Matrix Protein 2 Extracellular Domain-Specific Monoclonal Antibodies Are an Effective and Potentially Universal Treatment for Influenza A

Despite a seasonal vaccine and multiple therapeutic treatments, influenza A remains a significant threat to human health. The biggest obstacle in producing a vaccine or treatment for influenza A is their universality or efficacy against not only seasonal variances in the influenza virus but also all human, avian, and swine serotypes and, therefore, potential pandemic strains. ABSTRACT Influenza virus infection causes significant morbidity and mortality worldwide. Humans fail to make a universally protective memory immune response to influenza A. Hemagglutinin and neuraminidase undergo antigenic drift and shift, resulting in new influenza A strains to which humans are naive. Seasonal vaccines are often ineffective, and escape mutants have been reported to all treatments for influenza A. In the absence of a universal influenza A vaccine or treatment, influenza A will remain a significant threat to human health. The extracellular domain of the M2-ion channel (M2e) is an ideal antigenic target for a universal therapeutic agent, as it is highly conserved across influenza A serotypes, has a low mutation rate, and is essential for viral entry and replication. Previous M2e-specific monoclonal antibodies (M2e-MAbs) show protective potential against influenza A; however, they are either strain specific or have limited efficacy. We generated seven murine M2e-MAbs and utilized in vitro and in vivo assays to validate the specificity of our novel M2e-MAbs and to explore the universality of their protective potential. Our data show our M2e-MAbs bind to the M2e peptide, HEK cells expressing the M2 channel, as well as influenza virions, and MDCK-ATL cells infected with influenza viruses of multiple serotypes. Our antibodies significantly protect BALB/c mice that are highly susceptible to influenza A virus from lethal challenge with H1N1 A/PR/8/34, pH1N1 A/CA/07/2009, H5N1 A/Vietnam/1203/2004, and H7N9 A/Anhui/1/2013 by improving survival rates and weight loss. Based on these results, at least four of our seven M2e-MAbs show strong potential as universal influenza A treatments. IMPORTANCE Despite a seasonal vaccine and multiple therapeutic treatments, influenza A remains a significant threat to human health. The biggest obstacle in producing a vaccine or treatment for influenza A is their universality or efficacy against not only seasonal variances in the influenza virus but also all human, avian, and swine serotypes and, therefore, potential pandemic strains. The extracellular domain of the M2-ion channel (M2e) has huge potential as a target for a vaccine or treatment against influenza A. It is the most conserved external protein on the virus. Antibodies against M2e have made it to clinical trials but have not succeeded. Here, we describe novel M2e antibodies produced in mice that are protective at low doses; we also extensively tested them to determine their universality and found them to be cross protective against all strains tested. Additionally, our work begins to elucidate the critical role of isotype for an influenza A monoclonal antibody therapeutic.