Elsevier

Vaccine

Volume 27, Issue 12, 13 March 2009, Pages 1848-1857
Vaccine

Human PIV-2 recombinant Sendai virus (rSeV) elicits durable immunity and combines with two additional rSeVs to protect against hPIV-1, hPIV-2, hPIV-3, and RSV

https://doi.org/10.1016/j.vaccine.2009.01.041Get rights and content

Abstract

The human parainfluenza viruses (hPIVs) and respiratory syncytial viruses (RSVs) are the leading causes of hospitalizations due to respiratory viral disease in infants and young children, but no vaccines are yet available. Here we describe the use of recombinant Sendai viruses (rSeVs) as candidate vaccine vectors for these respiratory viruses in a cotton rat model. Two new Sendai virus (SeV)-based hPIV-2 vaccine constructs were generated by inserting the fusion (F) gene or the hemagglutinin-neuraminidase (HN) gene from hPIV-2 into the rSeV genome. The inoculation of either vaccine into cotton rats elicited neutralizing antibodies toward both homologous and heterologous hPIV-2 virus isolates. The vaccines elicited robust and durable antibodies toward hPIV-2, and cotton rats immunized with individual or mixed vaccines were fully protected against hPIV-2 infections of the lower respiratory tract. The immune responses toward a single inoculation with rSeV vaccines were long-lasting and cotton rats were protected against viral challenge for as long as 11 months after vaccination. One inoculation with a mixture of the hPIV-2-HN-expressing construct and two additional rSeVs (expressing the F protein of RSV and the HN protein of hPIV-3) resulted in protection against challenge viruses hPIV-1, hPIV-2, hPIV-3, and RSV. Results identify SeV vectors as promising vaccine candidates for four different paramyxoviruses, each responsible for serious respiratory infections in children.

Introduction

Respiratory syncytial virus (RSV) and the human parainfluenza viruses (hPIVs) are negative-strand RNA viruses (Paramyxoviridae) that replicate in epithelial cells of the human respiratory tract. RSV is the leading cause of hospitalizations for infants in the USA [1], [2], [3]. Most patients recover from RSV in the developed world, but in developing countries there are close to 1 million RSV-related deaths per year [4]. The hPIVs are also responsible for serious respiratory infections in the pediatric population. These viruses are categorized into four serotypes (hPIV-1, hPIV-2, hPIV-3 and hPIV-4). Human PIV-1 and hPIV-2 infections are often associated with severe croup involving the larynx and upper trachea, while RSV and hPIV-3 are more often associated with bronchiolitis, bronchitis and pneumonia. hPIV-4-disease is less frequent and less severe, but hPIV-4 can mediate significant morbidity/mortality in immunodeficient patients [5], [6], [7], [8], [9], [10], [11], [12], [13].

Since the 1960s, vaccine strategies have included the use of killed viruses [14], attenuated viruses [15], [16], [17], virus subunits [18], [19] virus recombinants [20], [21], [22], [23], and Jennerian vaccines [24]. The latter strategy refers to the use of a vaccine virus that is derived from a non-human species, but that has some similarity with the human virus target and that grows poorly or not at all in humans. Clinical trials have been initiated with several different vaccine candidates [16], [25], [26], each demonstrating some promise, but no vaccines have yet been clinically proven.

Sendai virus (SeV) is now being considered as a novel candidate vaccine for the pediatric respiratory viruses. SeV was originally discovered in Sendai Japan by Kuroya et al. during an epidemic of fatal pneumonitis in newborns [27]. At that time, lung tissue was taken from sick newborns and transferred to mice for expansion and isolation of the pathogen. When SeV was subsequently isolated, researchers believed that it derived from humans, but later realized that the virus originated in laboratory mice and was not responsible for the infant disease [28], [29]. More than 50 years have since passed, revealing no association between SeV and human infection or illness. Therefore, leaders in the field now describe SeV as a pathogen of mice and not of humans [10].

Since its first discovery, SeV has provided laboratories with a rich research model for the study of hPIV-1 infections in mice [30], [31]. Investigators then found that SeV elicited robust immunity in mice and established a permanent serum antibody response due to a long-sustained population of antibody-secreting cells in the bone marrow [32]. In addition, the virus elicited robust virus-specific T-helper cell and cytotoxic T lymphocyte function [33], [34], [35], [36], [37]. When individual T-cell clones were transferred to naïve animals, they conferred protection against subsequent virus challenge. The humoral and cellular responses were apparently complementary, as the antibodies neutralized virus particles while T-cells cleared infected cells [36], [37].

