A naturally hypersensitive porcine model may help understand the mechanism of COVID-19 mRNA vaccine-induced rare (pseudo) allergic reactions: complement activation as a possible contributing factor

Abstract

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.

Emotional Reaction to the First Dose of COVID-19 Vaccine: Postvaccination Decline in Anxiety and Stress among Anxious Individuals and Increase among Individuals with Normal Prevaccination Anxiety Levels

“…Lay people, even those who view vaccination as protective against COVID-19, feel anxious about the possibilities and risks of taking the vaccine [ 9 , 10 , 11 ]. Unfortunately, a significant number of people around the world still refuse to receive the vaccine [ 5 , 12 ]. Vaccination hesitancy is evoked by uncertainty and perceptual disintegration as a result of misinformation and conspiracy beliefs [ 13 ].…”

“…Vaccine-related anxiety may also be triggered by a reported cluster of anxiety-related adverse events, which take place after the administration of COVID-19 vaccines [ 21 , 22 ]. Sudden rise in blood pressure following vaccination may raise uncertainties, since it is a typical symptom of both pseudo-allergy and anxiety [ 12 ]. In fact, high anxiety among adults attending COVID-19 vaccination centers is associated with fear that terrible consequences may happen [ 6 , 23 , 24 ].…”

“…Most events of allergic anaphylaxis occur in individuals with a prior history of allergy such as food allergy and allergy to wasp stings [ 26 , 27 ]. Animal studies report higher occurrence of such anaphylaxis and relate it to C-activation [ 12 ].…”

Understanding the Role and Impact of Poly (Ethylene Glycol) (PEG) on Nanoparticle Formulation: Implications for COVID-19 Vaccines

“…Furthermore, a preprint publication provided evidence that i. v. injection of an adenoviral vaccine might lead to platelet-adenovirus aggregate formation leading to platelet clearance and thrombocytopenia ( Nicolai et al, 2021 ). Moreover, through the infiltration of the axillary lymph nodes, the mRNA vaccines could reach the vena cava via the thoracic duct ( Dézsi et al, 2022 ). Taken together, accidental i. v. administration of a vaccine intended for i. m. administration could potentially trigger adverse events.…”

“…It was proposed that the interaction between naturally occurring anti-cholesterol antibodies and microcrystal aggregates formed by excess cholesterol trigger complement activation thereby manifesting as increased pulmonary hypertension through the release of anaphylatoxins. Furthermore, other positively charged components or the mRNA have been also identified as possible factors could activate the complement ( Dézsi et al, 2022 ). Notably, the latter study showed that incubation of the Pfizer/BioNTech mRNA vaccine with pig serum ex vivo resulted in significant elevation of C3a anaphylatoxin and sC5b-9, the terminal complement complex.…”