Influenza A viruses with truncated NS1 as modified live virus vaccines: Pilot studies of safety and efficacy in horses

Chambers, Thomas M.; Quinlivan, Michelle; Sturgill, Tracy L.; Cullinane, Ann; Horohov, David W.; Zamarin, Dmitriy; Arkins, Seán; Garcı́a-Sastre, Adolfo; Palese, Peter

doi:10.2746/042516408x371937

Cited by 51 publications

(54 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Biphasic febrile responses are often observed in horses infected with EIV and are reproducibly observed in horses experimentally inoculated with the virus via an ultrasonic nebulizer in the evaluation of the efficacy of vaccines or antiviral agents [5, 10, 15, 19, 25]. The initial febrile response that occurs 2 or 3 days after inoculation is considered to be related mainly to viral replication in the respiratory epithelial cells.…”

mentioning

confidence: 99%

Time-related Pathological Changes in Horses Experimentally Inoculated with Equine Influenza A Virus

Muranaka

Yamanaka

Katayama

et al. 2012

JES

View full text Add to dashboard Cite

To investigate the pathology of equine influenza, necropsy of 7 horses experimentally infected with equine influenza A virus (EIV) subtype H3N8 was conducted on post-infection days (PID) 2, 3, 7, and 14. Histopathologically, rhinitis or tracheitis including epithelial degeneration or necrosis with loss of ciliated epithelia and a reduction in goblet cell numbers, was observed in the respiratory tracts on PIDs 2 and 3. Epithelial hyperplasia or squamous metaplasia and suppurative bronchopneumonia with proliferation of type II pneumocytes were observed on PIDs 7 and 14. Viral antigen was detected immunohistochemically in the epithelia of the nasal mucosa, trachea, and bronchi on PIDs 2 and 3. The sodA gene of Streptococcus equi subsp. zooepidemicus , a suspected cause of suppurative bronchopneumonia, was detected in paraffin-embedded lung tissue sections, but only on PIDs 7 and 14. These findings suggest that damage caused to ciliated epithelia and goblet cells by EIV infection results in secondary bacterial bronchopneumonia due to a reduction in mucociliary clearance.

show abstract

mentioning

confidence: 99%

Time-related Pathological Changes in Horses Experimentally Inoculated with Equine Influenza A Virus

Muranaka

Yamanaka

Katayama

et al. 2012

JES

View full text Add to dashboard Cite

show abstract

“…Indeed, NS1 mutant influenza viruses are potent activators of dendritic cells (14,26) and potent immunostimulators (15). NS1-modified live attenuated vaccines have furthermore been shown to be safe and efficacious in swine, equine, and poultry hosts challenged with homologous or heterologous influenza virus isolates (12,40,42,43,50).…”

mentioning

confidence: 99%

Blocking Interhost Transmission of Influenza Virus by Vaccination in the Guinea Pig Model

Lowen¹,

Steel²,

Mubareka³

et al. 2009

J Virol

View full text Add to dashboard Cite

Interventions aimed at preventing viral spread have the potential to effectively control influenza virus in all age groups, thereby reducing the burden of influenza illness. For this reason, we have examined the efficacy of vaccination in blocking the transmission of influenza viruses between guinea pigs. Three modes of immunization were compared: (i) natural infection; (ii) intramuscular administration of whole, inactivated influenza virus in 2 doses; and (iii) intranasal inoculation with live attenuated influenza virus in 2 doses. The ability of each immunization method to block the spread of a homologous (A/Panama/2007/99) H3N2 subtype and a heterologous (A/Wisconsin/67/05) H3N2 subtype influenza virus was tested. We found that previous infection through a natural route provided sterilizing immunity against both homologous and heterologous challenges; thus, no transmission to or from previously infected animals was observed. Vaccination with an inactivated influenza virus vaccine, in contrast, did not prevent guinea pigs from becoming infected upon challenge with either virus. Thus, both intranasal inoculation and exposure to an acutely infected guinea pig led to the infection of vaccinated animals. Vaccination with inactivated virus did, however, reduce viral load upon challenge and decrease the number of secondary transmission events from vaccinated animals to naïve cage mates. Vaccination with a live attenuated virus was found to be more efficacious than vaccination with inactivated virus, resulting in sterilizing immunity against homologous challenge and full protection against the transmission of the homologous and heterologous viruses to naïve contacts. In conclusion, we have shown that the guinea pig model can be used to test influenza virus vaccines and that the efficiency of transmission is a valuable readout when vaccine efficacy is evaluated.

show abstract

“…Differences in pathogenicity between EIVs are linked to the induction of different levels of such pro-inflammatory cytokines as IL-6 and IFN-α [32], [33]. Studies in horses have focused on the role of the NS1 protein (which interferes with the induction of type 1 interferon [34]) in cytokine production. However, virulent variants of PB1-F2 proteins with inflammatory and cytotoxic residues also have potential to contribute to this phenomenon.…”

Section: Resultsmentioning

confidence: 99%

Non-Avian Animal Reservoirs Present a Source of Influenza A PB1-F2 Proteins with Novel Virulence-Enhancing Markers

2014

View full text Add to dashboard Cite

PB1-F2 protein, expressed from an alternative reading frame of most influenza A virus (IAV) PB1 segments, may possess specific residues associated with enhanced inflammation (L62, R75, R79, and L82) and cytotoxicity (I68, L69, and V70). These residues were shown to increase the pathogenicity of primary viral and secondary bacterial infections in a mouse model. In contrast to human seasonal influenza strains, virulence-associated residues are present in PB1-F2 proteins from pandemic H1N1 1918, H2N2 1957, and H3N2 1968, and highly pathogenic H5N1 strains, suggesting their contribution to viruses' pathogenic phenotypes. Non-human influenza strains may act as donors of virulent PB1-F2 proteins. Previously, avian influenza strains were identified as a potential source of inflammatory, but not cytotoxic, PB1-F2 residues. Here, we analyze the frequency of virulence-associated residues in PB1-F2 sequences from IAVs circulating in mammalian species in close contact with humans: pigs, horses, and dogs. All four inflammatory residues were found in PB1-F2 proteins from these viruses. Among cytotoxic residues, I68 was the most common and was especially prevalent in equine and canine IAVs. Historically, PB1-F2 from equine (about 75%) and canine (about 20%) IAVs were most likely to have combinations of the highest numbers of residues associated with inflammation and cytotoxicity, compared to about 7% of swine IAVs. Our analyses show that, in addition to birds, pigs, horses, and dogs are potentially important sources of pathogenic PB1-F2 variants. There is a need for surveillance of IAVs with genetic markers of virulence that may be emerging from these reservoirs in order to improve pandemic preparedness and response.

show abstract

Influenza A viruses with truncated NS1 as modified live virus vaccines: Pilot studies of safety and efficacy in horses

Cited by 51 publications

References 38 publications

Time-related Pathological Changes in Horses Experimentally Inoculated with Equine Influenza A Virus

Time-related Pathological Changes in Horses Experimentally Inoculated with Equine Influenza A Virus

Blocking Interhost Transmission of Influenza Virus by Vaccination in the Guinea Pig Model

Non-Avian Animal Reservoirs Present a Source of Influenza A PB1-F2 Proteins with Novel Virulence-Enhancing Markers

Contact Info

Product

Resources

About