title: Universal vaccine against influenza virus: linking TLR signaling to anti-viral protection.
abstract: A vaccine protecting against all influenza strains is a long-sought goal, particularly for emerging pandemics. As previously shown, vaccines based on the highly conserved extracellular domain of M2 (M2e) may protect against all influenza A strains. Here, we demonstrate that M2e-specific monoclonal antibodies (mAbs) protect mice from a lethal influenza infection. To be protective, antibodies had to be able to bind to Fc receptors and fix complement. Furthermore, mAbs of IgG2c isotype were protective in mice, while antibodies of identical specificity, but of the IgG1 isotype, failed to prevent disease. These findings readily translated into vaccine design. A vaccine targeting M2 in the absence of a toll-like receptor (TLR) 7 ligand primarily induced IgG1, whilst the same vaccine linked to a TLR7 ligand yielded high levels of IgG2c antibodies. Although both vaccines protected mice from a lethal challenge, mice treated with the vaccine containing a TLR7 ligand showed significantly lower morbidity. In accordance with these findings, vaccination of TLR7(-/-) mice with a vaccine containing a TLR7 ligand did not result in protection from a lethal challenge. Hence, the innate immune system is required to direct isotype switching toward the more protective IgG2a/c antibodies.
authors.affiliation: Cytos Biotechnology AG, Schlieren-Zürich, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Schmitz
authors.forename: Roger R
authors.initials: RR
authors.lastname: Beerli
authors.forename: Monika
authors.initials: M
authors.lastname: Bauer
authors.forename: Andrea
authors.initials: A
authors.lastname: Jegerlehner
authors.forename: Klaus
authors.initials: K
authors.lastname: Dietmeier
authors.forename: Melanie
authors.initials: M
authors.lastname: Maudrich
authors.forename: Paul
authors.initials: P
authors.lastname: Pumpens
authors.forename: Philippe
authors.initials: P
authors.lastname: Saudan
authors.forename: Martin F
authors.initials: MF
authors.lastname: Bachmann
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000276:immunology / Q000494:pharmacology; D000914:Antibodies, Viral / Q000097:blood / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics; D017578:Immunoglobulin Class Switching / Q000187:drug effects / Q000235:genetics; D007074:Immunoglobulin G / Q000097:blood / Q000235:genetics / Q000276:immunology*; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007252:Influenza Vaccines / Q000276:immunology* / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D058873:Pandemics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014611:Vaccination
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000914:Antibodies, Viral; D007074:Immunoglobulin G; D007252:Influenza Vaccines; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7