Delay of innate immune responses following influenza B virus infection affects the development of robust antibody response in ferrets

Due to its natural influenza susceptibility, clinical signs, transmission, and similar sialic acid residue distribution, the ferret is the primary animal model for human influenza research. Antibodies generated following infection of ferrets with human influenza viruses are used in surveillance to detect antigenic drift and cross-reactivity with vaccine viruses and circulating strains. Inoculation of ferrets, with over 1500 human clinical influenza isolates (1998-2019) resulted in lower antibody responses (HI<1:160) to 86% (387/448) influenza B viruses (IBV) compared to 2.7% (30/1094) influenza A viruses (IAV). In this directed analysis, we show that the immune responses in ferrets inoculated with IBV (B/Victoria or B/Yamagata lineage) were delayed and reduced compared to IAV (A/H1pdm09 or A/H3N2). Analysis of innate gene expression in the ferret upper respiratory tract and peripheral blood indicated that IAV generated a strong inflammatory response, including an early activation of the interferon (IFN) response; whereas IBV elicited a delayed and reduced response. Serum levels of cytokines, chemokines, and IFNs were all much higher following IAV-infection than IBV-infection in ferrets. Pro-Inflammatory (MCP-1, MIP-1B, TNFA), IFN (IFNB, IFNG), TH1/TH2 (IP-10, IL-2), and T-effector (IL-12p40) proteins were significantly higher in sera of IAV-infected than IBV-infected ferrets over twenty-eight days following challenge. Serum levels of Type-I/II/III IFNs were detected following IAV-infection throughout the 28-day period and Type-III IFN was only detected by day 28 for IBV. An early increase in IFN-lambda levels corresponded to gene expression following IAV-infection. Reduced innate immune responses detected following IBV-infection reflected the subsequent delayed and reduced serum antibodies. Differences in serum antibody responses by IBV were not observed in antibody secreting cells in the spleen or peripheral blood. These findings help in understanding the antibody responses in humans following IBV vaccination or infection and consideration of potential addition of innate immunomodulators to overcome low responses.