International Journal of Clinical Case Reports, 2025, Vol.15, No.6, 271-282 http://medscipublisher.com/index.php/ijccr 275 4.2 Allergies or cross-reactions caused by excipients such as gelatin, protein and preservatives Excipients are components added to enhance the stability, solubility or preservation of vaccines and are now regarded as one of the main causes of direct vaccine allergic reactions. Common allergenic excipients include gelatin, egg protein, milk protein, polyethylene glycol (PEG), and polysorbate 80, which can induce IgE-mediated or even severe systemic reactions in susceptible individuals (Cabanillas and Novak, 2021; Caballero et al., 2021; Kounis et al., 2021; Kim et al., 2021). Gelatin has been confirmed to be an important allergen for allergic reactions to MMR and varicella vaccines. Some patients have specific IgE to gelatin and cross-react with gelatin-containing foods. Similarly, bovine serum albumin and other residual proteins during the production process can induce reactions in those allergic to the corresponding foods. Preservatives and stabilizers, such as thimerosal, formaldehyde and neomycin, although less common, can also cause allergies. PEG and polysorbate 80, which have similar structures and are widely used in vaccines and other drugs, have a significant risk of cross-reaction. If allergic reactions to excipients are misdiagnosed or not identified, it may lead to repeated adverse reactions. Therefore, detailed medical history collection should be emphasized and vaccine component allergy tests should be conducted when necessary. And carefully select or change the formula for high-risk individuals (Cabanillas and Novak, 2021; Caballero et al., 2021; Kim et al., 2021). 4.3 Novel adjuvants and delivery systems may induce inflammation and complement activation With the use of new adjuvants and drug delivery vectors (such as lipid nanoparticles in mRNA vaccines), the mechanisms by which vaccines may trigger allergic reactions have also increased. These components can activate the immune system through conventional or special pathways, directly trigger complement activation, and thereby induce pseudo-allergic reactions independent of IgE (Kounis et al., 2021; Xu and Li, 2025). The pegylated lipid nanoparticles in mRNA COVID-19 vaccines are associated with complement activation-related pseudo-hypersensitivity reactions (CARPA). The allergens such as C3a and C5a they produce can cause mast cells to release granules and also lead to systemic inflammation. If there are already anti-PEG antibodies in the body or if repeated exposure to PEG intensifies its immune irritability, the risk of such allergic reactions will further increase (Caballero et al., 2021; Risma et al., 2021). Other novel adjuvants and drug delivery carriers, such as polysorbate 80 and various nanoparticle formulations, may also trigger inflammation and immediate allergic reactions by activating complement or directly acting on immune cells-even if there has been no previous allergic reaction and no specific IgE has been detected. Therefore, in the process of promoting new vaccine technologies, it is necessary to continuously carry out drug safety monitoring and mechanism research. Only by identifying and reducing related risks can the safety of vaccination for different populations be guaranteed (Kozma et al., 2023; Pignatti et al., 2023). 5 Key Points of Clinical Manifestations and Differential Diagnosis 5.1 Short-term onset of the disease after vaccination involving multiple organs Most cases of anaphylactic shock after vaccination are acute attacks, occurring within minutes to half an hour after vaccination, and a few occur several hours later (Pennisi et al., 2025). Such rapidly occurring IgE or non-IgE-mediated reactions should be closely observed immediately after vaccination, especially for those with a history of allergies (Figure 2) (Kounis et al., 2021). Its obvious feature is that multiple organs are affected. The symptoms can involve the skin, respiratory system, cardiovascular system, and in some cases, the gastrointestinal tract (Paul et al., 2022; Li, 2025). The clinical manifestations range widely, from mild skin symptoms to life-threatening shock. Common ones include systemic urticaria, angioedema, respiratory distress, hypotension, and gastrointestinal symptoms such as nausea and vomiting (Hong and Sardinas, 2022; Paul et al., 2022). The symptoms have a rapid onset and may progress seriously. Although most patients can fully recover with timely treatment, the potential lethality suggests that all vaccination sites should be fully prepared and develop comprehensive emergency plans (Pennisi et al., 2025).
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