During laboratory studies of SeV, the profound sequence similarities between SeV (murine PIV-1) and hPIV-1 were recognized [38], [39]. Antigenic similarities were also revealed when virus-specific B-cells and T-cells were shown to cross-react between hPIV-1 and SeV [40], [41]. In fact, when hPIV-1 was administered intranasally to infant or adult mice, recipients were protected against a challenge with Sendai virus [42] and when African green monkeys were immunized with SeV, they were completely protected against hPIV-1 (protection was slightly superior to that conferred by hPIV-1 itself [43]). Each of these results highlighted SeV as a potential new Jennerian (xenotropic) vaccine for the protection of humans from hPIV-1, and prompted the initiation of clinical trials which have thus far demonstrated safety in adults and children ([44] and unpublished results).

As clinical trials were designed and implemented with SeV, further basic research indicated that the virus might also serve as a backbone for vaccines against pathogens other than hPIV-1. Specifically, reverse genetics was considered as a means to recombine foreign genes with the recombinant Sendai virus (rSeV) genome [45], [46], [47], [48], [49]. The current report describes the design of two new SeV recombinant constructs that express the hemagglutinin-neuraminidase (HN) and fusion (F) genes of hPIV-2. We show that each rSeV elicits immune activity and protection against hPIV-2 challenge. A single intranasal inoculation with rSeV is sufficient to sustain protection for as long as 11 months. Additionally, we show that an hPIV-2 recombinant SeV can be mixed with rSeVs expressing hPIV-3 and RSV antigens [46], [47] to protect cotton rats from challenges with four different respiratory viruses: hPIV-1, hPIV-2, hPIV-3 and RSV.

Section snippets

Construct design

Replication-competent recombinant SeVs were rescued using a reverse genetics system, described previously [45], [46], [47], [50]. For cloning of the hPIV-2-F and hPIV-2-HN genes into the plasmid containing full-length cDNA of Sendai virus (Enders strain) pSV(E) [48], LLC-MK2 (ATCC, Rockland, MD) cells were infected with the VR92 Greer strain of hPIV-2 (VR92, American Type Culture Collection [ATCC], Rockland, MD) and viral RNA was extracted. The hPIV-2-F and hPIV-2-HN genes were amplified by

Sendai virus vaccines expressing hPIV-2-F or hPIV-2-HN induce hPIV-2-specific binding and neutralizing antibodies in a cotton rat model

To study the capacity of SeV to serve as an hPIV-2 vaccine backbone, we inserted either hPIV-2-F or hPIV-2-HN genes into the full-length SeV cDNA (Enders strain) and rescued two new viruses, rSeV-hPIV-2-F and rSeV-hPIV-2-HN (see Fig. 1 and Section 2 for details). The immunogenicity of each new SeV-based vaccine was then examined by the inoculation of groups of 3–5 cotton rats intranasally. Animals received 2 × 106 PFU rSeV-hPIV-2-F (abbreviated ‘F’), rSeV-hPIV-2-HN (abbreviated ‘HN’), or a mixture

Discussion

This report describes the construction of two new rSeV vaccines that express the hPIV-2-F (rSeV-hPIV-2-F) and hPIV-2-HN (rSeV-hPIV-2-HN) proteins. In a cotton rat model, each vaccine was shown to elicit binding and neutralizing antibodies and to protect animals against hPIV-2 challenge. The antibodies elicited by the new hPIV-2 vaccines recognized both homologous and heterologous viruses. Antibodies were durable and protection was sustained for many months after vaccination. We also tested a

Acknowledgements

We thank Dr. Greg Prince and Jorge Blanco (Virion Systems) for providing cotton rat antibody reagents. We thank Dr. Randy Hayden (SJCRH) and the American Type Culture Collection (ATCC, Rockville, MD) for providing virus isolates. We thank Robert Sealy and Ruth Ann Scroggs for expert technical assistance. This work was supported by NIH NIAID grant P01 AI054955, NIH NCI grant P30-CA21765 and the American-Lebanese Syrian Associated Charities (ALSAC).

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  • Cited by (0)

    1

    Both authors contributed equally to this work.

    2

    Current address: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, United States.

    3

    Current address: Early Development, Novartis Vaccines and Diagnostics, 350 Mass Ave, Cambridge, MA 02139, United States.

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