Influenza A viruses with truncated NS1 as modified live virus vaccines: pilot studies of safety and efficacy in horses.
BACKGROUND
Three previously described NS1 mutant equine influenza viruses encoding carboxy-terminally truncated NS1 proteins are impaired in their ability to inhibit type I IFN production in vitro and are replication attenuated, and thus are candidates for use as a modified live influenza virus vaccine in the horse.


OBJECTIVE
One or more of these mutant viruses is safe when administered to horses, and recipient horses when challenged with wild-type influenza have reduced physiological and virological correlates of disease.


METHODS
Vaccination and challenge studies were done in horses, with measurement of pyrexia, clinical signs, virus shedding and systemic proinflammatory cytokines.


RESULTS
Aerosol or intranasal inoculation of horses with the viruses produced no adverse effects. Seronegative horses inoculated with the NS1-73 and NS1-126 viruses, but not the NS1-99 virus, shed detectable virus and generated significant levels of antibodies. Following challenge with wild-type influenza, horses vaccinated with NS1-126 virus did not develop fever (>38.5 degrees C), had significantly fewer clinical signs of illness and significantly reduced quantities of virus excreted for a shorter duration post challenge compared to unvaccinated controls. Mean levels of proinflammatory cytokines IL-1beta and IL-6 were significantly higher in control animals, and were positively correlated with peak viral shedding and pyrexia on Day +2 post challenge.


CONCLUSIONS
These data suggest that the recombinant NS1 viruses are safe and effective as modified live virus vaccines against equine influenza. This type of reverse genetics-based vaccine can be easily updated by exchanging viral surface antigens to combat the problem of antigenic drift in influenza viruses.
Chambers
T M
TM
Department of Veterinary Science, University of Kentucky, Lexington, Kentucky, USA.
Quinlivan
M
M
Sturgill
T
T
Cullinane
A
A
Horohov
D W
DW
Zamarin
D
D
Arkins
S
S
García-Sastre
A
A
Palese
P
P
D000281:Administration, Intranasal; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood*; D016207:Cytokines / Q000096:biosynthesis; D006734:Horse Diseases / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D006736:Horses; D053123:Influenza A Virus, H3N8 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000009:adverse effects / Q000235:genetics / Q000276:immunology*; D009330:Nebulizers and Vaporizers / Q000662:veterinary; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000517:prevention & control / Q000662:veterinary* / Q000821:virology; D010865:Pilot Projects; D011995:Recombination, Genetic; D012449:Safety; D013997:Time Factors; D016896:Treatment Outcome; D014611:Vaccination / Q000662:veterinary; D014613:Vaccines, Attenuated / Q000009:adverse effects / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000276:immunology; D017201:Virus Shedding
D000914:Antibodies, Viral; D016207:Cytokines; C085820:INS1 protein, influenza virus; D007252:Influenza Vaccines; D014613:Vaccines, Attenuated; D017361:Viral Nonstructural Proteins