Causes and consequences of anti-PEG antibodies

The quick development of mRNA vaccines in response to the global SARS-CoV-2 pandemic has shown the promises of this technology. Now a manufacturing and regulatory precedent exists, it is likely that these technologies will become an important tool for future biomedical applications. Both mRNA vaccines currently approved are protein-free lipid nanoparticles stabilized with poly(ethylene glycol) (PEG), a water-soluble polymer forming a hydrophilic corona on the surface of the particle. Despite the absence of proteins in the vaccine, the incidence of anaphylactic shock in the population appears to be 2- to 5-fold higher than with traditional immunization strategies. This increased reactivity has been tentatively attributed to PEG, an ingredient that is shared with many pharmaceutical, cosmetic and processed foods products. Due to its non-peptidic nature, PEG is likely a T cell-independent antigen, a type of antigen for which reactivity remains poorly characterized. We will look, in animal models, at the determinants driving the immune response toward PEG, following exposure to various PEGylated systems. We will investigate how the physicochemical properties of the antigens influence immune response, but also look at which biological pathways are implicated. Importantly, reactivity toward PEG will be related to the efficacy of PEG containing medicines in animals. In brief, this research project will investigate how a chemical present in drugs and the environment can affect the reactivity toward pharmaceuticals, including mRNA-containing technologies. We will obtain a clearer understanding of how to prepare safer PEGylated pharmaceuticals and the factors driving the immune response toward PEG. Altogether, these advances will guide toward the design of safer drugs, and better clinical managements of patients with pre-existing antiPEG antibodies.