Prevention of mRNA vaccine-induced anaphylaxis by peripheral cyclooxygenase inhibitors in an anti-PEG hyperimmune pig model: clinical relevance for nanomedicine-induced infusion reactions

Anti-polyethylene glycol (PEG) hyperimmune pigs, immunized against PEG, provide a sensitive experimental model for the rare anaphylactic reactions induced by mRNA-PEGylated lipid nanoparticle (LNP)-based COVID-19 vaccines, such as Comirnaty. These pseudo-allergic infusion reactions can usually be prevented or attenuated by multicomponent anti-inflammatory premedication regimens; however, no established protocol exists for mRNA-LNP-based COVID-19 vaccines. The aim of the present study was to identify an effective premedication strategy capable of preventing or attenuating these reactions in hypersensitive subjects, using the hyperimmune porcine model. We compared the protective effects of individual pretreatment components; dexamethasone, famotidine, levocetirizine, acetaminophen, diclofenac, indomethacin, by analyzing hemodynamic endpoints (systemic and pulmonary arterial pressure, pulse pressure). All tested compounds modulated Comirnaty-induced anaphylactic responses; however, only cyclooxygenase (COX) inhibitors provided complete protection against anaphylaxis and other abnormal processes. This finding is consistent with the low incidence of infusion reactions to cancer nanomedicines at the Shaare Zedek Oncology Center in Israel which uses COX-inhibitors as premedication. Given that most currently used human infusion-reaction prevention protocols do not include COX inhibitors, and that steroid-containing regimens may potentially counteract vaccine efficacy, our results suggest that COX inhibitors may offer a clinically effective standalone option or form the basis of simplified premedication regimens for preventing this life-threatening condition.