Giuseppe
Emeritus
[Source: PLoS ONE, full text: (LINK). Abstract, edited.]
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Cloned Defective Interfering Influenza Virus Protects Ferrets from Pandemic 2009 Influenza A Virus and Allows Protective Immunity to Be Established
Nigel J. Dimmock<SUP>1</SUP><SUP>*</SUP>, Brian K. Dove<SUP>2</SUP><SUP>#</SUP>, Paul D. Scott<SUP>1</SUP><SUP>#</SUP>, Bo Meng<SUP>1</SUP><SUP>#</SUP>, Irene Taylor<SUP>2</SUP>, Linda Cheung<SUP>1</SUP>, Bassam Hallis<SUP>2</SUP>, Anthony C. Marriott<SUP>1</SUP><SUP>?</SUP>, Miles W. Carroll<SUP>2</SUP>, Andrew J. Easton<SUP>1</SUP>
<SUP></SUP>
1 School of Life Sciences, University of Warwick, Coventry, United Kingdom, 2 Health Protection Agency, Porton Down, Salisbury, United Kingdom
Abstract
Influenza A viruses are a major cause of morbidity and mortality in the human population, causing epidemics in the winter, and occasional worldwide pandemics. In addition there are periodic outbreaks in domestic poultry, horses, pigs, dogs, and cats. Infections of domestic birds can be fatal for the birds and their human contacts. Control in man operates through vaccines and antivirals, but both have their limitations. In the search for an alternative treatment we have focussed on defective interfering (DI) influenza A virus. Such a DI virus is superficially indistinguishable from a normal virus but has a large deletion in one of the eight RNAs that make up the viral genome. Antiviral activity resides in the deleted RNA. We have cloned one such highly active DI RNA derived from segment 1 (244 DI virus) and shown earlier that intranasal administration protects mice from lethal disease caused by a number of different influenza A viruses. A more cogent model of human influenza is the ferret. Here we found that intranasal treatment with a single dose of 2 or 0.2 ?g 244 RNA delivered as A/PR/8/34 virus particles protected ferrets from disease caused by pandemic virus A/California/04/09 (A/Cal; H1N1). Specifically, 244 DI virus significantly reduced fever, weight loss, respiratory symptoms, and infectious load. 244 DI RNA, the active principle, was amplified in nasal washes following infection with A/Cal, consistent with its amelioration of clinical disease. Animals that were treated with 244 DI RNA cleared infectious and DI viruses without delay. Despite the attenuation of infection and disease by DI virus, ferrets formed high levels of A/Cal-specific serum haemagglutination-inhibiting antibodies and were solidly immune to rechallenge with A/Cal. Together with earlier data from mouse studies, we conclude that 244 DI virus is a highly effective antiviral with activity potentially against all influenza A subtypes.
Citation: Dimmock NJ, Dove BK, Scott PD, Meng B, Taylor I, et al. (2012) Cloned Defective Interfering Influenza Virus Protects Ferrets from Pandemic 2009 Influenza A Virus and Allows Protective Immunity to Be Established. PLoS ONE 7(12): e49394. doi:10.1371/journal.pone.0049394
Editor: Paulo Lee Ho, Instituto Butantan, Brazil
Received: May 30, 2012; Accepted: October 11, 2012; Published: December 12, 2012
Copyright: ? 2012 Dimmock et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The authors received a technology transfer award (no. 090441Z09Z) from the Wellcome Trust. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have read the journal's policy and NJD and AJE have the following conflicts: patents relating to 244 defective interfering influenza virus. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. Patent details: 2007, NJD. Defective interfering virus: P113084WO. 2009, NJD and AJE. Antiviral protection with viruses containing a defective genome: P120930WO.
* E-mail: n.j.dimmock@warwick.ac.uk
# These authors contributed equally to this work.
?Current address: Health Protection Agency, Porton Down, Salisbury, United Kingdom
-Nigel J. Dimmock<SUP>1</SUP><SUP>*</SUP>, Brian K. Dove<SUP>2</SUP><SUP>#</SUP>, Paul D. Scott<SUP>1</SUP><SUP>#</SUP>, Bo Meng<SUP>1</SUP><SUP>#</SUP>, Irene Taylor<SUP>2</SUP>, Linda Cheung<SUP>1</SUP>, Bassam Hallis<SUP>2</SUP>, Anthony C. Marriott<SUP>1</SUP><SUP>?</SUP>, Miles W. Carroll<SUP>2</SUP>, Andrew J. Easton<SUP>1</SUP>
<SUP></SUP>
1 School of Life Sciences, University of Warwick, Coventry, United Kingdom, 2 Health Protection Agency, Porton Down, Salisbury, United Kingdom
Abstract
Influenza A viruses are a major cause of morbidity and mortality in the human population, causing epidemics in the winter, and occasional worldwide pandemics. In addition there are periodic outbreaks in domestic poultry, horses, pigs, dogs, and cats. Infections of domestic birds can be fatal for the birds and their human contacts. Control in man operates through vaccines and antivirals, but both have their limitations. In the search for an alternative treatment we have focussed on defective interfering (DI) influenza A virus. Such a DI virus is superficially indistinguishable from a normal virus but has a large deletion in one of the eight RNAs that make up the viral genome. Antiviral activity resides in the deleted RNA. We have cloned one such highly active DI RNA derived from segment 1 (244 DI virus) and shown earlier that intranasal administration protects mice from lethal disease caused by a number of different influenza A viruses. A more cogent model of human influenza is the ferret. Here we found that intranasal treatment with a single dose of 2 or 0.2 ?g 244 RNA delivered as A/PR/8/34 virus particles protected ferrets from disease caused by pandemic virus A/California/04/09 (A/Cal; H1N1). Specifically, 244 DI virus significantly reduced fever, weight loss, respiratory symptoms, and infectious load. 244 DI RNA, the active principle, was amplified in nasal washes following infection with A/Cal, consistent with its amelioration of clinical disease. Animals that were treated with 244 DI RNA cleared infectious and DI viruses without delay. Despite the attenuation of infection and disease by DI virus, ferrets formed high levels of A/Cal-specific serum haemagglutination-inhibiting antibodies and were solidly immune to rechallenge with A/Cal. Together with earlier data from mouse studies, we conclude that 244 DI virus is a highly effective antiviral with activity potentially against all influenza A subtypes.
Citation: Dimmock NJ, Dove BK, Scott PD, Meng B, Taylor I, et al. (2012) Cloned Defective Interfering Influenza Virus Protects Ferrets from Pandemic 2009 Influenza A Virus and Allows Protective Immunity to Be Established. PLoS ONE 7(12): e49394. doi:10.1371/journal.pone.0049394
Editor: Paulo Lee Ho, Instituto Butantan, Brazil
Received: May 30, 2012; Accepted: October 11, 2012; Published: December 12, 2012
Copyright: ? 2012 Dimmock et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The authors received a technology transfer award (no. 090441Z09Z) from the Wellcome Trust. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have read the journal's policy and NJD and AJE have the following conflicts: patents relating to 244 defective interfering influenza virus. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. Patent details: 2007, NJD. Defective interfering virus: P113084WO. 2009, NJD and AJE. Antiviral protection with viruses containing a defective genome: P120930WO.
* E-mail: n.j.dimmock@warwick.ac.uk
# These authors contributed equally to this work.
?Current address: Health Protection Agency, Porton Down, Salisbury, United Kingdom
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