Infection of Ferrets with Influenza Virus Elicits a Light Chain–Biased Antibody Response against Hemagglutinin

Abstract

The domestic ferret () is a commonly used animal model for the study of influenza virus infection and vaccination. Recently, our group has developed murine mAbs with specificity for the κ (Igκ) and λ (Igλ) L chains of ferret Ig. These mAbs were used to quantify the abundance of Igκ and Igλ in serum and to evaluate L chain usage of the Ab response against the hemagglutinin (HA) protein elicited by influenza infection. After influenza A infection of immunologically naive ferrets with various H1N1 or H3N2 strains, the acute Ab response against HA exhibited an inherent bias toward λ L chain usage. In contrast, secondary infection of H1N1 preimmune ferrets with an antigenically distinct H1N1 virus elicited a recall response against the original HA that was no longer biased toward Igλ and possessed differential specificity. Moreover, sequential infection of ferrets with H1N1 influenza viruses elicited an Igκ-biased Ab response directed against the HA globular head and stem regions. Furthermore, sequential infection of ferrets with viral vectors expressing chimeric HA, aimed at boosting Ab reactivity against the HA stem region, also elicited an Igκ-biased response. Collectively, these findings suggest that ferret B cells expressing an Igκ or Igλ BCR possess differential specificities, and highlight the utility of our recently developed mAbs for studying the immune response to influenza virus infection and vaccination in the ferret model.

Preexisting subtype immunodominance shapes memory B cell recall response to influenza vaccination

“…Full-length HA proteins were developed for each of the Fluozone 2016/17 quadrivalent vaccine components: H1N1, H3N2, Victoria-lineage, and Yamagata-lineage. Chimeric HA proteins were generated with the globular head portion of A/mallard/Sweden/81/2002 (A/H6N2) in the context of A/ California/07/2009 (A/H1N1 pan ) stem (cH6/1) or A/Anhui/1-YK/2013 (A/H7/N2) in the context of A/ Perth/16/2009 (A/H3N2) stem, as previously described (78,79). Correct stem conformation was validated by ELISA using CR6261 or CR8020 stem-directed monoclonal antibodies.…”

Comprehensive analysis of N-glycans in IgG purified from ferrets with or without influenza A virus infection

“…It has been reported that an abundance of sialylated Fc glycans predicts influenza vaccine efficiency in humans (21). In ferrets, influenza exposure elicits a light chain-biased antibody response against the surface glycoprotein hemagglutinin (HA) (18). The shift of ferret IgG glycan profiles observed in this study might be a programmed inflammatory reaction after exposure to influenza virus or may just reflect an augmented antibody-mediated immune response in infected ferrets or decreased/increased clearance of certain glycoforms.…”

“…Because of this human-like respiratory physiology in ferrets, antisera collected from influenzainfected experimental ferrets have been used as reference standards to monitor virus antigenic changes for annual influenza vaccine strain selection (7)(8)(9)(10). However, ferret antibodies have also been shown to target antigenic epitopes on influenza viruses differently than human antibodies (11)(12)(13)(14)(15)(16)(17)(18). This difference between ferret immunity and human immunity is one of the factors responsible for influenza vaccine strain mismatch (7,19).…”

Immune Imprinting in the Influenza Ferret Model

“…Before this reagent development, research was limited to characterizing serum and nasal washes for neutralizing antibodies and measuring clinical signs after infection. Therefore, future studies can capture the cellular immune reactions of T-cell responses with IFN-γ ELISAs [120], peripheral blood leukocyte tracking [121], and ELISpots [88,122], as well as the humoral immunity [18,92,123,124].…”