The current state of H5N1 vaccines and the use of the ferret model for influenza therapeutic and prophylactic development

Highly pathogenic avian influenza H5N1 is a threat to global public health as a natural pandemic causing agent but has recently been considered a bioterrorism concern. The evolving view of the H5N1 virus necessitates the re-evaluation of the current status of H5N1 therapeutics and prophylactics, in particular the preparation of viable H5N1 vaccination strategies as well as the use of ferrets in influenza research. Here the highly pathogenic H5N1 virus dilemma is discussed in context with the current H5N1 vaccine status and the use of the ferret model. Previously, the development of various H5N1 vaccine platforms have been attempted, many of them tested in the ferret model, including vector vaccines, adjuvant vaccines, DNA vaccines, and reverse engineered vaccines. Moreover, as ferrets are a superlative animal model for influenza investigation and vaccine testing, it is imperative that this model is recognized for its uses in prophylactic development and not only as an agent for creating transmissible influenza viruses. Elucidating the ferret immune response and creating ferret immune reagents remain important goals in conjunction with the development and manufacture of H5N1 vaccines. In summary, an efficacious H5N1 vaccine is urgently needed and the ferret model remains an appropriate model for its development.

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Apoptotic and Early Innate Immune Responses to PB1-F2 Protein of Influenza A Viruses Belonging to Different Subtypes in Human Lung Epithelial A549 Cells

Advances in Virology ◽

10.1155/2018/5057184 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12

Author(s):

Gunisha Pasricha ◽

Sanjay Mukherjee ◽

Alok K. Chakrabarti

Keyword(s):

Inflammatory Response ◽

Influenza A ◽

H5n1 Virus ◽

A549 Cells ◽

Terminal Region ◽

Influenza Viruses ◽

Influenza A Viruses ◽

Highly Pathogenic ◽

Lung Epithelial ◽

Pathogenic H5n1

PB1-F2 is a multifunctional protein and contributes to the pathogenicity of influenza A viruses. PB1-F2 is known to have strain and cell specific functions. In this study we have investigated the apoptotic and inflammatory responses of PB1-F2 protein from influenza viruses of diverse pathogenicities in A549 lung epithelial cells. Overexpression of PB1-F2 resulted in apoptosis and heightened inflammatory response in A549 cells. Comparison revealed that the response varied with each subtype. PB1-F2 protein from highly pathogenic H5N1 virus induced least apoptosis but maximum inflammatory response. Results indicated that apoptosis was mediated through death receptor ligands TNFα and TRAIL via Caspase 8 activation. Significant induction of cytokines/chemokines CXCL10, CCL5, CCL2, IFNα, and IL-6 was noted in A549 cells transfected with PB1-F2 gene construct of 2008 West Bengal H5N1 virus (H5N1-WB). On the contrary, PB1-F2 construct from 2007 highly pathogenic H5N1 isolate (H5N1-M) with truncated N-terminal region did not evoke as exuberant inflammatory response as the other H5N1-WB with full length PB1-F2, signifying the importance of N-terminal region of PB1-F2. Sequence analysis revealed that PB1-F2 proteins derived from different influenza viruses varied at multiple amino acid positions. The secondary structure prediction showed each of the PB1-F2 proteins had distinct helix-loop-helix structure. Thus, our data substantiate the notion that the contribution of PB1-F2 to influenza pathogenicity is greatly strain specific and involves multiple host factors. This data demonstrates that PB1-F2 protein of influenza A virus, when expressed independently is minimally apoptotic and strongly influences the early host response in A549 cells.

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Potency of an inactivated influenza vaccine prepared from a non-pathogenic H5N1 virus against a challenge with antigenically drifted highly pathogenic avian influenza viruses in chickens

Veterinary Microbiology ◽

10.1016/j.vetmic.2013.01.041 ◽

2013 ◽

Vol 164 (1-2) ◽

pp. 39-45 ◽

Cited By ~ 15

Author(s):

Shintaro Shichinohe ◽

Masatoshi Okamatsu ◽

Naoki Yamamoto ◽

Yu Noda ◽

Yuka Nomoto ◽

...

