Multiple heterologous M2 extracellular domains presented on virus-like particles confer broader and stronger M2 immunity than live influenza A virus infection

Abstract

The influenza M2 ectodomain (M2e) is poorly immunogenic and has some amino acid changes among isolates from different host species. We expressed a tandem repeat construct of heterologous M2e sequences (M2e5x) derived from human, swine, and avian origin influenza A viruses on virus-like particles (M2e5x VLPs) in a membrane-anchored form. Immunization of mice with M2e5x VLPs induced protective antibodies cross-reactive to antigenically different influenza A viruses and conferred cross protection. Anti-M2e antibodies induced by heterologous M2e5x VLPs showed a wider range of cross reactivity to influenza virus at higher levels than those by live virus infection, homologous M2e VLPs, or M2e monoclonal antibody 14C2. Fc receptors were found to be important for mediating protection by immune sera from M2e5x VLP vaccination. The present study provides evidence that heterologous recombinant M2e5x VLPs can be more effective in inducing protective M2e immunity than natural virus infection and further supports an approach for developing an effective universal influenza vaccine.

Influenza M2 virus-like particles confer a broader range of cross protection to the strain-specific pre-existing immunity

“…A possible mechanism by which M2 antibodies provide protection is that influenza viruses bound to non-neutralizing antibodies are likely to be recognized and removed by opsonophagocytosis via Fc receptors [12, 23–27]. In this study, M2e specific antibody after M2e5x VLP immunization was reactive to M2-expressing MDCK cell or MDCK cells infected with influenza viruses, which suggests that binding antibody to infected cell can mediate opsonophagocytosis.…”

“…In our previous studies, M2e5x VLP was shown to confer effective cross protection against H1, H3, and H5 subtype influenza viruses [11–12]. Here, we investigated whether immunization with M2e5x VLPs would improve the efficacy of cross-protection against influenza A viruses in the presence of pre-existing vaccine immunity.…”

“…A molecular construct with M2e tandem repeat (M2e5x) that contains M2e sequences derived from human, swine, and avian influenza viruses was developed in a membrane-anchored form and presented on enveloped VLPs (M2e5x VLP) as a potential universal influenza A vaccine [11–12]. Most pre-clinical studies have been carried out using naïve animals.…”

A Novel Vaccination Strategy Mediating the Induction of Lung-Resident Memory CD8 T Cells Confers Heterosubtypic Immunity against Future Pandemic Influenza Virus

“…These results are consistent with previous studies reporting that M2e conjugate protein vaccines with adjuvants were shown to confer survival protection but not effective in preventing weight loss (40-42). Encouragingly, M2e5x VLP vaccination in the absence of adjuvants was effective in preventing weight loss as well as broadening cross protection against H1, H3, and H5 subtype IAVs (22, 43). Thus, as shown herein, it is highly significant that a universal vaccination strategy can provide superior cross protection to current vaccines in the scenario of when a first infecting virus is antigenically different from a vaccine strain.…”

Immunogenicity and efficacy of replication-competent recombinant influenza virus carrying multimeric M2 extracellular domains in a chimeric hemagglutinin conjugate

“…At day 7, lung samples were collected from three mice of each group to titer viruses. Lung extracts were prepared and the viral titers were determined (Kim et al, 2013a). …”