Cross-Lineage Influenza B and Heterologous Influenza A Antibody Responses in Vaccinated Mice: Immunologic Interactions and B/Yamagata Dominance

Abstract

The annually reformulated trivalent inactivated influenza vaccine (TIV) includes both influenza A/subtypes (H3N2 and H1N1) but only one of two influenza B/lineages (Yamagata or Victoria). In a recent series of clinical trials to evaluate prime-boost response across influenza B/lineages, influenza-naïve infants and toddlers originally primed with two doses of 2008–09 B/Yamagata-containing TIV were assessed after two doses of B/Victoria-containing TIV administered in the subsequent 2009–10 and 2010–11 seasons. In these children, the Victoria-containing vaccines strongly recalled antibody to the initiating B/Yamagata antigen but induced only low B/Victoria antibody responses. To further evaluate this unexpected pattern of cross-lineage vaccine responses, we conducted additional immunogenicity assessment in mice. In the current study, mice were primed with two doses of 2008–09 Yamagata-containing TIV and subsequently boosted with two doses of 2010–11 Victoria-containing TIV (Group-Yam/Vic). With the same vaccines, we also assessed the reverse order of two-dose Victoria followed by two-dose Yamagata immunization (Group-Vic/Yam). The Group-Yam/Vic mice showed strong homologous responses to Yamagata antigen. However, as previously reported in children, subsequent doses of Victoria antigen substantially boosted Yamagata but induced only low antibody response to the immunizing Victoria component. The reverse order of Group-Vic/Yam mice also showed low homologous responses to Victoria but subsequent heterologous immunization with even a single dose of Yamagata antigen induced substantial boost response to both lineages. For influenza A/H3N2, homologous responses were comparably robust for the differing TIV variants and even a single follow-up dose of the heterologous strain, regardless of vaccine sequence, substantially boosted antibody to both strains. For H1N1, two doses of 2008–09 seasonal antigen significantly blunted response to two doses of the 2010–11 pandemic H1N1 antigen. Immunologic interactions between influenza viruses considered antigenically distant and in particular the cross-lineage influenza B and dominant Yamagata boost responses we have observed in both human and animal studies warrant further evaluation.

Comparison of immunogenicity of cell-and egg-passaged viruses for manufacturing MDCK cell culture-based influenza vaccines

“…In this present study, no amino acid change was detected in the main antigens (either HA or NA) of influenza cell seed viruses after three passages in suspension MDCK cells. However, a mutation that already existed in egg seed viruses as previously discussed has been maintained in cell seed viruses (Skowronski et al, 2012). These results are in agreement with previous observations that propagation of influenza viruses in mammalian cells may induce less mutation than that in eggs (Suphaphiphat et al, 2010).…”

“…No change was observed in the amino acid sequence of either HA or NA of all three cellpassaged viruses after three passages in suspension MDCK cells. B/Brisbane/60/2008 had one mutation (N212S) in HA compared to the reference wild-type strain; however, this mutation already existed in the candidate vaccine virus obtained from NIBSC as previously discussed (Skowronski et al, 2012). This mutation, which may result from egg adaptation, did not induce any reversion after propagation three times in MDCK cells.…”

Endocine™, N3OA and N3OASq; Three Mucosal Adjuvants That Enhance the Immune Response to Nasal Influenza Vaccination

“…Interestingly, in the Skowronski study, also the A/H1N1/Brisbane/59/2009 strain was included. They demonstrated that the immunogenicity against the A/H1N1/Brisbane strain was relatively poor in contrast to the compared A/H1N1/California/7/2009 strain that also was included in the study [38]. Thus in this study, our nasal TIV vaccine candidate (with Endocine™ or N3OA) obtained fair humoral IgG immune responses towards all three influenza strains (A/H1N1/Brisbane/59/2007, A/H3N2/Brisbane/10/2007 and the B/Brisbane/60/2008) in comparison to what was obtained with the TIV given parentally.…”

Randomized Controlled Ferret Study to Assess the Direct Impact of 2008–09 Trivalent Inactivated Influenza Vaccine on A(H1N1)pdm09 Disease Risk

“…The potency of all three vaccine strains of the post-expiry but cold-chain maintained 2008-09 Fluviral lot that was used was confirmed by single radial immuno-diffusion (SRID) testing by the Center for Biologics Evaluation and Research, United States (US) Food and Drug Administration (FDA) [21]. US specifications require $27 mg/mL hemagglutinin (HA) for each antigen (dose 0.5 mL) based on the mean of three tests, with additional requirements around the standard deviation (SD).…”