Effective multiple oral administration of reverse genetics engineered infectious bursal disease virus in mice in the presence of neutralizing antibodies.
BACKGROUND
Despite spectacular successes in hepatitis B and C therapies, severe hepatic impairment is still a major treatment problem. The clinically tested infectious bursal disease virus (IBDV) superinfection therapy promises an innovative, interferon-free solution to this great unmet need, provided that a consistent manufacturing process preventing mutations or reversions to virulent strains is obtained.


METHODS
To address safety concerns, a tissue culture adapted IBDV vaccine strain V903/78 was cloned into cDNA plasmids ensuring reproducible production of a reverse engineered virus R903/78. The therapeutic drug candidate was characterized by immunocytochemistry assay, virus particle determination and immunoblot analysis. The biodistribution and potential immunogenicity of the IBDV agent was determined in mice, which is not a natural host of this virus, by quantitative detection of IBDV RNA by a quantitative reverse transcriptase-polymerase chain reaction and virus neutralization test, respectively.


RESULTS
Several human cell lines supported IBDV propagation in the absence of visible cytopathic effect. The virus was stable from pH 8 to pH 6 and demonstrated significant resistance to low pH and also proved to be highly resistant to high temperatures. No pathological effects were observed in mice. Single and multiple oral administration of IBDV elicited antibodies with neutralizing activities in vitro.


CONCLUSIONS
Repeat oral administration of R903/78 was successful despite the presence of neutralizing antibodies. Single oral and intravenous administration indicated that IBDV does not replicate in mammalian liver alleviating some safety related concerns. These data supports the development of an orally delivered anti-hepatitis B virus/ anti-hepatitis C virus viral agent for human use.
National Food Chain Safety Office, Budapest, Hungary.
Ákos
Á
Hornyák
Vibalogics GmbH, Cuxhaven, Germany.
Kai S
KS
Lipinski
Department of Microbiology and Infectious Diseases, Faculty of Veterinary Science, Szent István University, Budapest, Hungary.
Tamás
T
Bakonyi
Department of Microbiology and Infectious Diseases, Faculty of Veterinary Science, Szent István University, Budapest, Hungary.
Petra
P
Forgách
National Food Chain Safety Office, Budapest, Hungary.
Ernő
E
Horváth
National Food Chain Safety Office, Budapest, Hungary.
Attila
A
Farsang
VectorLogics, Inc., Birmingham, AL, USA.|Present address: Meridian Life Science, Inc., Memphis, TN, USA.
Susan J
SJ
Hedley
CEVA-Phylaxia Inc., Budapest, Hungary.
Vilmos
V
Palya
HepC Ltd, Budapest, Hungary.
Tibor
T
Bakács
HepC Ltd, Budapest, Hungary.|ImiGene, Inc., Rockville, MD, USA.
Imre
I
Kovesdi
D000284:Administration, Oral; D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage / Q000276:immunology; D000914:Antibodies, Viral / Q000008:administration & dosage / Q000276:immunology; D002460:Cell Line; D006509:Hepatitis B / Q000276:immunology / Q000628:therapy; D006526:Hepatitis C / Q000276:immunology / Q000628:therapy; D006801:Humans; D007243:Infectious bursal disease virus / Q000235:genetics / Q000276:immunology; D051379:Mice; D059386:Reverse Genetics; D015163:Superinfection / Q000276:immunology / Q000628:therapy*; D014765:Viral Vaccines / Q000008:administration & dosage / Q000235:genetics
D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D014765:Viral Vaccines
IBDV; immune response; infectious bursal disease virus; oral dosing; replication; superinfection therapy