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| GNRH-leukotoxin chimeras |
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| Polynucleotides encoding LKT 111 |
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| Methods and compositions for the treatment of defects in lipoprotein metabolism |
| In one aspect, the invention provides a recombinant viral vector comprising the DNA of, or ... |
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| Antisera against a PEB1 antigen from Campylobacter jejuni |
| It is an object of the present invention to provide highly specific and highly sensitive diagnostic ... |
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| Gene encoding invasion protein of campylobacter species |
| OF PREFERRED EMBODIMENTS The following standard abbreviations for the amino acid residues are used ... |
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| Preservatives for vaccines |
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| Methods and reagents for HLA class I A locus DNA typing |
| OF THE INVENTION To aid in understanding the invention, several terms are defined below. The terms ... |
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Recombinant influenza A viruses
| Details |
Inventors: Ferko, Boris; Egorov, Andre; Voglauer, Regina;
Assignee: Polymun Scientific Immunbiologische Forschung GmbH (Vienna, AT)
Primary Examiner: Mosher; Mary E.
Assistant Examiner:
Attorney, Agent or Firm: Oliff & Berridge, PLC
The invention relates to a recombinant NS gene of an influenza A virus comprising a functional RNA binding domain and a gene sequence modification after nucleotide position 400 of the NS1 gene segment, counted on the basis of influenza A/PR/8/34 Virus, wherein the modification bars transcription of the remaining portion of the NS1 gene segment. It further relates to embodiments, wherein the modification comprises deletions, insertions, or a shift of the open reading frame, and particularly to constructs comprising an insertion of an autocleavage site 2A, the nef gene from HIV-1 or the sequence encoding the ELDKWA-epitope of gp4l of HIV-1. The invention also relates to influenza virus transfectants that contain the modified NS gene and have an IFN inducing phenotype but which may or may not be sensitive towards IFN. The invention also relates to vaccines comprising such a chimeric virus. |
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DETAILED DESCRIPTION OF THE INVENTION In one embodiment, the invention relates to genetically engineered NS gene constructs of an influenza A virus comprising sequence modifications, i.
e.
deletions or insertions, between nucleotide (nt) positions 400 and 525 of the NS1 gene segment (numbering is based on the NS gene of influenza A/PR/8/34 virus).
Unexpectedly, it turned out that maintaining functionality of the NS1 gene segment up to nt position 400 (corresponding to aa position 124 of the NS1 protein) while concomitantly deleting the remaining portion or at least a major part thereof or inserting a foreign nt sequence into the region after nt position 400 or shifting the reading frame to cause wrong transscription and translation of the remaining NS1 portion resulted in the rescue of NS gene constructs that rendered their viral vectors IFN inducing but not IFN sensitive.
This surprising finding was confirmed by experiments wherein the chimeric influenza viruses engineered according to the present invention not only induced a strong IFN response in MDCK cells and hen eggs but were also able to grow on these host substrates at an efficiency comparable to the wildtype PR8 virus.
In contrast, chimeric influenza viruses containing deletions of the first third of the NS1 gene or deletions of the entire NS1 gene displayed an IFN inducing as well as an IFN sensitive phenotype.
They were unable to grow on hen eggs or MDCK cells and therefore could only be cultivated on IFN deficient cell lines such as Vero cells.
Chimeric influenza viruses of the latter type have been disclosed in WO 99/64571.
It is assumed that the viruses of the present invention, which are not as strongly attenuated as the viruses of WO 99/64571, are more immunogenic and therefore better suitable for the manufacture of highly effective live vaccines against various kinds of viral infections.
In another embodiment of the invention the genetically engineered NS gene is used as a genomic fragment of influenza A virus in a method wherein it is transferred to any desired influenza A virus strains or live influenza vaccines by means of genetic reassortment
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