Do Vaccines Cause Hypersensitivity Reactions?

Conclusion

Vaccines can very rarely cause immediate hypersensitivity reactions (i.e. anaphylaxis, angioedema, and/or hives) usually within minutes, but up to several hours of vaccination in persons with allergy to a vaccine component. Also, vaccines can cause large local swelling reactions or nodules at the injection site due to delayed-type hypersensitivity reactions.

International consensus for evaluation and management of allergic reactions to vaccines can be found at the following link: https://waojournal.biomedcentral.com/articles/10.1186/s40413-016-0120-5 [1].

Epidemiological Evidence

Allergic reactions to vaccines (including immediate hypersensitivity reactions) have been estimated to occur approximately once per 50,000-1,000,000 doses. Anaphylaxis, the most concerning type of such reactions, has been estimated to occur approximately once per 100,000-1,000,000 doses for most commonly administered vaccines [1]. Rates of anaphylaxis can differ depending on the vaccine, age of the recipient, and gender; for example, adult females are at a relatively higher risk of hypersensitivity reactions including anaphylaxis than males. However, anaphylaxis is very rare [2]. Hives occurs more commonly, but no precise rate is available.

The 2012 report by the Institute of Medicine (IOM), now called the National Academy of Medicine (NAM), described one study assessing influenza vaccination and anaphylaxis [3]; however, this study did not provide convincing evidence of an association due to a lack of validity and precision. The IOM found no relevant studies of quality in the literature assessing any other vaccines and anaphylaxis, since the only applicable studies available used passive surveillance systems and therefore lacked an unvaccinated comparison group [4]. However, numerous case studies have provided strong mechanistic evidence, as described in the the Proposed Biological Mechanism section below.

Most studies published since the 2012 IOM report have not found a statistically significant association between vaccination and anaphylaxis [5-8], but this is unsurprising considering the rarity of this adverse event and possibility of misclassification; prospective cohort studies are usually too small to detect the small increased risk of anaphylaxis following vaccines [2]. A Vaccine Safety Datalink study identified 33 confirmed vaccine-triggered anaphylaxis cases among 25,173,965 vaccine doses, which corresponds to a rate of 1.3 cases of anaphylaxis per million vaccine doses [9]. Two studies of the 2013-2014 and 2014-2015 flu seasons in the United Kingdom study found no occurrences of systemic allergic reactions following LAIV in young people with egg allergy, even among those who had previously experienced anaphylaxis to eggs [10, 11]. A prospective observational cohort study of California children and adults 2-49 years of age found no significantly increased risk of hypersensitivity during the 3-day risk interval for 62,040 quadrivalent LAIV recipients during the 2013–2014 influenza season overall; although when restricting the analysis to recipients 5-8 years of age, a significantly higher risk of hypersensitivity was observed [12]. mRNA COVID-19 vaccines have been shown to cause allergic reactions anaphylaxis. An analysis of VAERS reports found an early anaphylaxis reporting rate after the Pfizer vaccine of 4.7 cases/million doses administered, or about 1 case in 200,000 doses, and 2.5 cases/million doses administered or 1 in 400,000 doses after the Moderna vaccine [13].

The IOM found no relevant studies of quality in the literature assessing chronic urticaria and diphtheria, tetanus or pertussis vaccines [4]. Since the publication of the 2012 IOM report, randomized controlled trials in Hong Kong and Korea found no increased risk of urticaria in recipients of the AS04-adjuvanted HPV-16/18 vaccine (Cervarix®) [14, 15]. A randomized controlled trial in the U.S. found no association between localized or systemic urticaria and the inactivated influenza vaccine Fluzone® [16]. A randomized controlled trial in the U.S. and South America found no association between quadrivalent meningococcal conjugate vaccine and urticaria in young infants in the year following vaccination [17]. A retrospective observational study of California infants had 3 cases of urticaria considered related to vaccine receipt out of 46,486 doses of DTaP-IPV/Hib vaccine administered [18].

A few studies have reported an association between vaccines containing aluminum adjuvants and persistent nodules at the injection site, at an estimated rate of 0.03-0.83% [19-22]. Extensive swelling reactions in the injected limb after vaccination with DTaP has also been reported [23-25].

Proposed Biological Mechanism

Vaccines have been shown to incite immediate hypersensitivity reactions, including anaphylaxis, usually mediated through IgE antibody. These reactions are more likely due to potential allergens among the vaccine constituents rather than to the active ingredients, but often the direct cause of the reaction is not discovered [26]. Chronic urticaria involves different pathogenic mechanisms [1]. A full list of potential allergens within vaccines can be found at the Johns Hopkins Institute for Vaccine Safety website at on our Components – Allergens page.

The 2012 IOM report provides case reports of anaphylaxis after MMR [27-38], varicella [39-46], influenza [39, 47-53], hepatitis B [39], meningococcal conjugate [54] and tetanus toxoid vaccines [55-58], which together present strong mechanistic evidence for a rare causal association with these vaccines. The report also provides several reports for HPV [59, 60] and hepatitis A vaccines [52], for which the mechanistic evidence is less conclusive [4].

The potential mechanism for allergic reaction after an mRNA is not yet understood. Early on, it was felt that it may be related to the presence of polyethylene glycol (PEG) or polysorbate in the vaccines, although this has yet to be clinically demonstrated [61].

Development of acute urticaria is associated with natural infections, including viral hepatitis and many different bacteria [62-64]. One mechanism that could contribute to the development of chronic urticaria is IgE hypersensitivity. Other possible mechanisms include activation of the complement system, in which a cascade of proteolysis and successive release of cytokines functions to amplify the immune response but can damage host cells if not properly regulated. However, the IOM concluded that there was no mechanistic evidence for an association between chronic urticaria and diphtheria, tetanus or pertussis vaccines [4].

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