What Are the Primary Limitations in B-Cell Affinity Maturation, and How Much Affinity Maturation Can We Drive with Vaccination? Is Affinity Maturation a Self-Defeating Process for Eliciting Broad Protection?

Vaccinations are one of the greatest success stories of modern medicine, saving millions of lives since their widespread adoption. However, several diseases continue to elude highly effective vaccination strategies. Chief among these are human immunodeficiency virus (HIV) and influenza (flu), both of which will require vaccines that can guide the creation of highly mutated, broadly neutralizing antibodies (bnAbs). The generation of bnAbs is hindered by our inability to effectively drive the high levels of affinity maturation required to achieve them in a large number of cells. Major limitations placed on affinity maturation derives from the inherent mutability of immunoglobulin genes, the evolved activation-induced cytidine deaminase (AID) targeting mechanisms that exist within them, and biases in targeting of particular epitope B cells.