Anaphylaxis to vaccines is historically a rare event. The coronavirus disease 2019 pandemic drove the need for rapid vaccine production applying a novel antigen delivery system: messenger RNA vaccines packaged in lipid nanoparticles. Unexpectedly, public vaccine administration led to a small number of severe allergic reactions, with resultant substantial public concern, especially within atopic individuals. We reviewed the constituents of the messenger RNA lipid nanoparticle vaccine and considered several contributors to these reactions: (1) contact system activation by nucleic acid, (2) complement recognition of the vaccine-activating allergic effector cells, (3) preexisting antibody recognition of polyethylene glycol, a lipid nanoparticle surface hydrophilic polymer, and (4) direct mast cell activation, coupled with potential genetic or environmental predispositions to hypersensitivity. Unfortunately, measurement of anti–polyethylene glycol antibodies in vitro is not clinically available, and the predictive value of skin testing to polyethylene glycol components as a coronavirus disease 2019 messenger RNA vaccine-specific anaphylaxis marker is unknown. Even less is known regarding the applicability of vaccine use for testing (in vitro/vivo) to ascertain pathogenesis or predict reactivity risk. Expedient and thorough research-based evaluation of patients who have suffered anaphylactic vaccine reactions and prospective clinical trials in putative at-risk individuals are needed to address these concerns during a public health crisis.
Key words
COVID-19 vaccine
mRNA vaccine
anaphylaxis
allergy
polyethylene glycol
PEGylated liposome
lipid nanoparticle
mast cells
Abbreviations used
BAT
Basophil activation test
BST
Basal serum tryptase
C3a
Complement component 3a
C5a
Complement component 5a
COVID-19
Coronavirus disease 2019
DC
Dendritic cell
Fc
Fragment crystallizable region
HMW
High-molecular-weight
LNP
Lipid nanoparticle
mRNA
Messenger RNA
PEG
Polyethylene glycol
PEGylated
Polyethlene glycol conjugated
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Disclosure of potential conflict of interest: All authors have served as consultants to the Centers for Disease Control and Prevention (CDC)-sponsored Clinical Immunization Safety Assessment (CISA) Project. This work was not supported by CISA. K. M. Edwards has grant funding from the CDC and is a consultant for IBM and Bionet and a member of the data safety and monitoring boards for Pfizer, Sanofi, Moderna, Seqirus, CEPI, Merck, X-4 Pharma, and Roche. A. Stallings has support from Regeneron Pharmaceuticals. R. A. Wood, F. F. Little, K. M. Edwards, and J. D. Milner have grant funding from the National Institutes of Health. J. D. Milner is providing expert witness testimony on trauma and hypersensitivity. R. A. Wood receives research support from Aimmune, Astellas, DBV, HAL-Allergy, Genentech, Regeneron, and Sanofi, and royalties from Up To Date. A. E. Norton and K. A. Risma have no external funding sources to declare.
