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Attenuated Infectious Bronchitis Virus

a coronavirus and infectious bronchitis technology, applied in the field of attenuated coronavirus, can solve the problems of reduced egg production and quality, and death of kidney diseases

Active Publication Date: 2019-01-24
THE PIRBRIGHT INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention relates to a new type of virus that can cause reduced levels of disease when administered to embryo-based vaccination. This is achieved by using a reverse genetics approach to identify specific mutations in the virus that make it less harmful. Compared to existing attenuated vaccines, this new type of virus is a safer alternative for in ovo vaccination. Overall, the patent describes a method for creating a new virus that can protect embryos from disease while still being able to replicate in them.

Problems solved by technology

Meat-type birds have reduced weight gain, whilst egg-laying birds lay fewer eggs and produce poor quality eggs.
The virus can also cause permanent damage to the oviduct, especially in chicks, leading to reduced egg production and quality; and kidney, sometimes leading to kidney disease which can be fatal.
Although live attenuated vaccines and inactivated vaccines are universally used in the control of IBV, the protection gained by use of vaccination can be lost either due to vaccine breakdown or the introduction of a new IBV serotype that is not related to the vaccine used, posing a risk to the poultry industry.
A major challenge associated with in ovo vaccination is that the virus must be capable of replicating in the presence of maternally-derived antibodies against the virus, without being pathogenic to the embryo.
However such viruses almost always show an increased virulence to embryos and therefore cannot be used for in ovo vaccination as they cause reduced hatchability.
There are also efficacy problems associated with the process: some mutations will affect the replication of the virus and some of the mutations may make the virus too attenuated.
Mutations can also occur in the S gene which may also affect immunogenicity so that the desired immune response is affected and the potential vaccine may not protect against the required serotype.
In addition there are problems associated with reversion to virulence and stability of vaccines.

Method used

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  • Attenuated Infectious Bronchitis Virus
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Examples

Experimental program
Comparison scheme
Effect test

example 1

n of an IBV Reverse Genetics System Based on M41-CK

[0245]A M41-CK full-length cDNA was produced by replacement of the Beaudette cDNA in the Vaccinia virus reverse genetics system previously described in PCT / GB2010 / 001293 (herein incorporated by reference) with synthetic cDNA derived from the M41 consensus sequence.

[0246]The IBV cDNA within recombinant Vaccinia virus (rVV) rVV-BeauR-Rep-M41 Struct described in Armesto, Cavanagh and Britton (2009). PLoS ONE 4(10): e7384. doi:10.1371 / journal.pone.0007384, which consisted of the replicase derived from IBV Beaudette strain and the structural and accessory genes and 3′ UTR from IBV M41-CK, was further modified by replacement of the Beaudette 5′ UTR-Nsp2-Nsp3 sequence with the corresponding sequence from IBV M41-CK. The resulting IBV cDNA consisted of 5′ UTR-Nsp2-Nsp3 from M41, Nsp4-Nsp16 from Beaudette and the structural and accessory genes and 3′ UTR from M41. This cDNA was further modified by the deletion of the Beaudette Nsp4-Nsp16 seq...

example 2

ng the Pathogenicity of Recombinant M41 Viruses

[0247]Three recombinants were produced using the reverse genetics system described in Example 1. These recombinants were named rIBV M41K-S-ADRP, rIBV M41K-A-ADRP and rIBV M41K-del3ab.

[0248]The three recombinants were shown to grow in a similar manner in chicken kidney cells as wild-type M41-CK / M41-K (FIGS. 7 and 8).

[0249]rIBV M41K-S-ADRP has a mutation at nucleotide position G3685A in the adenosine diphosphate-ribose-1′-phosphatase (ADRP) region of nsp-3 resulting in an amino acid mutation from G to S. This mutation was introduced into the rVV containing M41-K using the plasmid shown in FIG. 1.

[0250]rIBV M41K-A-ADRP has two mutations at nucleotide positions A3664G and A3665C in the ADRP region of nsp-3 resulting in an amino acid mutation from N to A. This mutation was introduced into the rVV containing M41-K using the plasmid shown in FIG. 2.

[0251]rIBV M41K-del3ab has a deletion from nucleotide position 23867 to 24214 in gene 3 resultin...

example 3

on / Challenge Study with M41-R

[0253]Candidate vaccine viruses are tested in studies in which fertilized chicken eggs are vaccinated in ovo at 19 days embryonation and in which the hatchability of the inoculated eggs is determined. The clinical health of the chickens is investigated and the chickens are challenged at 21 days of age with a virulent IB M41 challenge virus at 103.65 EID50 per dose.

[0254]Clinical signs are investigated after challenge protection by the vaccine and a ciliostasis test is performed at 5 days after challenge to investigate the effect of the challenge viruses on movement of the cilia and protection by the vaccine against ciliostasis (inhibition of cilia movement).

TABLE 3Betweenhatch andEnd ofTreatmentEggsAt hatchchallengeChallengestudySalineMDA−DetermineClinicalChickens5 days postIB M41-MDA−hatchexaminationat age ofchallenge aK-A-percent-of birds21 daysciliostasisADRPagestest will beIB M41-MDA−doneK-S-ADRPIB M41-MDA−K-3abIn ovo vaccination of 19 days embryonat...

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Abstract

The present invention provides a live, attenuated coronavirus comprising a mutation in non-structural protein nsp-3 and / or deletion of accessory proteins 3a and 3b. The coronavirus may be used as a vaccine for treating and / or preventing a disease, such as infectious bronchitis, in a subject.

Description

FIELD OF THE INVENTION[0001]The present invention relates to an attenuated coronavirus comprising a mutation which causes the virus to have reduced pathogenicity. The present invention also relates to the use of such a coronavirus in a vaccine to prevent and / or treat a disease.BACKGROUND TO THE INVENTION[0002]Avian infectious bronchitis virus (IBV), the aetiological agent of infectious bronchitis (IB), is a highly infectious and contagious pathogen of domestic fowl that replicates primarily in the respiratory tract but also in epithelial cells of the gut, kidney and oviduct. IBV is a member of the Order Nidovirales, Family Coronaviridae, Subfamily Coronavirinae and Genus Gammacoronavirus; genetically very similar coronaviruses cause disease in turkeys, guinea fowl and pheasants.[0003]Clinical signs of IB include sneezing, tracheal rales, nasal discharge and wheezing. Meat-type birds have reduced weight gain, whilst egg-laying birds lay fewer eggs and produce poor quality eggs. The r...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/215A61P31/12
CPCA61K39/215A61P31/12A61K2039/5254A61K2039/543C07K14/005C12N7/00C12N2770/20021C12N2770/20022C12N2770/20034C12N2770/20051C12N2770/20062C12N2770/20071A61P31/14
Inventor BICKERTON, ERICAKEEP, SARAHBRITTON, PAUL
Owner THE PIRBRIGHT INST
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