Respiratory syncytial virus (RSV) fusion protein expressed by recombinant Sendai virus elicits B-cell and T-cell responses in cotton rats and confers protection against RSV subtypes A and B

Abstract

The respiratory syncytial virus (RSV) is a serious pediatric pathogen for which there is currently no clinically-approved vaccine. This report describes the design and testing of a new RSV vaccine construct (rSV-RSV-F), created by the recombination of an RSV F sequence with the murine parainfluenza virus type 1 (Sendai virus, SV) genome. SV was selected as the vaccine backbone for this study, because it has previously been shown to elicit high-magnitude, durable immune activities in animal studies and has advanced to human safety trials as a xenogenic vaccine for human parainfluenza virus-type 1 (hPIV-1). Cells infected with the recombinant SV expressed RSV F protein, but F was not incorporated into progeny SV virions. When cotton rats were inoculated with the vaccine, high-titer RSV-binding and neutralizing antibodies were induced as well as interferon-γ-producing T-cells. Most striking was the protection against intra-nasal RSV challenge conferred by the vaccine. The rSV-RSV-F construct was also tested as a mixture with a second SV construct expressing the RSV G protein, but no clear advantage was demonstrated by combining the two vaccines. As a final analysis, the efficacy of the rSV-RSV-F vaccine was tested against an array of RSV isolates. Results showed that neutralizing and protective responses were effective against RSV isolates of both A and B subtypes. Together, experimental results encourage promotion of this recombinant SV construct as a vaccine candidate for the prevention of RSV in humans.

Relationships among Dissemination of Primary Parainfluenza Virus Infection in the Respiratory Tract, Mucosal and Peripheral Immune Responses, and Protection from Reinfection: a Noninvasive Bioluminescence-Imaging Study

“…In addition to providing a mouse model to study respiratory paramyxovirus dissemination and pathogenesis, Sendai virus is also a promising Jennerian vaccine candidate against HPIV1 (1,56) and vaccine vector for preclinical HPIV2, HPIV3, and HRSV vaccines (57)(58)(59)(60)(61)(62)(63). There are no confirmed cases of pathogenic Sendai virus infection in humans, and i.n.…”

Influence of Antigen Insertion Site and Vector Dose on Immunogenicity and Protective Capacity in Sendai Virus-Based Human Parainfluenza Virus Type 3 Vaccines

“…Unmodified wild-type SeV elicits protective immunity against HPIV1 without causing adverse events in nonhuman primates (17,40) and is associated with no adverse events after intranasal inoculation into seropositive humans (18). Just as SeV is a promising Jennerian vaccine candidate against HPIV1, rSeV too is being developed as a vaccine vector against HPIV3, as reported here and in our earlier study (15), and other respiratory paramyxoviruses such as HRSV (13,14,41) and HPIV2 (16). Intranasal vaccination with the SeV-vectored HRSV vaccine, in which the HRSV F gene was inserted into the F-HN gene junction of rSeV, elicits protective immunity without causing pathology in both cotton rats (14) and African green monkeys (42).…”

“…Just as SeV is a promising Jennerian vaccine candidate against HPIV1, rSeV too is being developed as a vaccine vector against HPIV3, as reported here and in our earlier study (15), and other respiratory paramyxoviruses such as HRSV (13,14,41) and HPIV2 (16). Intranasal vaccination with the SeV-vectored HRSV vaccine, in which the HRSV F gene was inserted into the F-HN gene junction of rSeV, elicits protective immunity without causing pathology in both cotton rats (14) and African green monkeys (42). Analogous experimental trials in African green monkeys with the HPIV3 vaccine candidates described in our study are needed to compare rSeV-HPIV3HN(P-M) and rSeV-HPIV3HN(F-HN) for immunogenicity, protective capacity, and potential pathology in an animal model more closely related to humans.…”

“…Sendai virus (SeV), the murine counterpart of HPIV1, is also being developed as a Jennerian vaccine against HPIV1 and as a respiratory vaccine vector when containing an inserted F gene from the respiratory syncytial virus (RSV) or the HN gene from HPIV3 or HPIV2 (13)(14)(15)(16). SeV and HPIV1, like HPIV3, are from the genus Respirovirus and have an amino acid sequence homology of Ͼ75% among their six structural genes (13).…”

Prevalence of specific neutralizing antibodies against Sendai virus in populations from different geographic areas: Implications for AIDS vaccine development using Sendai virus vectors

“…This cross-reactivity applies to virus-specific B-and T-cells, and targets several distinct viral proteins. 13,14 SeV is pathogenic in mice, but is not known to cause disease in humans; SeV is now being developed as a xenotropic vaccine administered intranasally to prevent hPIV-1 infection or disease, and also as a delivery system (vector) for antigens from other human viruses including hPIV-3, 15 hPIV-2, 16 and RSV [17][18][19][20] and more recently for HIV. [21][22][23][24] SeV is also used as a vector to deliver human fibroblast growth factor 2, 25 and angiopoietin-1, 26 genes for the treatment of peripheral artery disease, oncolytic virotherapy, 27 and cancer immunotherapy.…”