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Who Might Be at Risk
Who Might Be at Risk
Pharmacological Research
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a r t i c l e i n f o a b s t r a c t
Article history: Vaccinations have been used as an essential tool in the fight against infectious diseases, and succeeded in
Received 24 May 2014 improving public health. However, adverse effects, including autoimmune conditions may occur follow-
Received in revised form 12 August 2014 ing vaccinations (autoimmune/inflammatory syndrome induced by adjuvants – ASIA syndrome). It has
Accepted 14 August 2014
been postulated that autoimmunity could be triggered or enhanced by the vaccine immunogen contents,
Available online xxx
as well as by adjuvants, which are used to increase the immune reaction to the immunogen. Fortunately,
vaccination-related ASIA is uncommon. Yet, by defining individuals at risk we may further limit the
Keywords:
number of individuals developing post-vaccination ASIA. In this perspective we defined four groups of
Vaccine
Autoimmunity
individuals who might be susceptible to develop vaccination-induced ASIA: patients with prior post-
Adjuvants vaccination autoimmune phenomena, patients with a medical history of autoimmunity, patients with a
Allergy history of allergic reactions, and individuals who are prone to develop autoimmunity (having a family
Autoantibodies history of autoimmune diseases; presence of autoantibodies; carrying certain genetic profiles, etc.).
© 2014 Elsevier Ltd. All rights reserved.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Patients with prior post-vaccination autoimmune phenomena: “rechallenge” cases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Patients with established autoimmune conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Patients with a history of allergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Individuals who are prone to develop autoimmunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Family history of autoimmune diseases and the genetic profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Presence of autoantibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Hormonal factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Introduction local reactions to systemic side effects, such as fever, flu-like symp-
toms, and autoimmune conditions (autoimmune/inflammatory
In the last two centuries, vaccinations have been used as an syndrome induced by adjuvants – ASIA syndrome) [2,3].
essential tool in the fight against infectious diseases, and suc- Considerable data have recently been gathered with regard
ceeded in improving public health and in eradicating or minimizing to involvement of the immune system following vaccination,
the extent of several diseases around the world [1]. However, although its precise role has not been fully elucidated [4]. It has
adverse effects may occur following vaccinations, ranging from been postulated that autoimmunity could be triggered or enhanced
by the vaccine immunogen contents, as well as by adjuvants, which
are used to increase the immune reaction to the immunogen [1].
∗ Corresponding author at: Department of Internal Medicine A, Shaare Zedek The relationship between vaccines and autoimmunity is bi-
Medical Center, P.O. Box 3235, Jerusalem 91031, Israel. Tel.: +972 6666372. directional [5]. On one hand, vaccines prevent infectious conditions,
E-mail address: [email protected] (G. Nesher). therefore preventing the development of overt autoimmune
http://dx.doi.org/10.1016/j.phrs.2014.08.002
1043-6618/© 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Soriano A, et al. Predicting post-vaccination autoimmunity: Who might be at risk? Pharmacol Res
(2014), http://dx.doi.org/10.1016/j.phrs.2014.08.002
G Model
YPHRS-2734; No. of Pages 5 ARTICLE IN PRESS
2 A. Soriano et al. / Pharmacological Research xxx (2014) xxx–xxx
Table 1 papilloma virus (HPV) vaccination (Gardasil® ). In all six cases, sev-
Persons who might be at risk of developing vaccination-related autoimmune,
eral common features were observed, namely, a personal or familial
inflammatoty, or allergic phenomena.
susceptibility to autoimmunity and an adverse response to a prior
1. Persons with prior post-vaccination autoimmune phenomena dose of the vaccine.
2. Persons with a medical history of autoimmunity
In regard to quadrivalent anti-HPV vaccine, a case of sudden
3. Persons with a history of allergic reactions (especially vaccination-related
reactions) death of a teenage girl approximately 6 months following her
4. Persons who are prone to develop autoimmunity (having a family history third Gardasil® booster has been reported [9]. The patient expe-
of autoimmune diseases, presence of autoantibodies, certain genetic rienced a range of non-specific symptoms shortly after the first
profiles, etc.) dose of Gardasil injection including dizziness spells, paresthesia in
her hands, and memory lapses. After the second injection, her con-
dition worsened, and she developed intermittent arm weakness,
diseases which in some individuals are triggered by infections. frequent tiredness requiring daytime naps, worsening paresthe-
On the other hand, many reports that describe post-vaccination sia, night sweats, intermittent chest pain and sudden unexpected
autoimmunity strongly suggest that vaccines can indeed trig- palpitations. A full autopsy analysis revealed no anatomical, histo-
ger autoimmunity. Defined autoimmune diseases that may occur logical, toxicological, genetic or microbiological findings that might
following vaccinations include arthritis, lupus (systemic lupus ery- be linked to a potential cause of death. On the other hand, the post-
thematosus, SLE), diabetes mellitus, thrombocytopenia, vasculitis, mortem analysis of blood and splenic tissues revealed the presence
dermatomyositis, Guillain-Barré syndrome and demyelinating dis- of HPV-16 L1 gene DNA fragments, thus implicating the vaccine
orders [6]. Almost all types of vaccines have been reported to be as a causal factor [9]. In particular, the sequence of the HPV DNA
associated with the onset of ASIA [6]. found in blood and spleen corresponded to that previously found
It is important to emphasize that a temporal relationship in 16 separate Gardasil® vials from different vaccine lots [10]. It
between autoimmunity and a specific vaccine is not always appar- was also determined that these HPV 16L1 DNA contaminants were
ent. This matter is complicated by the fact that a specific vaccine complexed with the aluminum adjuvant [11], which would explain
may cause more than one autoimmune phenomenon and, likewise, their long-term persistence in the body of this teenager (more than
a particular immune process may be triggered by more than one 6 months following her third injection). Adjuvants indeed can per-
type of vaccine [2,3,6]. sist in tissues for a long time (up to 8–10 years) [12] where they
Throughout our lifetime the normal immune system walks a stimulate the immune system. This chronic stimulation may lead in
fine line between preserving normal immune reactions and devel- certain cases to the development of a specific autoimmune disease.
