Universal vaccine against influenza virus: Linking TLR signaling to anti‐viral protection

• DOI: 10.1002/eji.201041225
• Publication Date: 2012-04-25T00:14:07Z
• Authors: Nicole Schmitz; Roger R. Beerli; Monika Bauer; Andrea Jegerlehner; Klaus Dietmeier; Melanie Maudrich; Paul Pumpens; Philippe Saudan; Martin F. Bachmann
• Keywords: 610 Medicine & health; Antibodies, Viral; Antibodies, Monoclonal, Murine-Derived; Mice; 03 medical and health sciences; 0302 clinical medicine; Orthomyxoviridae Infections; Animals; Humans; Pandemics; Mice, Knockout; 2403 Immunology; Membrane Glycoproteins; Vaccination; 10177 Dermatology Clinic; Immunoglobulin Class Switching; Immunity, Innate; 3. Good health; Toll-Like Receptor 7; Influenza A virus; Influenza Vaccines; Immunoglobulin G; 2723 Immunology and Allergy; Signal Transduction

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.