Ferret model of avian influenza demonstrates dose and strain dependant pathology and viral load in brain

Layton, Robert C.; Armijo, Penny; Myers, Leslie; Knight, Jennifer; Donart, Nathaniel; Sannes‐Lowery, Kristin A.; Blyn, Lawrence B.; Gigliotti, Andrew P.; Kunder, Steven C.; Fomukong, N.G.; Harrod, Kevin S.; Koster, Frederick

doi:10.1016/j.provac.2009.07.006

Cited by 3 publications

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“…Ferrets infected with 1 to 7 log 10 PFU of A/Vietnam/1203/04 and A/Hong Kong/483/97 strains had positive viral cultures in olfactory bulbs 24 h after intranasal inoculation and prior to appearance of virus in spleens and brains [31] (unpublished data) , and has been demonstrated by Shinya and colleagues [57] . In the turbinate tissue at 24 h pi viral antigen localized primarily to the sensory epithelial cells interfacing with neurons penetrating the cribiform plate to synapse in the olfactory bulbs [31] (S Kunder et al, unpublished observations). If brain invasion occurs within 24 h of viral challenge, alum-adjuvanted vaccine may stimulate mucosal immunity in the nasal turbinates to prevent early invasion.…”

Section: Discussionmentioning

confidence: 52%

“…Olfactory bulb infection occurs in ferrets inoculated intranasally with high- and low- pathogenic H5N1 strains [30]. Ferrets infected with 1 to 7 log 10 PFU of A/Vietnam/1203/04 and A/Hong Kong/483/97 strains had positive viral cultures in olfactory bulbs 24 h after intranasal inoculation and prior to appearance of virus in spleens and brains [31] (unpublished data) , and has been demonstrated by Shinya and colleagues [57]. In the turbinate tissue at 24 h pi viral antigen localized primarily to the sensory epithelial cells interfacing with neurons penetrating the cribiform plate to synapse in the olfactory bulbs [31] (S Kunder et al, unpublished observations).…”

Section: Discussionmentioning

confidence: 99%

“…Only a few strains of H5N1 HPAI have been shown to be fatal in ferrets [30] . The strain we used, A/Vietnam/1203/2004, has been shown to be fatal in ferrets in intranasal doses from 10 1 to 10 7 EID 50 [16] , [30] , [31] , [32] . The high level of virulence of the VN/1203 strain in ferrets [29] is attributable to multiple viral elements including the multibasic amino acids in the HA hinge region and replication competence expressed in the polymerase enzyme complex [33] .…”

Section: Discussionmentioning

confidence: 99%

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Enhanced Immunogenicity, Mortality Protection, and Reduced Viral Brain Invasion by Alum Adjuvant with an H5N1 Split-Virion Vaccine in the Ferret

et al. 2011

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BackgroundPre-pandemic development of an inactivated, split-virion avian influenza vaccine is challenged by the lack of pre-existing immunity and the reduced immunogenicity of some H5 hemagglutinins compared to that of seasonal influenza vaccines. Identification of an acceptable effective adjuvant is needed to improve immunogenicity of a split-virion avian influenza vaccine.Methods and FindingsFerrets (N = 118) were vaccinated twice with a split-virion vaccine preparation of A/Vietnam/1203/2004 or saline either 21 days apart (unadjuvanted: 1.9 µg, 7.5 µg, 30 µg, or saline), or 28 days apart (unadjuvanted: 22.5 µg, or alum-adjuvanted: 22.5 or 7.5 µg). Vaccinated animals were challenged intranasally 21 or 28 days later with 106 EID50 of the homologous strain. Immunogenicity was measured by hemagglutination inhibition and neutralization assays. Morbidity was assessed by observed behavior, weight loss, temperature, cytopenias, histopathology, and viral load.No serum antibodies were detected after vaccination with unadjuvanted vaccine, whereas alum-adjuvanted vaccination induced a robust antibody response. Survival after unadjuvanted dose regimens of 30 µg, 7.5 µg and 1.9 µg (21-day intervals) was 64%, 43%, and 43%, respectively, yet survivors experienced weight loss, fever and thrombocytopenia. Survival after unadjuvanted dose regimen of 22.5 µg (28-day intervals) was 0%, suggesting important differences in intervals in this model. In contrast to unadjuvanted survivors, either dose of alum-adjuvanted vaccine resulted in 93% survival with minimal morbidity and without fever or weight loss. The rarity of brain inflammation in alum-adjuvanted survivors, compared to high levels in unadjuvanted vaccine survivors, suggested that improved protection associated with the alum adjuvant was due to markedly reduced early viral invasion of the ferret brain.ConclusionAlum adjuvant significantly improves efficacy of an H5N1 split-virion vaccine in the ferret model as measured by immunogenicity, mortality, morbidity, and brain invasion.

