Background: Adverse allergic reactions due to the administration of vaccines developed for the protection of coronavirus disease 2019 (COVID-19) have been reported since the initiation of the vaccination campaigns in December 15, 2020. Current analyses provided by the Centers for Disease Control and Prevention and the U.S. Food and Drug Administration in the United States have estimated the rates of anaphylactic reactions in 2.5 and 11.1 per million of messenger RNA (mRNA) 1273 and BNT162b2 vaccines administered, respectively. The mechanisms by which these mRNA vaccines induce adverse vaccine reactions have been the subject of conflicting reports. Although skin testing with excipient components found in mRNA-1273 and BNT162b2 vaccines, such as polyethylene glycol (PEG) and related vaccine lipid products, were originally recommended to identify potential predictive biomarkers of adverse allergic reactions, more recent evidence has suggested that routine skin testing with these vaccine excipients have poor predictability and do not correlate with susceptibility to vaccine injury. Objective: The goal of this proof-of-concept (POC) exploratory study was to investigate the role of leukocyte activation (LA) induced by lipid excipients found in mRNA COVID-19 vaccines in the pathogenesis of COVID-19 mRNA vaccine-associated adverse reactions by using an LA assay developed in our laboratory. Results: An LA assay was performed on blood samples obtained from 30 study subjects who were assigned to three study groups: group 1 consisted of 10 subjects who had received an mRNA COVID-19 vaccine and developed a serious vaccine adverse reaction; group 2 consisted of 10 subjects who had received a COVID-19 vaccine and developed a mild adverse reaction; and group 3 consisted of 10 subjects who had not received a COVID-19 vaccine and were asymptomatic. Five excipients were tested in each of the 10 subjects; hence, a potential of 50 reactions could be expressed in each of the three groups. In the subjects in group 1 who had shown clinically severe vaccine effects, 8 of 50 (16%) had severe LA index (LAI) responses (>144.83), 12 of 50 (24%) had moderate LAI responses (87.62 -144.82), and 30 of 50 (60%) had no reaction (0 - 87.61). In the subjects in group 2 who had shown clinically mild vaccine effects, 4 of 50 (8%) had severe LAI responses (>144.83), 9 of 50 (18%) had moderate LAI responses (87.62 -144.82), and 37 of 50 (74%) had no reaction. In the subjects in group 3 who had not received the vaccine and, therefore, had no clinical vaccine effects, 2 of 50 (4%) had severe LAI responses (>144.83), 10 of 50 (20%) had moderate LAI responses (87.62 -144.82), and 38 of 50 (76%) had no reaction LA index (LAI) responses. Conclusion: The results of this exploratory POC study suggest that the measurement of LA induced by PEG and other vaccine-related lipid excipients found in mRNA COVID-19 vaccines may provide a novel and useful predictive biomarker associated with adverse non-immunoglobulin E (IgE) related allergic reactions to these vaccines. The study results also underscore growing concerns related to these non-IgE hypersensitivity reactions and their potential for pathogenesis of adverse vaccine reactions. This is particularly noteworthy because, with the continuing emergence of novel and evolving variants of severe acute respiratory syndrome corona-virus 2 mutants, yearly immunization with mRNA vaccines will most likely be recommended. Although the study was not sufficiently powered to draw definitive conclusions with regard to associations between vaccine-associated COVID-19 reactions and LA, the trends of a more severe set of clinical reactions seen associated with LAI reactivity scores, particularly with ALC-0159 (2-[{polyethylene glycol} 2000]-N,N-ditetradecylacetamide), suggest a potential benefit worthy of exploration in future randomized controlled trials.