International Journal of Clinical Case Reports, 2025, Vol.15, No.6, 271-282 http://medscipublisher.com/index.php/ijccr 274 activate mast cells and basophils through other receptors or immune complexes. Complement activation is a common pathway. The allergic toxins such as C3a and C5a produced in this process will prompt cells to release granules and inflammatory substances, which is called complement activation-associated pseudo-hypersensitivity reaction (CARPA), and it is closely related to vaccine excipients such as PEG and sorbitol 80 (Kounis et al., 2021; Laisuan, 2021; Hung et al., 2022; Ebo et al., 2022). An important non-ige pathway of action is related to the MRGPRX2 receptor. A variety of drugs and excipients can directly activate this receptor, enabling mast cells to release granules without the involvement of IgE. In clinical practice, some direct allergic reactions have not detected specific IgE, among which this non-ige mechanism may account for a considerable proportion. Therefore, when determining vaccination-related anaphylactic shock, this mechanism should be incorporated into diagnosis and risk assessment so that more appropriate prevention and treatment plans can be formulated (Barth et al., 2023; Worm et al., 2025). 4 Sensitization Mechanisms Related to Vaccine Components 4.1 Antigen proteins and pre-existing immune memories trigger specific allergic reactions The antigens in vaccines are components with immune functions extracted from pathogens, and sometimes they can become allergens. In a very small number of people who already have immune memory in their bodies-such as those who have had related infections or been exposed to related substances and thus developed an allergic constitution-after vaccination with attenuated live vaccines or protein vaccines, because the vaccine antigen is very similar to the antigen of the natural pathogen, it can also activate the memory B cells in the body that can produce IgE Therefore, it will rapidly trigger an immediate allergic reaction mediated by IgE (Figure 1) (Mok and Chan, 2020; Ota et al., 2024). Figure 1 Effects of antibody binding on B-cell activation (Adopted from Mok and Chan, 2020) Image caption: (a) Formation of viral immune complexes may result in cross-linking and activation of the inhibitory FcγRIIB, which in turn inhibits downstream BCR signaling. (b) Antibody binding may prevent the exposure of epitopes normally recognized by B-cells in a phenomenon known as “epitope masking”, thereby preventing B-cell activation (Adopted from Mok and Chan, 2020) Although most vaccine allergic reactions are attributed to excipients rather than the antigens themselves, there are still cases indicating that pathogen antigens in vaccines such as MMR, influenza or rabies can act as major triggers, inducing reactions ranging from urticaria to severe anaphylactic shock in individuals with an atopic basis or previous sensitization. Moreover, genetically susceptible individuals with high levels of antibodies against multiple allergens have a higher risk (Cabanillas and Novak, 2021; Kounis et al., 2021; Ota et al., 2024).
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