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Cold-adapted-viral-attenuation (cava) and novel attenuated poliovirus strains

A polio, virus strain technology, applied in the direction of viruses, viral peptides, antiviral agents, etc., can solve problems such as insufficient exploration

Active Publication Date: 2017-02-22
JANSSEN VACCINES & PREVENTION BV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Several rationally engineered attenuated PV strains exist, however, their potential as IPV vaccine strains has not been fully explored to date

Method used

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  • Cold-adapted-viral-attenuation (cava) and novel attenuated poliovirus strains
  • Cold-adapted-viral-attenuation (cava) and novel attenuated poliovirus strains
  • Cold-adapted-viral-attenuation (cava) and novel attenuated poliovirus strains

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example

[0132] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and use the invention and practice the claimed methods. Accordingly, the following working examples specifically point out certain embodiments of the invention and should not be construed as limiting in any way the remainder of the disclosure.

example 1

[0133] Example 1: Method for production of cold-adapted virus attenuation (CAVA) and CAVA poliovirus (CAVA-PV)

[0134] For this example, the Brunenders parental strain was grown in PER.C6 cells at low temperature (≤30°C) and low MOI (0.01) in Permexcis supplemented with 4 mM L-glutamine. TM 34 serial passages were performed in medium (chemically defined serum-free medium, eg, available from Lonza, catalog number BE02-039Q). The resulting virus population was split to identify temperature-sensitive virus clones in populations with impaired growth at physiological temperature (37°C) and wild-type growth at low temperature (30°C). In screening approximately 1000 clones, 3 clones (named G12P5, F9P4 and G11P3) were found to show temperature sensitivity with impaired growth at 37°C. Impaired growth was defined as a 100- to 1000-fold reduction in maximal titer compared to the parental virus. These 3 clones were still able to replicate at physiological temperature, but with reduced...

example 2

[0136] Example 2: CAVA-PV in sPAER.C6 cells compared to other type 1 PV strains 骨架 growth kinetics

[0137] CAVA-PV in suspension PER.C6 (sPER.C6) cells (production cell line) 骨架 The growth kinetics of were compared with the growth of other type 1 PV (PV1) strains at 30°C and 37°C. Other PV1 strains are Brunhilde, Brunenders, Mahoney and Sabin 1. Brunhilde is the parent strain of Brunenders which in turn is CAVA-PV 骨架 parent strain. Mahoney is a wild-type, neurovirulent PV strain typically used as a vaccine strain for the type 1 component of Salk's IPV. Sabin 1 is an attenuated strain of the vaccine strain used as live attenuated oral poliovirus vaccine (OPV). Suspension PER.C6 cells at the time of infection with 10x10 in Permexcis medium supplemented with 4 mM L-glutamine 6 The cell density of cells / ml. Cells were infected at an MOI of 2 and infection was performed once (N=1). Use TCID 50 The virus harvest was titrated at 30°C to give 50% of the samples an infectious...

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Abstract

A poliovirus (PV) strain was attenuated by a novel method of Cold-Adapted-Viral-Attenuation (CAVA). The resulting recombinant attenuated PV, CAVA-PV, shows wild- type replication at 30DEG C, but no substantial replication at 37DEG C. The inability to replicate at 37DEG C is defined by an inability to quantify virus during infection at this temperture by titration (infectious units), qPCR (viral RNA) or Electron Microscopy (visual signs of infection). CAVA-PV is genetically stable under production conditions and shows utility for use as the backbone to produce attenuated strains with the same antigenic profile as conventional vaccines by replacing the sequence coding for the capsid of CAVA-PV with sequences coding for capsids of different PV strains. Furthermore, mutations identified in CAVA-PV can be engineered into different, even wild-type and neurovirulent poliovirus background strains to obtain additional CAVA-PV strains.

Description

technical field [0001] The present invention relates to the field of virus attenuation and the development of novel attenuated poliovirus strains for use as vaccines. [0002] Background of the invention [0003] Poliovirus (PV) belongs to the Enterovirus genus within the Picornaviridae family. These picornaviruses have single-stranded positive-sense RNA genomes and are non-enveloped. They are subdivided into three serotypes; PV1, PV2 and PV3. Infection by PV is usually asymptomatic, however, 1%-2% of cases cause paralytic poliomyelitis, in which virus-induced destruction of motor neurons results in paralysis, usually in the extremities, termed acute flaccid paralysis ( AFP). Of these AFP cases, 5%-10% are fatal as the virus spreads to the brainstem region, causing respiratory arrest and ultimately death. (For a review of PV and pathogenesis see eg Minor 1999, Racaniello 2006, Pfeiffer 2010)). [0004] Today, polio is on the verge of being eradicated, of which there were...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N7/00C12N7/08A61K39/13A61P31/14
CPCA61K39/12C12N7/00A61K2039/5254C12N2770/32364C12N2770/32334C12N2770/32321C12N2770/32634C12N2770/32664C12N2770/32621A61P31/04A61P31/14A61P37/04Y02A50/30A61K2039/5252A61K2039/70C07K14/005
Inventor B·P·桑德斯J·H·H·V·屈斯泰D·埃多马塔斯T·G·乌伊尔J·A·刘易斯
Owner JANSSEN VACCINES & PREVENTION BV
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