Vaccine allergy and pseudo-allergy

ARTICLE

Vaccine allergy: myth or reality?

Allergic and pseudo-allergic reactions to vaccines frequently involve the skin, and can be generalized systemic symptoms (urticaria/angioedema, serum sickness, flares of eczema) or localized at the sites of vaccination (persistent nodules, abcesses, granulomas). Subjects of all ages report symptoms that suggest a hypersensitivity (HS) reaction to vaccine components [1, 2].

Most frequent reactions are large local inflammatory reactions, and mild to moderate non-immediate urticaria, angioedema and non-urticarial rashes induced by injections of diphtheria (D) and tetanus (T) toxoid-containing [1, 3-7] and hepatitis B virus (HBV) [8-12] vaccines. Other reactions, such as anaphylactic and anaphylactoid reactions, arthralgias, serum sickness, vasculitis, eczema, persistent nodules, recurrent abcesses, erythema multiforme, etc. are rare [1].

Data in the literature strongly suggest that most mild to moderate local and generalized reactions are not allergic, but instead result from non-specific activation of the inflammatory system, with good tolerance of booster injections [13-17]. In the study of Gold et al., only 10 % of children with suspected allergy to D.T toxoid-, hepatitis B-, ovalbumin-, and gelatin-containing vaccines relapsed when challenged with the suspected vaccines. Moreover, most relapses induced by challenge were large local reactions and fever, and did not evoke HS to vaccine components [14].

However, vaccine components may induce IgE-dependent HS reactions, such as anaphylaxis and immediate urticaria and angioedema to toxoid- [4, 18-20], ovalbumin- [21-26], gelatin- [27-34], and pneumococcal antigen [35]-containing vaccines. Dextran-containing vaccines (BCG) may induce IgG-dependent anaphylactoid reactions [36-39]. Finally, excipients of vaccines and toxoid-containing vaccines induce non immediate-type HS reactions, either local, such as eczema induced by aluminium hydroxide [40-44], mercurothiolate [45-47] and formaldehyde [48], and Arthus-type reactions [1, 5] and recurrent abcesses [49] induced by toxoids, or generalized, such as delayed urticaria, angioedema and non-urticarial rashes induced by gelatin-containing vaccines [29, 50-52].

Reactions at the site of vaccine injection

Diphtheria and tetanus toxoid-containing and HBV vaccines are the most frequently suspected vaccines.

Arthus-type reactions occur in patients hyperimmunized by previous injections of the vaccines [1, 5, 21, 53]. Facktor et al. reported semi-late responses in skin tests with the suspected vaccines in patients reporting Arthus-type reactions to toxoid-containing vaccines [53]. However, semi-late-reading skin tests were consistently negative in studies performed in children [19]. Moreover, Arthus-type reactions are easily diagnosed by clinical history and serum specific anti-toxoid antibody (IgM/IgG) determination, with high levels of these antibodies 3 to 4 weeks after the reaction [1, 54]. Large local inflammatory reactions may also occur in non immunized patients (ie. to the first injection of the vaccine) and in patients receiving booster injections of vaccines containing high concentrations of diphtheria toxoid or aluminium hydroxide, independently of their serum specific anti-tetanus, anti-diphtheria and anti-pertussis IgG levels [55, 56]. However, relationship between the quantity of diphtheria toxoid or aluminium and rate of extensive swelling was not found for all batches of vaccines. Recent results have shown that sensitization of mice with acellular pertussis-containing vaccines led to local swelling reaction to booster immunization with diphtheria toxoid-containing vaccine, but the mechanism responsible for this " adjuvant " effect is far from clear [57]. Thus, most large local reactions probably result from non specific activation of the inflammatory system by high doses of aluminium salts or microbial components, with good tolerance of sequential booster injections of the vaccines [19]. Finally, late responses in intradermal (ID) tests with tetanus toxoid led to diagnosis of delayed-type HS to tetanus toxoid in a child with recurrent abcesses induced by booster injections of toxoid-containing vaccines [49]. However, the diagnostic value of late responses in skin tests with toxoids is controversial, with false positive results in control subjects [53, 58-60].

One to 8 % of subjects of all ages receiving HBV vaccines report mild to moderately severe inflammatory reactions [8, 9, 11], and Arthus-like reactions are reported in patients receiving booster injections of pneumococcal vaccine [61-63]. In those cases, immuno-allergological studies have not been performed.

Aluminium hydroxide, mercurothiolate, and formaldehyde contained in vaccine may induce mild to moderate inflammatory reactions, resolving in a few days. However, cases of eczema induced by these agents have been reported in adults immunized with vaccines containing aluminium hydroxide [41-43], mercurothiolate [47, 64] and formaldehyde [48]. Diagnostic value of patch-tests with aluminium salts is good in aluminium hydroxide-induced eczema [40-42, 65, 66]. In contrast, sensitivity and specificity of patch-tests with mercurothiolate are low [64, 67, 68].

