Mechanisms of Action of anti-SARS-CoV-2 – MACoVA

Antibodies against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) contribute to vaccine efficacy and are used as therapy against Coronavirus Disease 2019 (COVID-19). They act by neutralizing viral replication, but also by recruiting immune effector mechanisms. These so-called non-neutralizing activities are required for optimal therapeutic efficacy of monoclonal antibodies, but their molecular and cellular mechanisms are poorly understood.

My goal is to define the landscape of antibody antiviral activities against SARS-CoV-2, characterize their impact on viral replication, and identify the underlying regulatory mechanisms. I will first determine how viral and cellular proteins modulate antibody recognition of infected cells, and how it subsequently influences cytotoxicity by Natural Killer (NK) cells and complement. Next, I will study how antibodies recruit complement and phagocytic cells to clear viral particles and determine whether the virus hijacks cellular proteins for protection. Finally, I will analyze serum and nasopharyngeal swabs from individuals receiving anti-SARS-CoV-2 therapeutic antibody to determine their polyfunctionality in vivo, predict their efficacy against emerging variants, and design new therapeutic strategies.

Overall, this project will extend the understanding of antibody polyfunctionality and associated viral countermeasures in the context of SARS-CoV-2, with implications for the development of the next generations of antibody-based vaccines and therapies.