Keyword(s):

Avian Influenza ◽

Influenza Vaccine ◽

H5n1 Virus ◽

Highly Pathogenic Avian Influenza ◽

Influenza Viruses ◽

Avian Influenza Viruses ◽

Highly Pathogenic ◽

Pathogenic Avian Influenza ◽

Pathogenic H5n1

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Inactivated influenza H5N1 whole-virus vaccine with aluminum adjuvant induces homologous and heterologous protective immunities against lethal challenge with highly pathogenic H5N1 avian influenza viruses in a mouse model

Vaccine ◽

10.1016/j.vaccine.2007.01.083 ◽

2007 ◽

Vol 25 (18) ◽

pp. 3554-3560 ◽

Cited By ~ 58

Author(s):

Ai Ninomiya ◽

Masaki Imai ◽

Masato Tashiro ◽

Takato Odagiri

Keyword(s):

Mouse Model ◽

Avian Influenza ◽

Virus Vaccine ◽

Influenza Viruses ◽

Avian Influenza Viruses ◽

Lethal Challenge ◽

Highly Pathogenic ◽

H5n1 Avian Influenza ◽

Pathogenic H5n1 ◽

Influenza H5n1

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Efficacy of Oseltamivir Therapy in Ferrets Inoculated with Different Clades of H5N1 Influenza Virus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01312-06 ◽

2007 ◽

Vol 51 (4) ◽

pp. 1414-1424 ◽

Cited By ~ 118

Author(s):

Elena A. Govorkova ◽

Natalia A. Ilyushina ◽

David A. Boltz ◽

Alan Douglas ◽

Neziha Yilmaz ◽

...

Keyword(s):

H5n1 Virus ◽

Direct Sequencing ◽

Influenza Viruses ◽

Upper Respiratory Tract ◽

Virus Inoculation ◽

Highly Pathogenic ◽

H5n1 Influenza ◽

Homologous Virus ◽

Ha1 Gene ◽

Pathogenic H5n1

ABSTRACT Highly pathogenic H5N1 influenza viruses have infected an increasing number of humans in Asia, with high mortality rates and the emergence of multiple distinguishable clades. It is not known whether antiviral drugs that are effective against contemporary human influenza viruses will be effective against systemically replicating viruses, such as these pathogens. Therefore, we evaluated the use of the neuraminidase (NA) inhibitor oseltamivir for early postexposure prophylaxis and for treatment in ferrets exposed to representatives of two clades of H5N1 virus with markedly different pathogenicities in ferrets. Ferrets were protected from lethal infection with the A/Vietnam/1203/04 (H5N1) virus by oseltamivir (5 mg/kg of body weight/day) given 4 h after virus inoculation, but higher daily doses (25 mg/kg) were required for treatment when it was initiated 24 h after virus inoculation. For the treatment of ferrets inoculated with the less pathogenic A/Turkey/15/06 (H5N1) virus, 10 mg/kg/day of oseltamivir was sufficient to reduce the lethargy of the animals, significantly inhibit inflammation in the upper respiratory tract, and block virus spread to the internal organs. Importantly, all ferrets that survived the initial infection were rechallenged with homologous virus after 21 days and were completely protected from infection. Direct sequencing of the NA or HA1 gene segments in viruses isolated from ferret after treatment showed no amino acid substitutions known to cause drug resistance in conserved residues. Thus, early oseltamivir treatment is crucial for protection against highly pathogenic H5N1 viruses and the higher dose may be needed for the treatment of more virulent viruses.

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Host Genetic Variation Affects Resistance to Infection with a Highly Pathogenic H5N1 Influenza A Virus in Mice

Journal of Virology ◽

10.1128/jvi.00514-09 ◽

2009 ◽

Vol 83 (20) ◽

pp. 10417-10426 ◽

Cited By ~ 123

Author(s):

Adrianus C. M. Boon ◽

Jennifer deBeauchamp ◽

Anna Hollmann ◽

Jennifer Luke ◽

Malak Kotb ◽

...

