Hierarchical and redundant roles of activating FcγRs in protection against influenza disease by M2e-specific IgG1 and IgG2a antibodies

The ectodomain of matrix protein 2 is a universal influenza A virus vaccine candidate that provides protection through antibody- dependent effector mechanisms. Here we compared the functional engagement of Fc gamma receptor (Fc gamma R) family members by two M2e- specific monoclonal antibodies (MAbs), MAb 37 (IgG1) and MAb 65 (IgG2a), which recognize a similar epitope in M2e with similar affinities. The binding of MAb 65 to influenza A virus- infected cells triggered all three activating mouse Fc gamma receptors in vitro, whereas MAb 37 activated only Fc gamma RIII. The passive transfer of MAb 37 or MAb 65 in wild- type, Fcer1g(-/-), Fcgr3(-/-) and Fcgr1(-/-) Fcgr3(-/-) BALB/ c mice revealed the importance of these receptors for protection against influenza A virus challenge, with a clear requirement of Fc gamma RIII for IgG1 MAb 37 being found. We also report that Fc gamma RIV contributes to protection by M2especific IgG2a antibodies. IMPORTANCE There is increased awareness that protection by antibodies directed against viral antigens is also mediated by the Fc domain of these antibodies. These Fc- mediated effector functions are often missed in clinical assays, which are used, for example, to define correlates of protection induced by vaccines. The use of antibodies to prevent and treat infectious diseases is on the rise and has proven to be a promising approach in our battle against newly emerging viral infections. It is now also realized that Fc gamma receptors significantly enhance the in vivo protective effect of broadly neutralizing antibodies directed against the conserved parts of the influenza virus hemagglutinin. We show here that two M2e- specific monoclonal antibodies with close to identical antigen- binding specificities and affinities have a very different in vivo protective potential that is controlled by their capacity to interact with activating Fc gamma receptors.