key: cord-0862055-eymij0b0 authors: Sampath, Vanitha; Rabinowitz, Grace; Shah, Mihir; Jain, Surabhi; Diamant, Zuzana; Jesenak, Milos; Rabin, Ronald; Vieths, Stefan; Agache, Ioana; Akdis, Mübeccel; Barber, Domingo; Breiteneder, Heimo; Chinthrajah, Sharon; Chivato, Tomas; Collins, William; Eiwegger, Thomas; Fast, Katharine; Fokkens, Wytske; O'Hehir, Robyn E.; Ollert, Markus; O'Mahony, Liam; Palomares, Oscar; Pfaar, Oliver; Riggioni, Carmen; Shamji, Mohamed H; Sokolowska, Milena; Jose Torres, Maria; Traidl‐Hoffmann, Claudia; van Zelm, Menno; Wang, De Yun; Zhang, Luo; Akdis, Cezmi A.; Nadeau, Kari C. title: Vaccines and allergic reactions: The past, the current COVID‐19 pandemic, and future perspectives date: 2021-06-04 journal: Allergy DOI: 10.1111/all.14840 sha: e5efcf4e294f7111cbc93925eff3bd99d6d7e2c0 doc_id: 862055 cord_uid: eymij0b0 Vaccines are essential public health tools with a favorable safety profile and prophylactic effectiveness that have historically played significant roles in reducing infectious disease burden in populations, when the majority of individuals are vaccinated. The COVID‐19 vaccines are expected to have similar positive impacts on health across the globe. While serious allergic reactions to vaccines are rare, their underlying mechanisms and implications for clinical management should be considered to provide individuals with the safest care possible. In this review, we provide an overview of different types of allergic adverse reactions that can potentially occur after vaccination and individual vaccine components capable of causing the allergic adverse reactions. We present the incidence of allergic adverse reactions during clinical studies and through post‐authorization and post‐marketing surveillance and provide plausible causes of these reactions based on potential allergenic components present in several common vaccines. Additionally, we review implications for individual diagnosis and management and vaccine manufacturing overall. Finally, we suggest areas for future research. TA B L E 1 Key Characteristics of COVID-19 vaccines (approved and in phase 3 clinical trials) 7 (Table 1) . [6] [7] [8] With the authorization of COVID-19 vaccines, vaccination campaigns have been initiated in many areas throughout the world. Within the first few days of public vaccinations, however, BNT162b2 was associated with a few severe cases of anaphylaxis. Anaphylactic reactions are considered adverse events of special interest (AESI), 27 that is, adverse events that are of significant medical and scientific concern for which immediate medical action with ongo- Table 3 lists Pharmacovigilance Practices that follow authorization of a vaccine. In the last 120 years, global vaccination programs have eradicated or vastly reduced the incidence of debilitating infectious diseases such as smallpox, polio, and measles. 30 36 The study also found that 85% of cases of anaphylaxis had pre-existing atopic disease, which was consistent with earlier reports emphasizing coexisting atopic disease, particularly asthma, as being clinical risk factors for anaphylaxis. 37 In Asian children, analysis of a large-linked database found risk of anaphylaxis to be 1.21 cases/million doses. 38 A study conducted in Australia found that estimated incidence rate of anaphylaxis for DTaP vaccines was 0.36 cases per 100,000 doses, and 1.25 per 100,000 doses for MMR vaccines. 39 Overall, rates of reported anaphylaxis occur at a rate of about 1 per 100,000 to one per 1,000,000 depending on the vaccine. 40 Figure 1 and Table 4 show the frequency of anaphylaxis for specific vaccines. Immunological hypersensitivity is either IgE-mediated (hypersensitivity reaction type 1), 54 IgG-mediated (hypersensitivity reaction Although the clinical presentations of both IgE-mediated anaphylaxis and non-immunologic anaphylaxis are similar, measurements of tryptase and SC5b-9may assist in differentiating the two types. 71, 72 Tryptase is a marker of mast cell activation which is released following mast cell degranulation while SC5b-9 is a marker of complement activation and is a terminal complement complex. 71, 73 As both tryptase and SC5b-9 are transiently elevated soon after an anaphylaxis episode, blood should ideally be collected between 30 and 90 min after the onset of reaction. 71 Acute serum total tryptase should be at least 20% plus 2 ng/mL over the baseline tryptase level. 73 Another novel emerging biomarker is hereditary α-tryptasemia which is present in mastocytosis and may be useful for determining the individual patient's risk of developing severe anaphylaxis. 74 Figure 3 depicts the mechanisms of IgE-mediated and non-immunological anaphylaxis. 75-81 Anaphylaxis to vaccines is rare and occurs primarily among individuals who have histories of allergies to the components of the vaccines. 19 Allergic reactions after vaccination can be due to any of the vaccine components such as antigens, adjuvants, stabilizers, preservatives, emulsifiers, leached packaging components, residual antibiotics, cell culture materials, and inactivating ingredients (Box 1). 82 Table 6 lists components that have been implicated in allergenic reactions and related adverse events. Here, we discuss some of the most common allergenic or potentially allergenic components of vaccines. Many vaccines contain small amounts of the egg protein ovalbumin. Influenza, yellow fever, and rabies vaccines tend to have higher concentrations of ovalbumin because they are cultured in embryonated chicken eggs. 85 Vaccines cultured in chicken embryo fibroblasts, such as the MMR vaccine, have lower concentrations of egg protein than those cultured in embryonic eggs. 86 94, 95 and that cellular immunity to gelatin from the DTaP vaccine can persist for more than three years. 96 However, sensitization may also persist due to exposure to gelatin in foods or through cross-reactivity to other allergens such as egg, chicken, and cow's milk. 97 Gelatin is also a source of alpha-gal, an carbohydrate allergen that causes meat allergy. 98 As stated above, dextran present in one preparation of MMR vaccine was responsible for numerous cases of anaphylaxis, but this brand of MMR vaccine has since been withdrawn from the market. 103 123 It is used to inactivate virus or for the detoxification of bacterial toxin. Formaldehyde-specific contact dermatitis had also been reported following formaldehyde-containing influenza vaccine. 124 It is hypothesized that the introduction of carbonyl groups on antigens by formaldehyde in vaccines profoundly affects its immunogenicity, thus explaining adverse effects due to formaldehyde-containing vaccines. 125, 126 Adjuvants are incorporated into some vaccines to boost T-cell immunity and increase helper T-cell function. The most commonly used adjuvants in vaccines are aluminum hydroxide and aluminum phosphate. Despite its long-standing use as an adjuvant in vaccines, aluminum has always been the target of controversy. Although no association between direct toxicity of aluminum and vaccines has been established, several delayed-type hypersensitivity reactions have been reported. [127] [128] [129] In Denmark, 39 out of 42 children with persistent skin reactions following vaccination had positive patch tests for aluminum. 130 In another study, vaccination-induced granulomas and contact allergy to aluminum was reported in 60 out of 63 Swedish children receiving DTP vaccines. 131 In contrast, an in vivo study in a mouse model of peanut allergy found that the severity of peanut-hypersensitivity was reduced by an alum/CpG-adjuvanted vaccine while exposure to endotoxin and alum did not influence allergic symptoms. 132 Other novel adjuvants such as MF59, AS03, and AF03, which are squalene-based are also used in vaccines. 133 Although safety concerns were raised due to presence of antibodies to squalene, clinical evidence clearly suggested that squalene is poorly immunogenic and that low titers of antibodies to squalene are found in healthy individuals. 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