Keyword(s):

Influenza Virus ◽

Influenza A ◽

H5n1 Virus ◽

Lethal Dose ◽

Influenza Virus Infection ◽

Virus Titer ◽

Influenza Viruses ◽

Highly Pathogenic ◽

H5n1 Influenza ◽

Pathogenic H5n1

ABSTRACT Despite the prevalence of H5N1 influenza viruses in global avian populations, comparatively few cases have been diagnosed in humans. Although viral factors almost certainly play a role in limiting human infection and disease, host genetics most likely contribute substantially. To model host factors in the context of influenza virus infection, we determined the lethal dose of a highly pathogenic H5N1 virus (A/Hong Kong/213/03) in C57BL/6J and DBA/2J mice and identified genetic elements associated with survival after infection. The lethal dose in these hosts varied by 4 logs and was associated with differences in replication kinetics and increased production of proinflammatory cytokines CCL2 and tumor necrosis factor alpha in susceptible DBA/2J mice. Gene mapping with recombinant inbred BXD strains revealed five loci or Qivr (quantitative trait loci for influenza virus resistance) located on chromosomes 2, 7, 11, 15, and 17 associated with resistance to H5N1 virus. In conjunction with gene expression profiling, we identified a number of candidate susceptibility genes. One of the validated genes, the hemolytic complement gene, affected virus titer 7 days after infection. We conclude that H5N1 influenza virus-induced pathology is affected by a complex and multigenic host component.

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Live attenuated H5N1 vaccine with H9N2 internal genes protects chickens from infections by both Highly Pathogenic H5N1 and H9N2 Influenza Viruses

Influenza and Other Respiratory Viruses ◽

10.1111/j.1750-2659.2012.00363.x ◽

2012 ◽

Vol 7 (2) ◽

pp. 120-131 ◽

Cited By ~ 6

Author(s):

Nguyen Tai Nang ◽

Byung Min Song ◽

Young Myong Kang ◽

Heui Man Kim ◽

Hyun Soo Kim ◽

...

Keyword(s):

Influenza Viruses ◽

Highly Pathogenic ◽

Pathogenic H5n1 ◽

H5n1 Vaccine

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New Clade 2.3.4.4b H5N1 Highly Pathogenic Avian Influenza Genotype Detected in Europe in 2021

10.21203/rs.3.rs-1110578/v1 ◽

2021 ◽

Author(s):

Alexander Nagy ◽

Lenka Černíková ◽

Martina Stará

Keyword(s):

Avian Influenza ◽

H5n1 Virus ◽

Highly Pathogenic Avian Influenza ◽

Influenza Viruses ◽

Avian Influenza Viruses ◽

Highly Pathogenic ◽

The Czech Republic ◽

Pathogenic Avian Influenza ◽

Single Genotype ◽

Influenza H5n1

Abstract Despite their widespread distribution, the clade 2.3.4.4b H5N1 viruses have so far only been known in a single genotype variant in Europe. In the study presented, we report the first detection of a new highly pathogenic avian influenza H5N1 genotype in geese and ducks from a backyard farm in the Czech Republic. Phylogenetic analysis has revealed that the Czech H5N1 virus retained the A/Eurasian_Wigeon/Netherlands/1/2020-like backbone with an altered PB2 segment from co-circulating low pathogenic avian influenza viruses.

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Antibody responses to avian influenza viruses in wild birds broaden with age

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2016.2159 ◽

2016 ◽

Vol 283 (1845) ◽

pp. 20162159 ◽

Cited By ~ 11

Author(s):

Sarah C. Hill ◽

Ruth J. Manvell ◽

Bodo Schulenburg ◽

Wendy Shell ◽

Paul S. Wikramaratna ◽

...

Keyword(s):

Avian Influenza ◽

Haemagglutination Inhibition ◽

Wild Birds ◽

Influenza Viruses ◽

Antibody Responses ◽

Immune Recognition ◽

Avian Influenza Viruses ◽

Highly Pathogenic ◽

Age Related ◽

Pathogenic H5n1

For viruses such as avian influenza, immunity within a host population can drive the emergence of new strains by selecting for viruses with novel antigens that avoid immune recognition. The accumulation of acquired immunity with age is hypothesized to affect how influenza viruses emerge and spread in species of different lifespans. Despite its importance for understanding the behaviour of avian influenza viruses, little is known about age-related accumulation of immunity in the virus's primary reservoir, wild birds. To address this, we studied the age structure of immune responses to avian influenza virus in a wild swan population ( Cygnus olor ), before and after the population experienced an outbreak of highly pathogenic H5N1 avian influenza in 2008. We performed haemagglutination inhibition assays on sampled sera for five avian influenza strains and show that breadth of response accumulates with age. The observed age-related distribution of antibody responses to avian influenza strains may explain the age-dependent mortality observed during the highly pathogenic H5N1 outbreak. Age structures and species lifespan are probably important determinants of viral epidemiology and virulence in birds.

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