [16].
The study described in this report examined SeVRSV as a vaccine against RSV in African green monkeys. Results showed that immune responses were mounted soon after vaccination. The response was associated with safe and complete protection against RSV infection of the LRT.
Section snippets
Animals
African green monkeys (AGM) were feral caught and pre-screened to ensure sero-negativity against RSV and SeV. Twelve AGM were housed for vaccinations at BioQual (Rockville, MD) under BSL2 conditions as specified by the Association for Assessment and Accreditation for Laboratory Animal Care (AAALAC) guidelines. Prior to sample collections, vaccinations or challenges, animals were anesthetized with ketamine hydrochloride (Putney Inc., Portland, ME). Clinical assessments, sample collections,
Vaccination and clearance
Twelve African green monkeys (AGM) were used in this study. Four animals were vaccinated with PBS as controls. Four additional control animals were vaccinated with SeV (1 × 106 EID50 i.n. and 1 × 106 EID50 i.t.). The four test animals were vaccinated with SeVRSV (1 × 106 EID50 i.n. and 1 × 106 EID50 i.t.; Fig. 1A). The schedule for evaluations and challenges (with RSV A2 on day 28) is shown in Fig. 1B.
A first test was to determine the persistence of vaccines in the URT and LRT. For virus measurement,
Discussion
The clinical development of RSV vaccines began approximately 1/2 century ago with the study of a formalin-treated RSV (FI-RSV) product. Unfortunately, vaccinated children were not protected from RSV infection and were hospitalized at a significantly higher rate than placebo controls after a subsequent natural exposure to RSV. Two deaths were associated with vaccination [23], [24], [25], [26], [27]. Results were perhaps due to the absence of robust RSV-specific neutralizing antibodies in the
Acknowledgements
This study was supported in part by NIH P30 CA21765, P01 AI054955, R01 AI088729, TNPRC NIH NCRR grant P51RR000164 and the American Lebanese Syrian Associated Charities (ALSAC). We thank C. Russell, J. Shenep and J. DeVincenzo for useful discussions and advice. We thank P. Vogel and the Veterinary Pathology Core of the St. Jude Animal Resource Center for necropsy and histopathology studies.
Disclosure: A provisional patent application has been submitted describing the use of SeV as a vaccine
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