Isotype-specific outcomes in Fc gamma receptor targeting of PspA using fusion proteins as a vaccination strategy against Streptococcus pneumoniae infection

Streptococcus pneumoniae (Spn) remains a considerable threat to public health despite the availability of antibiotics and polysaccharide conjugate vaccines. The lack of mucosal immunity in addition to capsular polysaccharide diversity, has proved to be problematic in developing a universal vaccine against Spn. Targeting antigen to Fc receptors is an attractive way to augment both innate and adaptive immunity against mucosal pathogens, by promoting interactions with activating Fcγ receptors (FcγR) that mediate diverse immunomodulatory functions. The effect of targeting FcγR is highly influenced by the IgG subclass, which bares differential affinities for activating and inhibitory FcγR. In the current study we demonstrate targeting activating FcγR with fusion proteins consisting of PspA and IgG2a Fc enhance PspA-specific immune responses, and effectively protect against mucosal Spn challenge. Specifically, targeting PspA to FcγR polarized alveolar macrophage to the AM1 phenotype and increased conventional dendritic cell subsets in the lung in addition to augmenting Th1 cytokines and PspA-specific IgG and IgA. In contrast, fusion proteins consisting of PspA fused to the IgG1 Fc provided minimal benefit over administration of PspA alone, as a result of interaction with the inhibitory FcγRIIB. Protective efficacy of the IgG1 fusion protein was significantly enhanced in animals deficient for FcγRIIB accompanied by increased B cell maturation and proliferation levels in these animals. These studies demonstrate FcγR targeting is an effective strategy for inducing potent cellular and humoral responses via mucosal immunization with Fc fusion proteins, however, careful consideration of the Fc region utilized is required since Fc isotype subclass heavily influenced immunization induced effector functions and survival against lethal Spn challenge. Fc-engineering with specific attention to FcγRIIB engagement presents a valuable vaccine strategy for protecting against Spn infection