Dissecting the Functional Role of Mucosal IgA Clonal and Glycoprofiles for Effective Humoral Mucosal Protection

Numerous mucosal vaccines and IgA-based monoclonal antibodies aimed at a robust immunity within the respiratory tract are in development to combat viral endemics and pandemics. However, investigations into humoral immunity have predominantly focused on circulating antibodies, particularly those of the IgG isotype. This has left a significant void in our understanding of the role of mucosal IgA proteoforms in conveying effective immune protection. This crucial knowledge gap deprives vaccine and antibody development of crucial determinants or immune characteristics to replicate. In response to this, we will conduct in-depth investigations of mucosal IgA including in vitro and in vivo functional evaluations. We will capitalize on recent advances in liquid chromatography and mass spectrometry-based approaches for the detailed characterization of mucosal IgA clonal repertoires and glycosylation profiles, a field that has remained completely unexplored until now, B-cell receptor sequencing, monoclonal IgA glycoengineering and in vitro functional assays. We will take advantage of our unparalleled biobank of human nasal secretion samples with clear documentations of infection outcomes on an individual level. What sets our approach apart is thereby the unprecedented molecular-level characterization of IgA, directly linked to their in vitro functionality and pre-defined clinical outcomes, which clearly surpasses current state-of-the-art. By harnessing our in-depth characterization of mucosal IgA coupled to functional traits, we will generate IgA templates with enhanced binding and neutralization capabilities as well as functionally advantageous Fc effector potencies. Our overarching aim is to provide molecular-level blueprints for protective monoclonal IgA-antibodies, enabling the fine-tuning of vaccine formulations and monoclonal antibody generation with a higher degree of accuracy, ultimately enhancing their efficacy and safety.