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.
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 . 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 . 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 ; 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 . However, numerous case studies have provided strong mechanistic evidence, as described in 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 [5-7], but this is unsurprising considering the rarity of this adverse event and possibility of misclassification . A recent 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 .
The IOM found no relevant studies of quality in the literature assessing chronic urticaria and diphtheria, tetanus or pertussis vaccines . 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) [9, 10]. A randomized controlled trial in the U.S. found no association between localized or systemic urticaria and the inactivated influenza vaccine Fluzone . 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 . However, prospective cohort studies are usually too small to detect the small increased risk of anaphylaxis following vaccines.
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% [13-16]. Extensive swelling reactions in the injected limb after vaccination with DTaP has also been reported [17-19].
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 . Chronic urticaria involves different pathogenic mechanisms .
The 2012 IOM report provides case reports of anaphylaxis after MMR [21-32], varicella [33-40], influenza [33, 41-47], hepatitis B , meningococcal conjugate  and tetanus toxoid vaccines [49-52], which together present strong mechanistic evidence for a rare causal association with these vaccines. The report also provides several reports for HPV [53, 54] and hepatitis A vaccines , for which the mechanistic evidence is less conclusive .
Development of acute urticaria is associated with natural infections, including viral hepatitis and many different bacteria [55-57]. 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. However, the IOM concluded that there was no mechanistic evidence for an association between chronic urticaria and diphtheria, tetanus or pertussis vaccines 
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