tetano
Editor, Senior Moderator
Sci Transl Med 29 May 2013:
Vol. 5, Issue 187, p. 187ra72
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3006299
Research Article
Influenza
Intranasal Antibody Gene Transfer in Mice and Ferrets Elicits Broad Protection Against Pandemic Influenza
Maria P. Limberis1,*,?,
Virginie S. Adam1,?,
Gary Wong2,3,
Jason Gren2,3,
Darwyn Kobasa2,3,
Ted M. Ross4,5,
Gary P. Kobinger2,3,6,
Anna Tretiakova1 and
James M. Wilson1,*
+ Author Affiliations
1Gene Therapy Program, University of Pennsylvania, Philadelphia, PA 19104, USA.
2Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba R3E 3R2, Canada.
3Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada.
4Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA 15261, USA.
5Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15261, USA.
6Department of Immunology, University of Manitoba, Winnipeg, Manitoba R3E 0T5, Canada.
+ Author Notes
↵? These authors contributed equally to this work.
↵*Corresponding author. E-mail: limberis@mail.med.upenn.edu (M.P.L.); wilsonjm@mail.med.upenn.edu (J.M.W.)
Abstract
The emergence of a new influenza pandemic remains a threat that could result in a substantial loss of life and economic disruption worldwide. Advances in human antibody isolation have led to the discovery of monoclonal antibodies (mAbs) that have broad neutralizing activity against various influenza strains, although their direct use for prophylaxis is impractical. To overcome this limitation, our approach is to deliver antibody via adeno-associated virus (AAV) vectors to the site of initial infection, which, for respiratory viruses such as influenza, is the nasopharyngeal mucosa. AAV vectors based on serotype 9 were engineered to express a modified version of the previously isolated broadly neutralizing mAb to influenza A, FI6. We demonstrate that intranasal delivery of AAV9.FI6 into mice afforded complete protection and log reductions in viral load to 100 LD50 (median lethal dose) of three clinical isolates of H5N1 and two clinical isolates of H1N1, all of which have been associated with historic human pandemics (including H1N1 1918). Similarly, complete protection was achieved in ferrets challenged with lethal doses of H5N1 and H1N1. This approach serves as a platform for the prevention of natural or deliberate respiratory diseases for which a protective antibody is available.
http://stm.sciencemag.org/content/5/187/187ra72
Vol. 5, Issue 187, p. 187ra72
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3006299
Research Article
Influenza
Intranasal Antibody Gene Transfer in Mice and Ferrets Elicits Broad Protection Against Pandemic Influenza
Maria P. Limberis1,*,?,
Virginie S. Adam1,?,
Gary Wong2,3,
Jason Gren2,3,
Darwyn Kobasa2,3,
Ted M. Ross4,5,
Gary P. Kobinger2,3,6,
Anna Tretiakova1 and
James M. Wilson1,*
+ Author Affiliations
1Gene Therapy Program, University of Pennsylvania, Philadelphia, PA 19104, USA.
2Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba R3E 3R2, Canada.
3Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada.
4Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA 15261, USA.
5Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15261, USA.
6Department of Immunology, University of Manitoba, Winnipeg, Manitoba R3E 0T5, Canada.
+ Author Notes
↵? These authors contributed equally to this work.
↵*Corresponding author. E-mail: limberis@mail.med.upenn.edu (M.P.L.); wilsonjm@mail.med.upenn.edu (J.M.W.)
Abstract
The emergence of a new influenza pandemic remains a threat that could result in a substantial loss of life and economic disruption worldwide. Advances in human antibody isolation have led to the discovery of monoclonal antibodies (mAbs) that have broad neutralizing activity against various influenza strains, although their direct use for prophylaxis is impractical. To overcome this limitation, our approach is to deliver antibody via adeno-associated virus (AAV) vectors to the site of initial infection, which, for respiratory viruses such as influenza, is the nasopharyngeal mucosa. AAV vectors based on serotype 9 were engineered to express a modified version of the previously isolated broadly neutralizing mAb to influenza A, FI6. We demonstrate that intranasal delivery of AAV9.FI6 into mice afforded complete protection and log reductions in viral load to 100 LD50 (median lethal dose) of three clinical isolates of H5N1 and two clinical isolates of H1N1, all of which have been associated with historic human pandemics (including H1N1 1918). Similarly, complete protection was achieved in ferrets challenged with lethal doses of H5N1 and H1N1. This approach serves as a platform for the prevention of natural or deliberate respiratory diseases for which a protective antibody is available.
http://stm.sciencemag.org/content/5/187/187ra72