The COVID-19 mRNA vaccine Comirnaty induces anaphylactic shock in an anti-PEG hyperimmune large animal model

Abstract Background The polyethylene-glycol (PEG)-containing COVID-19 mRNA vaccines can cause hypersensitivity reactions (HSRs), or rarely, life-threatening anaphylaxis in a small fraction of patients. The role of anti-PEG antibodies (Abs) has been proposed, but causality has not yet been proven in an animal model. Purpose The aim of this study was to provide such evidence using an anti-PEG hyperimmune porcine model wherein the Ab levels are increased by PEGylated liposomes called Doxebo. We also aimed to find evidence for a role of complement activation and thromboxane A2 release in blood. Methods Experimental pigs (n=6) were immunized with 0.1 mg/kg BW Doxebo i.v., and the rise of anti-PEG Abs were measured with ELISA. 2-3 weeks later the animals were injected with 1/3 human dose of Pfizer’s COVID-19 mRNA vaccine Comirnaty i.v., and the hemodynamic, hematological and blood immune mediator changes were measured to assess the severity of hypersensitivity reaction (HSR). The endpoints were PAP, SAP, HR, EtCO2, WBC, granulocyte, lymphocyte and platelet counts, C3a and plasma TXB2. Results The level of anti-PEG IgM rose 5-10-thousand-fold in all pigs immunized with Doxebo by day 10. Each of the 6 animals developed an anaphylactic shock to injection of 1/3 human dose of Comirnaty that required cardiopulmonary resuscitation in 4 cases. The reaction, starting within 1 min involved maximal pulmonary hypertension (PAP 13±2 before vs. 37±6mmHg after Comirnaty, median±MAD, P<0.05) and severe systemic hypotension (SAP 63±8 before vs. 42±11mmHg after Comirnaty, median±MAD, P<0.05), tachycardia, granulo- and thrombocytopenia, and skin flushing or rash. These hemodynamic changes were paralleled by C3a and TXB2 levels in blood. Conclusion We have established the first relevant large animal model of anaphylactic reaction induced by an mRNA vaccine. Consistent with previous studies, our current data show a causal role of anti-PEG Abs in the anaphylaxis to Comirnaty, which involves complement activation, and, hence, it represents CARPA (complement activation-related pseudo-allergy).