Aluminium hydroxide in vaccines (and in allergenic extracts) also induces subcutaneous nodules in up to 19 % of patients [40, 44, 69-72]. Nodules usually resolve in a few months, but rare cases of persistent nodules have been reported [69-72]. Diagnosis is based on clinical history. Skin tests (patches) with aluminium salts are usually negative, because subcutaneous nodules result from non specific reaction to foreign substance, with a positive correlation between concentration of aluminium hydroxide in situ and the size of the nodule, as shown by studies in experimental animals [73] and human patients [69, 71, 72].

Generalized reactions to vaccines

Generalized reactions to vaccines are less frequent but more worrying than reactions at the site of injection.

Reactions to toxoid-containing vaccines

Urticaria, angioedema and unidentified rashes are reported in 5 to 13 % of patients receiving toxoid-containing vaccines [5, 7]. Immuno-allergological studies based on immediate-, semi-late-, and late-reading skin tests, specific serum anti-toxoid antibody determination (IgM/IgG, and IgE) and challenge suggest that most mild to moderate generalized reactions result from non specific activation of the inflammatory system by high doses of bacterial components, with good tolerance of booster injections of the suspected vaccines [14-17, 19].

However, urticaria and angioedema resulting from immediate-type or immune-complex-related HS to toxoids have been reported [5, 19, 74, 75]. In the study of Ponvert et al. [19], 19 children reported generalized skin reactions to toxoid-containing vaccines. Skin test and CAP-Rast results suggested the diagnosis of immediate HS to diphtheria or tetanus toxoid in 6 children reporting immediate and accelerated urticaria and angioedema to booster injections of the vaccine. Immediate-, semi-late- and late-reading skin tests were negative in the other children reporting non immediate and non urticarial reactions, and the children tolerated booster sequential injections of the vaccines. Thus, in children reporting generalized skin reactions, and especially in children with immediate and accelerated urticaria and angioedema to booster injections of toxoid-containing vaccines, an immuno-allergologic work-up based on skin tests (pricks with the undiluted vaccine, and ID with 1/1000 and 1/100 diluted vaccine) and serum specific anti-toxoid antibody (IgM/IgG, and IgE) determination should be performed, to diagnose possible immediate or semi-late HS to diphtheria or tetanus toxoid. However, IgE specific for diphtheria and tetanus toxoids were found in sera of most children [76], adolescents and adults [77, 78] who had tolerated immunizations with DT-containing vaccines. Highest levels were found in sera of atopic subjects. Finally, one case of urticaria, with immediate response in skin tests with formaldehyde, has been reported in an adult patient after injection of tetanus toxoid vaccine [79].

Since the introduction of highly purified toxoids, anaphylactic reactions to toxoid-containing vaccines have become rare. In a study of 784 DT immunizations and 15,752 DTP (pertussis) immunizations in children aged 0 to 6 years, no severe urticaria or anaphylaxis was reported [80]. Other studies in adults found an incidence of anaphylactic reaction to tetanus toxoid-containing vaccines of 1 per 100,000 [81, 82]. Isolated cases of anaphylaxis induced by tetanus and diphtheria toxoid-containing vaccines have been reported, but skin tests and specific IgE determination were not performed [74, 83-85]. Jacobs et al. reported only one patient with anaphylaxis induced by injection of a tetanus toxoid-containing vaccine, diagnosed allergic to tetanus toxoid with skin tests [5]. In the study of Ponvert et al., 6 children reported anaphylactic reactions induced by booster injections of D.T-containing vaccines [19]. Immediate responses in skin tests and detection of serum specific IgE diagnosed immediate HS to toxoids in 4 children, including one child sensitized to diphtheria toxoid and 3 children sensitized to tetanus toxoid, consistent with results of other studies in a few patients with anaphylaxis to booster injections of D.T-containing vaccines [4, 5, 20].

Reactions to pertussis-containing vaccines

Allergic-like reactions to pertussis vaccines are uncommon [86]. Rare cases of urticaria, angioedema and anaphylactic/anaphylactoid reactions have been reported, but have not been explored [87, 88]. Pertussis antigens induce specific IgE production in up to 65 % of children immunized with P-containing vaccines. Highest levels are found in children immunized with acellular vaccine, particularly in atopic children [89-91]. Serum specific IgE levels are positively correlated with specific IgG responses, and reflect immunogenicity rather than allergenicity of pertussis antigens [89, 91]. Moreover, no correlation was found between levels of specific IgE and frequency of adverse events, except for large local inflammatory reactions [89].

