Sendai virus recombinant vaccine expressing hPIV-3 HN or F elicits protective immunity and combines with a second recombinant to prevent hPIV-1, hPIV-3 and RSV infections.

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, United States.
Vaccine (Impact Factor: 3.49). 07/2008; 26(27-28):3480-8. DOI: 10.1016/j.vaccine.2008.04.022
Source: PubMed

ABSTRACT The human parainfluenza viruses (hPIVs) and respiratory syncytial virus (RSV) are the leading causes of serious respiratory illness in the human pediatric population. Despite decades of research, there are currently no licensed vaccines for either the hPIV or RSV pathogens. Here we describe the testing of hPIV-3 and RSV candidate vaccines using Sendai virus (SeV, murine PIV-1) as a vector. SeV was selected as the vaccine backbone, because it has been shown to elicit robust and durable immune activities in animal studies, and has already advanced to human safety trials as a xenogenic vaccine for hPIV-1. Two new SeV-based hPIV-3 vaccine candidates were first generated by inserting either the fusion (F) gene or hemagglutinin-neuraminidase (HN) gene from hPIV-3 into SeV. The resultant rSeV-hPIV3-F and rSeV-hPIV3-HN vaccines expressed their inserted hPIV-3 genes upon infection. The inoculation of either vaccine into cotton rats elicited binding and neutralizing antibody activities, as well as interferon-gamma-producing T cells. Vaccination of cotton rats resulted in protection against subsequent challenges with either homologous or heterologous hPIV-3. Furthermore, vaccination of cotton rats with a mixture of rSeV-hPIV3-HN and a previously described recombinant SeV expressing the F protein of RSV resulted in protection against three different challenge viruses: hPIV-3, hPIV-1 and RSV. Results encourage the continued development of the candidate recombinant SeV vaccines to combat serious respiratory infections of children.

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    ABSTRACT: Respiratory syncytial virus (RSV) and the human parainfluenza viruses (hPIV) are the leading causes of hospitalizations for viral respiratory tract diseases in infants and young children. Despite approximately 50 years of research, there is currently no vaccine available for any of these pathogens. Sendai virus (SeV) is a mouse respiratory virus that merits consideration as a Jennerian vaccine for hPIV-1 due to its similarity with hPIV-1 in terms of sequence, structure and antigenicity. The SeV backbone can also be manipulated using reverse genetics to create SeV-based RSV and hPIV-3 vaccines. We have prepared two recombinant SeV vaccines, expressing the fusion protein of RSV and the hemagglutinin-neuraminidase protein of hPIV-3, respectively. We found that a single intranasal vaccination with the combined recombinant SeVs (‘mixed-rSeV’) protected cotton rats from challenges with hPIV-1, hPIV-3 and RSV. This discovery, combined with our preliminary clinical demonstration that intranasal administration of unmodified SeV is safe in adults and children, makes a compelling case for advanced development of the SeV-based vaccine product.
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    ABSTRACT: A stable packaging cell line (Vero/BC-F) constitutively expressing fusion (F) protein of the human parainfluenza virus type 2 (hPIV2) was established for production of the F-defective and single round-infectious hPIV2 vector in a strategy for recombinant vaccine development. The F gene expression has not evoked cytostatic or cytotoxic effects on the Vero/BC-F cells and the F protein was physiologically active to induce syncytial formation with giant polykaryocytes when transfected with a plasmid expressing hPIV2 hemagglutinin-neuraminidase (HN). Transduction of the F-defective replicon RNA into the Vero/BC-F cells led to the release of the infectious particles that packaged the replicon RNA (named as hPIV2ΔF) without detectable mutations, limiting the infectivity to a single round. The maximal titer of the hPIV2ΔF was 6.0 × 10(8) median tissue culture infections dose per ml. The influenza A virus M2 gene was inserted into hPIV2ΔF, and the M2 protein was found to be highly expressed in a human lung cancer cell line after transduction. Furthermore, in vivo airway infection experiments revealed that the hPIV2ΔF was capable of delivering transgenes to hamster tracheal cells. Thus, non-transmissible or single round-infectious hPIV2 vector will be potentially applicable to human gene therapy or recombinant vaccine development.Gene Therapy advance online publication, 19 June 2014; doi:10.1038/gt.2014.55.
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May 26, 2014