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Attenuated human-bovine chimeric parainfluenza virus (PIV) vaccines

A parainfluenza and virus technology, applied in the direction of viruses, viral peptides, antiviral agents, etc.

Inactive Publication Date: 2008-07-16
UNITED STATES OF AMERICA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] Although BPIV3 is known to have host-range genes that restrict replication in the respiratory tract of macaques, orangutans, and humans, it remains unknown which bovine protein or non-coding sequence determines this host-range restriction of replication

Method used

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  • Attenuated human-bovine chimeric parainfluenza virus (PIV) vaccines
  • Attenuated human-bovine chimeric parainfluenza virus (PIV) vaccines
  • Attenuated human-bovine chimeric parainfluenza virus (PIV) vaccines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0199] Construction of antigenomic cDNA encoding chimeric HPIV3 / BPIV3 and infectious virus recovery

[0200] The following three example studies identify proteins that contribute to host range restriction of BPIV3 in primates. The method is to replace the N protein of wild-type HPIV3 virus with the corresponding part on BPIV3. This replacement was accomplished by recovering infectious PIV from cDNA using the reverse genetics system described above. This study started with BPIV3N because, compared to other HPIV3 and BPIV3 proteins, this protein has modest differences in the amino acid sequence of its HPIV3 counterpart (see Example I).

[0201] A chimeric recombinant virus was constructed in which the N ORF of the HPIV3JS strain was replaced by that of the BPIV3Ka or SF strain (Figure 1). These chimeric viruses possess the HN and F glycoproteins of the HPIV3 parent and induce high levels of immunity to HPIV3 in primates. Two chimeric viruses were successfully obtained. A...

Embodiment II

[0210] Replication of HPIV3 / BPIV3 chimeric virus in cell culture

[0211] Efficient replication of live attenuated virus vaccines in tissue culture cells is a feature of the human-bovine chimeric PIV of the present invention, thus enabling efficient production of recombinant vaccine materials. Multicycle replication of rJS parent, cKa, Ka parent, cSF and SF parent in bovine cell line (MDBK) and simian cell line (LLC-MK2) by the method described above (Tao et al., 1998, incorporated herein by reference) To determine, ie, the virus infected the cells at a MOI of 0.01, samples were collected (in triplicate) over a period of 5 days (Figure 5). These chimeric viruses replicated as efficiently in both cell lines as their human or bovine parental viruses, without significant delays in replication, or significant reductions in the resulting virus titers. In either case, the chimeric virus replicated to 10 7.0 TCID 50 / ml (i.e., far greater than the live attenuated human or bovine...

Embodiment III

[0213] Evaluation of Attenuation and Protection Efficiency of HPIV3 / BPIV3 Chimeric Viruses in Rhesus Monkeys

[0214] Both BPIV3Ka and SF are attenuated in both the upper and lower airways of rhesus monkeys (van Wyke Coelingh et al., 1988, supra). This attenuated phenotype correlates with attenuation in humans (Karron et al., 1995a, supra), as Ka replication is highly restricted in the upper respiratory tract of sufficiently sensitive seronegative infants and children. Cough, croup, bronchiolitis, or lung disease did not develop in BPIV3-infected vaccinators, suggesting that Ka BPIV3 virus is also attenuated in the lower respiratory tract. Therefore, macaques are considered a widely accepted, reasonably relevant model to assess the attenuation of candidate PIV vaccine viruses and their effectiveness against wild-type PIV.

[0215] rJS, cKa, Ka parent, cSF and SF parent were administered intranasally and intratracheally to rhesus monkeys, 10 per dose per site 5.0 TCID 50 ....

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Abstract

Chimeric human-bovine parainfluenza viruses (PIVs) are infectious and attenuated in humans and other mammals and useful individually or in combination in vaccine formulations for eliciting an anti-PIV immune response. Also provided are isolated polynucleotide molecules and vectors incorporating a chimeric PIV genome or antigenome which includes a partial or complete human or bovine PIV "background" genome or antigenome combined or integrated with one or more heterologous gene(s) or genome segment(s) of a different PIV.

Description

[0001] Cross-references to related applications [0002] This application claims priority to US Provisional Patent Application 60 / 143,134, filed July 9,1999 by Bailly et al. Background of the invention [0003] Human parainfluenza virus type 3 (HPIV3) is a common cause of severe lower respiratory tract infections in young children and children under 1 year of age. It is second only to respiratory syncytial virus (RSV) in causing hospital admissions for viral lower respiratory disease in children in this age group (Collins et al., B.N. Fields Virology, p1205-1243,3 rd ed., vol.1., edited by Knipe et al., Lippincott-Raven Publishers, Philadelphia, 1996; Crowe et al., Vaccine 13： 415-421, 1995; Marx et al., J. Infect. Dis. 176 : 1423-1427, 1997, incorporated herein by reference). Infection with this virus causes significant disease in children under 3 years of age. HPIV1 and HPIV2 are major causes of laryngotracheobronchitis (croup) and can also cause severe pneumonia an...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12N15/45C12N5/10C12N7/00C07K14/115A61K39/155C12N15/09A61K9/12A61K39/145A61P31/16C12R1/93
CPCA61K2039/5256C07K2319/00C12N2760/18622C07K14/005A61P31/16A61P37/00C12N15/11
Inventor 亚历山大·C·施密特马里奥·H·斯基亚道普洛斯彼得·L·柯林斯布赖恩·R·墨菲简·E·贝利安娜·P·德宾
Owner UNITED STATES OF AMERICA
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