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Investigation of antibody-mediated protection against Influenza A virus in a neonatal model

par Fraikin, Audrey
Président du jury Vuckovic, Aline
Promoteur Flamand, Véronique
Co-Promoteur Marchant, Arnaud
Publication Non publié, 2026-06-30

Thèse de doctorat

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Résumé :

The neonatal period is not simply a phase of “immune immaturity” as it has been for long believed, but is rather “specifically adapted” to meet the requirements that are associated with early life. As a direct consequence, neonates are particularly vulnerable to respiratory infections, such as influenza, and develop poor vaccine responses. A key challenge remains how to effectively protect newborns against these pathogens during their window of vulnerability. Over the years, the scientific community has explored different strategies to address this, and monoclonal antibodies (mAbs)-based prophylactic strategies have emerged as a very promising approach. The goal of my PhD thesis was to evaluate and characterize antibody-mediated protection against influenza in a relevant preclinical neonatal infection model. To address this, neonatal mice humanized for Fc-mediated effector functions were administered with human anti-influenza A virus (IAV) mAbs prior to challenge with IAV.In the first part of this PhD work, we explored the protection induced by two mAbs targeting different epitopes on the influenza virus, and we demonstrated that targeting conserved epitopes on the HA stalk by using the human CR9114 conferred a robust protection in early life, which was not the case with the head-specific CH65.In the second part, we further dissected the mechanisms of protection mediated by the stalk-specific mAb CR9114. More precisely, we demonstrated that all CR9114 subclasses confer protection against influenza in early life, while Fc subclass differentially influences viral burden and inflammatory responses independently of survival outcomes. Strikingly, alveolar macrophages (AM) loss induced by the IAV infection was prevented only in pups receiving CR9114 IgG1. Consistently, AM depletion abolishes the protective effect of CR9114 IgG1, underscoring their essential role in mediating IgG1-driven protection in early life. These findings correlate with enhanced Fc gamma receptors (FcγRs) binding and antibody-dependent cellular phagocytosis (ADCP), in line with the superior effector profile of IgG1. Single-cell transcriptomic analysis further revealed that IgG1 selectively programs AM toward a distinct transcriptional state characterized by preserved antiviral sensing, restrained inflammatory signaling, and a lipid-associated metabolic programming.Overall, my PhD work highlights the critical contribution of FcγR-engaging IgG subclasses in shaping neonatal antiviral immunity and supports the rational design of Fc-optimized mAbs to enhance protection against IAV in early life.