Pertussis antigens are also potent adjuvants of IgE production to unrelated antigens in experimental animals [92, 93]. However, the human IgE response to diphtheria and tetanus toxoids in vivo is inhibited rather than enhanced by covaccination with Bordetella pertussis [94], and the frequency of allergic (like) reactions is similar in subjects immunized with DT and DTP vaccines respectively.

Reactions to HBV vaccines

Unidentified rashes and arthralgias are reported in subjects immunized with HBV vaccines [9-12], but their frequency is not significantly different in placebo groups [12].

Reactions suggesting an immediate HS (ie. generalized pruritus, urticaria and/or Quincke oedema, asthma, anaphylaxis) have been reported in a few patients immunized with a Saccharomyces cerevisiae-derived recombinant vaccine [8, 9, 95]. However, immuno-allergological tests were not performed, except for one patient diagnosed allergic to Saccharomyces cerevisiae, based on immediate response in skin tests and specific IgE determination [95]. In the study of Bakonde et al. [17], children reporting accelerated urticaria, angioedema, and asthma were diagnosed non allergic to HBV vaccines. All children had negative responses in skin tests (pricks with 1/10-diluted vaccine, and ID with 1/100-diluted vaccine) and tolerated booster injection of the suspected vaccines, except for a child with chronic urticaria.

Reactions to pneumococcal vaccines

With the exception of mild and transient reactions at the injection site, which are quite common, injections of pneumococcal vaccines are usually well tolerated. Allergic-like reactions are rare, and include Arthus-like reactions in patients receiving booster injections, acute generalized exanthematous pustulosis, and anaphylactic or anaphylactoid reactions that have not been explored [61-63, 96].

In a recent study, immediate responses in skin tests (pricks with undiluted vaccine, and ID with 1/1000 and 1/100-diluted vaccine) and self-made CAP-Rast were positive in a child reporting a severe anaphylactic reaction to a first injection of 23-valent pneumococcal vaccine [35]. Skin tests and CAP-Rast were negative with the solvent of the vaccine (phenol) in the patient and 10 control children. Skin tests and CAP-Rast were negative in 9 control children, including one child with a well-tolerated vaccination. However, skin tests with the vaccine were slightly positive in a 10^th control non vaccinated child. These results strongly suggest that immediate responses in skin tests and specific IgE determination have a good diagnostic value in children reporting severe reactions suggestive of IgE-dependent HS to pneumococcal vaccines. They also suggest that occult sensitization to pneumococcal antigens may occur in non vaccinated subjects, probably due to carriage or occult infection with Streptococcus pneumoniae.

Reactions to ovalbumin in vaccines

Vaccines, such as measles, mumps, and rubella vaccines (single or associated), and influenza, yellow-fever, and tick-borne encephalitis vaccines, may contain low amounts of ovalbumin and be responsible for anaphylactic reactions in egg-allergic patients [21-26]. Lavi et al. showed that all children with negative skin tests with vaccines tolerated a complete dose of ovalbumin-containing vaccines [97]. In contrast, generalized reactions to vaccine injections performed using a " desensitization " procedure at the hospital were observed in 12.5 % of children with immediate responses in skin tests. Most children with positive skin tests reported severe anaphylactic reactions to egg and egg-containing foods, whereas most children with negative skin tests reported mild to moderate reactions, such as atopic dermatitis and isolated urticaria and/or angioedema.

Thus, immediate-reading skin tests with ovalbumin-containing vaccines should be performed in children with severe IgE-dependent allergic reactions to egg, but are useless in children with non threatening reactions to this food. However, anaphylactic reactions to ovalbumin-containing vaccines have been reported in children without egg allergy [98-100]. In most cases, immuno-allergological studies suggested or diagnosed immediate HS to gelatin included in ovalbumin-containing vaccines (see below).

Reactions to gelatin

Anaphylactic reactions have been reported in patients without ovalbumin allergy immunized with ovalbumin- and gelatin-containing vaccines, such as measles, mumps, and rubella vaccines (single or associated), and in patients immunized with other gelatin-containing vaccines such as Japanese encephalitis virus (JEV) and varicella vaccines [27-34]. Gelatin allergy was diagnosed by immediate responses in skin tests with gelatin-containing vaccines and gelatin, positivity of self-made Rast with vaccine and gelatin, and inhibition of Rast-vaccine with gelatin. Clinical history of allergy to gelatin-containing foods was found a posteriori in several patients, and allergy to gelatin-containing foods developed after reaction to vaccine in 20 to 25 % of patients [31, 32].

In practice, diagnosis is based on immediate responses in skin tests with gelatin-containing vaccine (pricks and ID with 1/10 and 1/100 diluted vaccine respectively) and gelatin (pricks to 1/10 diluted gelatin), and on serum specific anti-gelatin IgE determination. However, the predictive value of skin tests with gelatin-containing vaccines is unknown.

