A tiny fraction of people immunized with
lipid nanoparticle (LNP)-enclosed
mRNA (LNP-
mRNA) vaccines develop allergic symptoms following their first or subsequent vaccinations, including
anaphylaxis. These reactions resemble
complement (C) activation-related pseudoallergy (CARPA) to i.v. administered
liposomes, for which pigs provide a naturally oversensitive model. Using this model, we injected i.v. the human vaccination dose (HVD) of
BNT162b2 (
Comirnaty, CMT) or its 2-fold (2x) or 5-fold (5x) amounts and measured the hemodynamic changes and other parameters of CARPA. We observed in 6 of 14 pigs transient
pulmonary hypertension along with
thromboxane A2 release into the blood and other hemodynamic and blood cell changes, including
hypertension, granulocytosis,
lymphopenia, and
thrombocytopenia. One pig injected with 5x CMT developed an
anaphylactic shock requiring
resuscitation, while a repeat dose failed to induce the reaction, implying tachyphylaxis. These typical CARPA symptoms could not be linked to animal age, sex, prior immune stimulation with
zymosan, immunization of animals with
Comirnaty i.v., or i.m. 2 weeks before the
vaccine challenge, and anti-PEG
IgM levels in
Comirnaty-immunized pigs. Nevertheless,
IgM binding to the whole
vaccine, used as
antigen in an ELISA, was significantly higher in reactive animals compared to non-reactive ones. Incubation of
Comirnaty with pig serum in vitro showed significant elevations of C3a
anaphylatoxin and sC5b-9, the C-terminal complex. These data raise the possibility that C activation plays a causal or contributing role in the rare HSRs to
Comirnaty and other
vaccines with similar side effects. Further studies are needed to uncover the factors controlling these
vaccine reactions in pigs and to understand their translational value to humans.