Background: mRNA-containing, PEGylated Covid-19 vaccines can cause hypersensitivity reactions (HSRs), or rarely, life-threatening anaphylaxis in a small fraction of immunized people. A causal role of anti-PEG antibodies (Abs) has been proposed but not yet proven in a large animal model. Methods: Domestic pigs (n=6) were immunized with 0.1 mg/kg PEGylated liposome (Doxebo) i.v., and the rise of anti-PEG IgG and IgM were measured in serial blood samples with ELISA. During the plateau of seroconversion, in the 1-3 weeks postvaccination period, the animals were injected i.v. with 1/3 human dose of the PEGylated mRNA vaccine, Comirnaty, and the hemodynamic (PAP, SAP, pulse pressure), cardiopulmonary (HR, EtCO2,), hematological (WBC, granulocyte, lymphocyte and platelet counts) parameters and blood immune mediators (anti-PEG IgM and IgG antibodies, thromboxane B2, C3a) were measured as endpoints of anaphylaxis. Results: In about a week, the level of anti-PEG IgM and IgG rose 5-10-thousand-fold in all of 6 pigs immunized with Doxebo, after which time all animals developed anaphylactic shock to i.v. injection of 1/3 human dose of Comirnaty. The reaction, starting within 1 min, involved maximal pulmonary hypertension, decreased systemic pulse amplitude, tachycardia, granulopenia and thrombocytopenia. These physiological changes were paralleled by C3a and TXB2 rises in blood and were absent in non-immunized pigs. Conclusions: Consistent with previous studies, these data show a causal role of anti-PEG Abs in the anaphylaxis to Comirnaty. Based on the involvement of C activation and identity of symptoms with those observed in pseudoallergy to PEGylated liposomes, the reaction represents C activation-related pseudoallergy (CARPA). The applied sensitization of the porcine CARPA model may help better understand these reactions, and, thus, make Comirnaty and other mRNA-LNP-based Vaccines and PEGylated Nanopharmaceuticals safer.