Deciphering Fc-mediated Antiviral Antibody Functions in Animal Models

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

Some viruses yielded long ago to empirical approaches to vaccines and Ab therapies, and those who led such progress (e.g., Jenner, Pasteur, Theiler, Salk, Sabin, Hilleman) are due tremendous credit for their insights, inventiveness, boldness, and dogged determination. Many other viruses have not surrendered so easily to either serendipity or brilliance, and in the more advanced examples, promising vaccines or Ab therapies have not yet completed their costly and uncertain journeys to licensure. It is the intractable and previously orphaned problems at which research is now directed. Restricting attention here to Ab-mediated immunity to viral infections, three major and interrelated questions arise on the path to vaccines and therapies (Figure 1) . What Ab specificities are responsible for protection and are most desirable for their breadth and safety? What other characteristics of Abs are important for protection, especially in the Fc part of the molecule? And when these answers are known, how might vaccine be configured to elicit the most desirable specificities and types of Abs? The latter questions of immunogenicity and immunodominance have proven problematic for the diverse human population, and rational shaping of immune responses (e.g., fine specificities, types, durability) remains perhaps the greatest challenge of immunology. Here, we focus on experimental approaches to the precursor questions of what kinds of Ab response are desirable, and more specifically how hypotheses drawn from provisional in vitro correlates of protection might withstand the test of in vivo veracity.