Message Number: SG18407 | New FHL Archives Search
Date: 2006-10-06 00:30:28 UTC
Subject: [ferrethealth] Ferrets in research

Ferrets in influenza vaccine and influenza inhibitor research.

Strong local and systemic protective immunity induced in the ferret model b=
y an intranasal virosome-formulated influenza subunit vaccine
Lambkin R, Oxford JS, Bossuyt S, Mann A, Metcalfe IC, Herzog C, Viret JF, G=
luck R.

Department of Medical Microbiology and Retroscreen Virology, St. Bartholome=
w's and the Royal London, Queen Mary School of Medicine and Dentistry, Univ=
ersity of London, 327 Mile End Road, London E1 4NS, UK.

The proliferation of influenza viruses causes costly, recurrent, annual epi=
demics. Current vaccines, mainly administered parenterally, have been shown=
to be suboptimal in terms of efficacy, particularly where local IgA respon=
ses are concerned. Recent investigations of virosomes as delivery systems f=
or viral HA and NA antigens have demonstrated an improved immune response. =
This paper investigates the efficacy of a novel virosome-based intranasal i=
nfluenza vaccine by its ability to reduce disease symptoms and its effect o=
n viral shedding in nasal secretions of immunised ferrets. The use of ferre=
ts in the study of influenza vaccines is based on the good comparability be=
tween ferret and human response to the disease. Intranasal, as opposed to p=
arenteral, administration of a trivalent virosome-based subunit vaccine adj=
uvanted with HLT provides an almost total prevention of virus shedding comb=
ined with a high level of immunological protection against homologous virus=
challenge. The ease of application of an intranasal vaccine may have posit=
ive repercussions in the adoption of influenza vaccinations, particularly i=
n 'at-risk' groups.
PMID: 15474733 [PubMed - indexed for MEDLINE]

Protection afforded by intranasal immunization with the neuraminidase-lacki=
ng mutant of influenza A virus in a ferret model.
Mishin VP, =

Nedyalkova MS, =

Hayden FG, =

Gubareva LV.

Division of Infectious Diseases and International Health, Department of Int=
ernal Medicine, Health Sciences Center, University of Virginia, 1300 Jeffer=
son Park Avenue, P.O. Box 800473, Charlottesville, Virginia 22908, USA.

Protective efficacy of the intranasal immunization with the neuraminidase (=
NA)-deficient mutant of the influenza A virus was investigated in ferrets. =
Despite the highly attenuated replication in vivo, the mutant completely pr=
otected the animals against the wild type virus challenge. When challenge w=
as done with antigenic drift variants, significant reductions in the viral =
titers, inflammatory cell counts, and protein concentrations were observed =
in the nasal washes of the immunized animals. The genetically engineered NA=
-deficient mutant also protected animals against the challenge and induced =
humoral immune response against the foreign protein that replaced the NA. W=
e conclude that the NA as antigen is dispensable in the live attenuated inf=
luenza virus vaccine and that the NA-lacking mutant can be used as a virus =
PMID: 15780741 [PubMed - indexed for MEDLINE]

Interfering vaccine (defective interfering influenza A virus) protects ferr=
ets from influenza, and allows them to develop solid immunity to reinfectio=
Mann A, =

Marriott AC, =

Balasingam S, =

Lambkin R, =

Oxford JS, =

Dimmock NJ.

Retroscreen Virology Ltd., Barts and London Hospital Medical School, 327 Mi=
le End Road, London E1 4NS, UK.

Defective interfering (DI) virus RNAs result from major deletions in full-l=
ength viral RNAs that occur spontaneously during de novo RNA synthesis. The=
se RNAs are packaged into virions that are by definition non-infectious, an=
d are delivered to cells normally targeted by the virion. DI RNAs can only =
replicate with the aid of a coinfecting infectious helper virus, but the sm=
all size of DI RNA allows more copies of it to be made than of its full-len=
gth counterpart, so the cell produces defective virions in place of infecti=
ous progeny. In line with this scenario, the expected lethal disease in an =
influenza A virus-mouse model is made subclinical by administration of DI v=
irus, but animals develop solid immunity to the infecting virus. Hence DI v=
irus has been called an 'interfering vaccine'. Because interfering vaccine =
acts intracellularly and at a molecular level, it should be effective again=
st all influenza A viruses regardless of subtype. Here we have used the fer=
ret, widely acknowledged as the best model for human influenza. We show tha=
t an interfering vaccine with defective RNAs from an H3N8 virus almost comp=
letely abolished clinical disease caused by A/Sydney/5/97 (H3N2), with abro=
gation of fever and significant reductions in clinical signs of illness. An=
imals recovered fully and were solidly immune to reinfection, in line with =
the view that treatment converts the otherwise virulent disease into a subc=
linical and immunizing infection.
PMID: 16621180 [PubMed - indexed for MEDLINE]

