Speaker
Description
Several broadly neutralizing antibodies (bnAbs) that confer protection against diverse influenza strains have been identified. Still, our understanding of the evolutionary pathways leading to these rare antibodies, and thus how best to elicit them, remains limited. To address this, we measure equilibrium dissociation constants of combinatorially complete mutational libraries (of up to ~100k variants each) for naturally isolated bnAbs, reconstructing all possible evolutionary intermediates back to the unmutated germline sequences. We find that these libraries exhibit strikingly different patterns of breadth: variants of CR9114, perhaps the broadest anti-influenza bnAb characterized, display appreciable affinity to diverse antigens only in specific, nested combinations. In contrast, many variants of a related antibody, CR6261, display moderate affinity to diverse antigens. Extensive pairwise and higher-order epistasis between mutations create binding affinity landscapes that strongly favor sequential acquisition of affinity to diverse antigens for CR9114, while the acquisition of breadth to more similar antigens for CR6261 is less constrained. We are now investigating how common these features are across divergent bnAbs, as these binding affinity landscapes may explain the molecular basis for the widespread observation that sequential exposure regimens favor greater breadth. Such mechanistic insight will be essential for predicting and eliciting broadly protective immune responses.