Non-immediate reactions (ie. urticaria, angioedema, and non urticarial rashes) have also been reported in patients immunized with gelatin-containing vaccines [29, 50-52]. These reactions may result from IgG-dependent HS to gelatin, as suggested by a study showing high levels of serum anti-gelatin IgG in most patients with accelerated reactions [51]. However, in this study, specific anti-gelatin IgG antibodies were also detected in serum of patients with IgE-dependent reaction to gelatin-containing vaccines. Non immediate reactions may also result from delayed-type HS to gelatin, as suggested by a study showing late responses in skin tests with gelatin and positive lymphocyte proliferation and IL-2 production in vitro in most patients with delayed reactions to gelatin-containing vaccines [52]. However, other studies have shown that lymphocytes from patients with immediate HS reactions to gelatin contained in vaccines [29, 101] and from subjects tolerant to injections of gelatin-containing vaccines [102] also reacted with gelatin.

Reactions to dextran contained in BCG vaccines

Non explored cases of urticaria and angioedema have been reported in patients receiving booster injections of the BCG vaccine [103]. More recently, severe anaphylactoid reactions were reported in neonates receiving a first injection of BCG. Diagnosis of dextran HS was suggested by high levels of anti-dextran antibody (IgM/IgG) in mother’s serum and cord blood, with low levels in the child’s serum [37, 38, 39]. High levels of anti-dextran antibodies were also found in the serum of an adolescent, 4 weeks after a severe generalized reaction induced by booster injection of the BCG vaccine [36].

These reactions result from circulating immune complex (CIC) formation between preexisting anti-dextran IgG antibodies and dextran injected with the BCG vaccine, complement system activation by CIC, and mast cell and basophil activation by complement-derived factors (anaphylatoxins). Anti-dextran IgG in serum of neonates result from materno-fetal placental transfert. Anti-dextran antibodies in serum of children, adolescents and adults may result from previous immunization with BCG or from occult sensitization by saccharides expressed on the outer membrane of bacterial microorganisms. Those sensitizations may be responsible for low levels of anti-dextran-reacting antibodies (IgM/IgG) in serum of up to 70 % of healthy subjects [104].

Diagnosis is based on anti-dextran antibody determination in mother’s serum and cord blood (neonates), and in the patient’s serum (children, adolescents and adults), three to 4 weeks after the reaction.

Miscellaneous

Poliomyelitis vaccine, MMR and influenza vaccines may contain low amounts of antibiotics. These antibiotics (ie. neomycin) have been suspected in some cases of anaphylaxis [21, 105, 106] and eczema [107] induced by injections of antibiotic-containing vaccines. Immediate urticaria, Quincke oedema and unidentified rashes are reported in 15 % of subjects receiving rabies vaccine. Some cases were related to immediate HS to beta-propionolactone contained in vaccine, based on specific IgE determination with an immunofluorescent method [108].

CONCLUSION

Prevention of (suspected) allergic reactions to vaccines

Prevention of allergic and pseudo-allergic reactions to vaccines is based on judicious consideration of a patient’s clinical history (ie. history of ovalbumin, gelatin or mould allergy; chronology, type and severity of reaction to previous vaccine injection), of the characteristics of the suspected vaccine, and of the risk-clinical benefit ratio of the vaccine.

1. If vaccination or booster immunization is not essential (patients with high levels of serum specific IgM/IgG; vaccination not compulsory; high risk of reaction versus low benefit of the vaccine), withholding of injection of the vaccine is advised.

2. If vaccination is compulsory or essential in patients with proven or highly suspected allergy, choice of a vaccine that does not contain the responsible substance (eg. formaldehyde, mercurothiolate, and aluminium hydroxide) is advised. Recent results in vitro and in vivo have shown that hydrolyzed gelatin in vaccines was equally efficient, but significantly less immunogenic and allergenic than native gelatin [109, 110]. If such vaccine does not exist, management of patients depends on the nature and severity of the reaction:

in patients with large local inflammatory reactions to multivalent vaccines, booster immunization based on sequential injections of vaccines containing a single or a limited number of vaccinating agent(s), at 7- to 10-days intervals, is usually well tolerated.

in patients reporting IgE-dependent urticaria, angioedema, and anaphylactic or anaphylactoid reactions to injections of vaccine, the responsible vaccine should be injected using an appropriate " desensitization " procedure, performed under medical supervision at the hospital (Tables I and II). Injection of a monovalent hapten of dextran (Promit^&circR;) prior to BCG injection may prevent anaphylactoid reactions to dextran-containing BCG vaccine, but, at present, no study of the efficacy of this method has been published.

Finally, to our knowledge, there is no valid method for prevention of other reactions to vaccines, such as eczema, persistent nodules, sterile abcesses, and serum sickness.

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