Oral Administration of Cyclopentane Neuraminidase Inhibitors Protects Ferre=
ts against Influenza Virus Infection
Clive Sweet,1* Kenneth J. Jakeman,1 Karen Bush,2 Pamela C. Wagaman,3 Linda =
A. Mckown,4 Anthony J. Streeter,4 Daksha Desai-Krieger,4 Pooran Chand,5 and=
Yarlagadda S. Babu5 =

School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 =
2TT, United Kingdom,1 The R. W. Johnson Pharmaceutical Research Institute, =
Raritan, New Jersey,2 The R. W. Johnson Pharmaceutical Research Institute, =
La Jolla, California,3 The R. W. Johnson Pharmaceutical Research Institute,=
Spring House, Pennsylvania,4 BioCryst Pharmaceuticals, Inc., Birmingham, A=

Received 7 August 2001/ Returned for modification 16 November 2001/ Accepte=
d 4 January 2002

Several cyclopentane inhibitors of influenza virus neuraminidase that have =
inhibitory activities in tissue culture similar to those of zanamivir and o=
seltamivir have recently been described. These new inhibitors have been exa=
mined for efficacy against a virulent H3N2 influenza virus when administere=
d orally to infected ferrets. Preliminary studies indicated that oral admin=
istration of BCX-1923, BCX-1827, or BCX-1812 (RWJ-270201) at a dose of 5 or=
25 mg/kg of body weight was active in ferrets in reducing respiratory and =
constitutional signs and symptoms, but these antivirals affected virus tite=
rs in the upper and lower respiratory tracts only marginally. Of the three =
compounds, BCX-1812 seemed to be the most efficacious and was examined furt=
her at higher doses of 30 and 100 mg/kg. These doses significantly reduced =
peak virus titers in nasal washes and total virus shedding as measured by a=
reas under the curve. Virus titers in lung homogenates were also reduced co=
mpared to those in controls, but the difference was not statistically signi=
ficant. As was observed with BCX-1812 at lower doses, the nasal inflammator=
y cellular response, fever, and nasal signs were reduced while ferret activ=
ity was not, with activity remaining similar to uninfected animals.

Peramivir (BCX-1812, RWJ-270201): potential new therapy for influenza
Donald F Smee, Robert W Sidwell
Institute for Antiviral Research, Utah State University, Logan, UT 84322-56=
00, USA, Tel: +1 435 797 1902; Fax: +1 435 797 3959;, E-mail: rsidwell@cc.u=

The cyclopentane peramivir (BCX-1812, RWJ-270201) is a highly selective inh=
ibitor of influenza A and B virus neuraminidases and a potent inhibitor of =
influenza A and B virus replication in cell culture. The in vitro potency a=
ppears to be greater than either zanamivir or oseltamivir carboxylate based=
on the generally lower EC50 values seen using peramivir in studies run in =
parallel with each compound. In mice infected with influenza A or B viruses=
, oral treatment with peramivir was highly effective in preventing death, s=
igns of the disease and in lowering lung virus titres. Similar effects were=
seen in influenza A virus-infected ferrets. Efficacy was seen in mice when=
therapy began after virus exposure. Peramivir is non-toxic in mice and rat=
s at doses of ≥ 1000 mg/kg/day and ferrets tolerated doses of ≥=
100 mg/kg/day. Doses of 100 mg/kg/day do not appear to affect murine immun=
e parameters. A pharmacokinetic study of this compound in influenza virus-i=
nfected mice indicates once-, twice- or thrice-daily oral dosing was equal =
in efficacy; once-daily dosing has been recommended in clinical trials of i=
nfluenza therapy. Treatment of influenza virus infections in cyclophosphami=
de-immunosuppressed mice was effective in inhibiting the infection; an infe=
ction induced in severe combined immunodeficient mice was only weakly affec=
ted. Development of viral resistance to peramivir can occur by serial cell =
culture passage of the virus in the presence of the compound but the resist=
ant virus was less virulent than the wild type virus. Viruses with neuramin=
idase mutations are not necessarily all cross-resistant to peramivir, zanam=
ivir and oseltamivir carboxylate. In Phase I studies, peramivir was well-to=
lerated, with single or multiple oral doses up to 800 mg/kg/day evaluated. =
In clinical trials with patients experimentally infected with influenza A o=
r B viruses, oral treatment with peramivir significantly reduced nasal wash=
virus titres with no adverse effects. Phase III clinical trials are underw=

Tony, Sugar and Suki
In memory of ally and Sue



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