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

Project description

Role of IgA glycoprofiles in mucosal vaccine and antibody development

Mucosal immunity in the airways plays a crucial role in protecting against respiratory infections. However, research on vaccines and therapeutic antibodies has largely focused on IgG antibodies, providing limited insight into the potential of secretory IgA – the principal antibody on mucosal surfaces – in the development of effective mucosal vaccines and antibody therapeutics. The ERC-funded D-MAP project aims to address this by exploring mucosal IgA through comprehensive in vitro and in vivo studies. By integrating a unique biobank of human nasal secretions with detailed infection outcome data, recent advances in mass spectrometry, glycoengineering and cell-based functional assays, the project seeks to define optimal IgA glycoprofiles for the development of mucosal vaccines and therapeutic IgA antibodies.

Objective

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.

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HORIZON-ERC - HORIZON ERC Grants

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(opens in new window) ERC-2024-STG

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Host institution

KAROLINSKA INSTITUTET
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 941 310,00
Address
NOBELS VAG 5
171 77 STOCKHOLM
Sweden

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Region
Östra Sverige Stockholm Stockholms län
Activity type
Higher or Secondary Education Establishments
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 941 310,00

Beneficiaries (4)

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