11  Conclusion
As shown in this review, several species of laboratory animals have proved to be very useful for research on influenza. Mice, particularly the BALB/c strain, are currently intensively employed for studying pathogenesis, for demonstrating the efficacy of antiviral drugs, and for preliminary efficacy studies for vaccines. Studies with antiviral agents have shown the infection in mice to be predictive of efficacy in humans. For example, all of the currently approved drugs for treating influenza virus infections were first shown to be efficacious in mice. Although mice are not readily susceptible to newly isolated human seasonal influenza viruses and require virus adaptation, many highly pathogenic avian influenza strains require no adaptation and readily infect mice to cause lethal disease. Mice also do not exhibit some of the clinical symptoms detected in humans such as nasal exudate, fever, sneezing, and coughing. However, many clinical signs that seem to markers of disease severity can be measured in mice to study influenza disease, such as saturated oxygen levels, virus lung titers, cytokine levels, serum and acute phase proteins. In addition, the use of mouse models enable the investigator to rapidly evaluate the efficacy of antiviral agents and vaccines at relatively lesser costs than other animal models.
Ferrets are now being widely used to supplement or validate studies in mice, especially for H5N1 virus studies in order to comply with new FDA “two animal rule”. A tremendous advantage of ferrets is that these animals display many clinical symptoms of human influenza. The model also has a similar complexity to that of humans. However, as with the mouse model, many host factors found associated with humans are missing or have not yet been discovered in the ferret. The costs of ferrets, space needed for housing, temperament of the animal once handled experimentally, and the availability of animals without prior exposure to influenza remain of concern.
The other animal species that could be used as models have not been sufficiently studied for their suitability for routine use in studying influenza disease and influenza pathogenesis. In addition, immune reagents for some of these other species remain yet to be developed. The availability of some of the species is very limited, and the costs for housing and handling of some of the larger species are great.
Despite the evidence of the great influenza pandemic of 1918, which brought about the death of some 50 million people, influenza is often viewed as a “nuisance” disease, for which adequate countermeasures are already available. However, the recent emergence of the highly virulent H5N1 avian influenza virus in Southeast Asia has served as a wake-up call, reminding the medical community that novel influenza A viruses can unexpectedly enter the human population and that even the currently circulating seasonal strains are responsible for hundreds of thousands of deaths worldwide each year. Influenza A viruses, far from being benign respiratory pathogens, are a major public health problem that calls for a serious and sustained research response. An essential part of that process is the development of laboratory animal models of influenza virus infection for the study of pathogenesis and the evaluation of new drugs and vaccines. As described in this paper, a number of animal models have been developed, but many gaps remain. Many of the current models remain incompletely characterized, and none has been employed to its full potential. New and better models are needed to provide more accurate answers to critical questions in pathogenesis and therapy. It is hoped that this paper will contribute to the better use of laboratory animal models to combat the continuing threat of influenza.