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Enhanced Immunogenicity, Mortality Protection, and Reduced Viral Brain Invasion by Alum Adjuvant with an H5N1 Split-Virion Vaccine in the Ferret

et al. 2011

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“…Thus, any protective effect of the unadjuvanted vaccine appeared to be mediated relatively late after day 5 post-infection, timing that is consistent with the onset of T-cell immunity [47]. In contrast, ferrets receiving adjuvanted vaccine did not experience any major morbidity, And most of the ferrets had no evidence of brain invasion, including the olfactory bulbs [48 and unpublished data]. Prevention of virus spread to the brain had been similarly noted in a study of alum-adjuvanted whole virion H5N1 vaccine [49], consistent with the idea that higher levels of neutralizing antibody induced by adjuvanted vaccine reduced brain invasion through olfactory neurons early in infection [50].…”

Section: Discussionmentioning

confidence: 99%

Delta inulin polysaccharide adjuvant enhances the ability of split-virion H5N1 vaccine to protect against lethal challenge in ferrets

Layton

Petrovsky

Gigliotti

et al. 2011

Vaccine

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Background The reduced immunogenicity of the H5 hemagglutinin (HA), compared to seasonal HA serotypes, has stimulated searches for effective adjuvants to improve H5 vaccine efficacy. This study examined the immunogenicity and protective efficacy in ferrets immunized with a split-virion H5N1 vaccine combined with Advax™, a novel delta inulin-based polysaccharide adjuvant technology that has previously demonstrated ability to augment humoral and cellular immunity to co-administered antigens. Methods Ferrets were vaccinated twice 21 days apart with 7.5 µg or 22.5 µg of a split-virion preparation of A/Vietnam/1203/2004 with or without adjuvant. An additional group received just one immunization with 22.5 µg HA plus adjuvant. Serum antibodies were measured by hemagglutination inhibition and microneutralization assays. Vaccinated animals were challenged intranasally 21 days after the last immunization with 106 EID50 of the homologous strain. Morbidity was assessed by observed behavior, weight loss, temperature, cytopenias, histopathology, and viral load. Results No serum neutralization antibody was detected after two immunizations with unadjuvanted vaccine. Two immunizations with high or low dose adjuvanted vaccine stimulated high neutralizing antibody titers. Survival was 100% in all groups receiving adjuvanted-vaccine including the single dose group, compared to 67% survival with unadjuvanted vaccine, and 0% survival in saline or adjuvant-alone controls. Minimal morbidity was seen in all animals receiving adjuvanted vaccine, and was limited to rhinorrhea and mild thrombocytopenia, without fever, weight loss, or reduced activity. H5N1 virus was cleared from the nasal wash by day 4 post-challenge only in animals receiving adjuvanted vaccine which also prevented viral invasion of the brain in most animals. Conclusions In this initial study, Advax™ adjuvant formulations improved the protective efficacy of a split-virion H5N1vaccine as measured by significantly enhanced immunogenicity, survival, and reduced morbidity.

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Cloned Defective Interfering Influenza Virus Protects Ferrets from Pandemic 2009 Influenza A Virus and Allows Protective Immunity to Be Established

Dimmock

Dove²,

Scott

et al. 2012

PLoS ONE

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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 µg 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.

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Ferret model of avian influenza demonstrates dose and strain dependant pathology and viral load in brain

Cited by 3 publications

References 0 publications

Enhanced Immunogenicity, Mortality Protection, and Reduced Viral Brain Invasion by Alum Adjuvant with an H5N1 Split-Virion Vaccine in the Ferret

Enhanced Immunogenicity, Mortality Protection, and Reduced Viral Brain Invasion by Alum Adjuvant with an H5N1 Split-Virion Vaccine in the Ferret

Delta inulin polysaccharide adjuvant enhances the ability of split-virion H5N1 vaccine to protect against lethal challenge in ferrets

Cloned Defective Interfering Influenza Virus Protects Ferrets from Pandemic 2009 Influenza A Virus and Allows Protective Immunity to Be Established

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