To evaluate the effect of a single NA amino acid substitution on the fitness of B/Yamanashi/166/1998-like viruses in a ferret model, we compared the disease progression (in terms of weight loss, temperature elevation, and activity score) and clinical signs of respiratory disease (sneezing and nasal discharge) induced by the parental rg-WT virus and the NAI-resistant rg-E119A and rg-H274Y viruses. The gene discussed is C4A; the disease is respiratory system disorder.