The Intersection of Age and Influenza Severity: Utility of Ferrets for Dissecting the Age-Dependent Immune Responses and Relevance to Age-Specific Vaccine Development

Abstract

Many factors impact the host response to influenza virus infection and vaccination. Ferrets have been an indispensable reagent for influenza virus research for almost one hundred years. One of the most significant and well-known factors affecting human disease after infection is host age. Another significant factor is the virus, as strain-specific disease severity is well known. Studying age-related impacts on viral infection and vaccination outcomes requires an animal model that reflects both the physiological and immunological changes that occur with human aging, and sensitivity to differentially virulent influenza viruses. The ferret is uniquely susceptible to a plethora of influenza viruses impacting humans and has proven extremely useful in studying the clinical and immunological pictures of influenza virus infection. Moreover, ferrets developmentally have several of the age-related physiological changes that occur in humans throughout infancy, adulthood, old age, and pregnancy. In this review, we discuss ferret susceptibility to influenza viruses, summarize previous influenza studies using ferrets as models of age, and finally, highlight the application of ferret age models in the pursuit of prophylactic and therapeutic agents to address age-related influenza disease severity.

Sex and age bias viral burden and interferon responses during SARS-CoV-2 infection in ferrets

“…Then able to make two distinct comparisons, on where 1-year old females were compared to 1-year-old males and the other where 1-year-old males were compared to 2-year-old males. As ferrets reach sexual maturity by 8-months-old, 1-year-old ferrets correspond to adults 53 . By age 6 ferrets are considered elderly, making a 2-year-old ferret correspond to middle age in humans 54 .…”

“…As COVID-19 severity has been associated with the male sex and age, we investigated these biological variables and their contribution to disease in ferrets infected with SARS-CoV-2. Ferrets were chosen for our analysis since we have previous experience showing sex-effects and age-effects in regard to respiratory viral infection in this model 24 , 43 , 46 . We characterized sex- and age-related viral load and shedding as well as immune gene expression after SARS-CoV-2 infection.…”

Nonrespiratory sites of influenza‐associated disease: mechanisms and experimental systems for continued study

“…Virus-associated seizures, which are known to occur during CNS viral infections in ferrets [44,182,183], are one such example of a hyperthermia induced phenotype difficult to model in mice. In particular, ferrets are an appropriate model for the impact of age on the response to influenza infection [184], an issue highlighted in this review by pediatric patients' vulnerability to neurological effects of influenza and older populations greater risk for cardiac and muscular manifestations of disease. In further support of future ferret research, tools and reagents for studies in ferrets are increasingly available [185].…”

A linear SARS-CoV-2 DNA vaccine candidate reduces virus shedding in ferrets

“…Ferrets have been used as animal models to study various respiratory viruses including influenza and SARS-CoV-2 [29][30][31][32] and to assess pathogenesis, vaccine and drug efficacy and safety, as well as immune responses [31]. In addition to its extensive use to investigate influenza A virus, respiratory syncytial virus and SARS-CoV, the ferret model has been considered a reliable tool to dissect the pathogenesis transmission, and assess therapy and vaccination options for SARS-CoV-2 [29,31,[33][34][35].…”