Deciphering Fc-mediated Antiviral Antibody Functions in Animal Models

Schmaljohn, Alan L.; Orlandi, Chiara; Lewis, George K.

While some elements of Ab-mediated antiviral immunity appear to be largely or completely independent of Fc function, others are highly reliant on Fc in order to exert biological effects that register as "protective" activity (Boxes 1, 2). Such Abs (CTAbs) share with a number of therapeutic anti-cancer Abs the aim of arresting or destroying cells recognized by such Abs, and mechanistic relevance can be gleaned from the extensive research and clinical trials with anti-tumor CTAbs. However, the efficacies of antiviral CTAbs are differently complex due to both the typical incapacities to obtain human protection data and the longstanding problems inherent with classical animal models of viral disease. More recently, newer approaches ( Table 1 ) have allowed increasing compatibility between a given virus (or its cell-expressed antigen), a susceptible animal model, Fc-FcR interactions, populations of FcR-bearing effector cells, etc. This brief review is intended to highlight and cite some of the recent literature that first points toward an almost bewildering complexity in the factors that intrude upon the subset of protective antiviral mechanisms that are Fc-dependent, and then to some feasible approaches to achieve clarity. Most likely, for a given virus with its unique structure and biology, and its unique pathogenetic profile in a chosen animal model, some Fc-dependent Ab-directed mechanisms will prove more reliably important than others. Moreover, each of the concepts illustrated in Figure 4 is meant here to be understood as scalable in its importance, but rarely if ever sufficient by itself to achieve a threshold that achieves enough efficacy to adequately suppress viral replication and prevent viral disease. It is most encouraging that experimental tools, including those shown in Table 1 , are emerging to affirm or refute the truth and biological importance of concepts previously mired in the complexities. To an increasing degree, rational selection and design of optimally effective MAbs (and the means to elicit them with vaccines) will inform antiviral research. Similarly, refinement and selection will continue to improve for in vitro assays that are not only statistical correlates but mechanistic correlates of protection. And still, the final proofs will continue to be an empirical matter of finding what is both safe and effective.