oping autoimmune diseases [4]. The healthy immune system is Konstantinou et al. [13] reported two successive episodes of
tolerant to self-antigens. When self-tolerance is disturbed, dysreg- leukoencephalitis associated with hepatitis B vaccination after
ulation of the immune system follows, resulting in emergence of administration of the second and third doses of vaccine in a pre-
an autoimmune disease. Vaccination is one of the conditions that viously healthy 39-year-old woman. Soriano et al. [14], in their
may disturb this homeostasis in susceptible individuals, resulting case-series of giant cell arteritis and polymyalgia rheumatic (PMR)
in autoimmune phenomena and ASIA. following influenza vaccination, described a patient who developed
Fortunately, vaccination-related ASIA is uncommon. Yet, by PMR 8 weeks after influenza vaccination; 2 years later, the patient
defining individuals at risk we may further limit the number of was in clinical remission when she received another influenza vac-
individuals developing post-vaccination ASIA. Who is suscepti- cination, and experienced recurrence of PMR.
ble to develop vaccination-induced ASIA? It is assumed that four Quiroz-Rothe et al. [15] also described a case of post-vaccination
groups of individuals are at risk (Table 1): patients with prior polyneuropathy resembling human Guillain-Barré syndrome in a
post-vaccination autoimmune phenomena, patients with a med- Rottweiler dog. The dog suffered two separated episodes of acute
ical history of autoimmunity, patients with a history of allergic polyneuropathy after receiving two vaccines (both adjuvanted).
reactions, and individuals who are prone to develop autoimmu- Inactivated rabies vaccine was administered 15 days before clinical
nity (having a family history of autoimmune diseases; presence of signs were first noted. Clinical remission was achieved with steroid
autoantibodies; carrying certain genetic profiles, etc.). therapy, but 3 months later the dog had recurrence of polyneuro-
pathy, following another vaccination 12 days earlier. The presence
Patients with prior post-vaccination autoimmune of antibodies against peripheral nerve myelin was demonstrated.
phenomena: “rechallenge” cases Although data is limited, it seems preferable that individuals
with prior autoimmune or autoimmune-like reactions to vaccina-
The notion that there is a tendency of progression to full- tions, should not be immunized, at least not with the same type of
blown immune-mediated disease in patients who experienced vaccine. If vaccination is of utmost importance, it might be given,
initial nonspecific symptoms (such as fever, arthralgia, transient but the patient should be followed closely and treated if necessary.
skin reactions) following the initial administration of vaccination,
if they continue with the scheduled regimen, is controversial. Thus,
the question of whether halting the vaccination protocol would Patients with established autoimmune conditions
have been beneficial for some susceptible groups is still a matter of
debate. The efficacy of vaccination in patients with autoimmunity may
In the analysis by Zafrir et al. [7] of 93 patients who experi- be reduced. On the other hand it is important to realize that the
enced new immune-mediated phenomena following hepatitis B immune system is stimulated by vaccinations (especially when
vaccination, 47% continued with the vaccination protocol despite adjuvants are added), and therefore the chance of side effects is
experiencing variable adverse events following administration of increased, in particular for patients with autoimmune diseases,
the first vaccine dose. Additionally, a personal or familial his- where the immune system is already stimulated. There is a poten-
tory of immune-mediated diseases was documented in 21% of the tial risk of flares following vaccination in such cases. Adjuvanted
cohort, which may have rendered this particular population more vaccines were reported to trigger autoantibodies and ASIA [3,6].
genetically predisposed to developing immune-mediated adverse Live vaccines including Bacillus Calmette-Guérin (BCG) and vac-
reactions following vaccination (see below). Gatto et al. [8] recently cines against herpes zoster, yellow fever (YF) and measles, and
described 6 cases of SLE following quadrivalent anti-human mumps measles and rubella triple vaccine (MMR) are generally
Please cite this article in press as: Soriano A, et al. Predicting post-vaccination autoimmunity: Who might be at risk? Pharmacol Res
(2014), http://dx.doi.org/10.1016/j.phrs.2014.08.002
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YPHRS-2734; No. of Pages 5 ARTICLE IN PRESS
A. Soriano et al. / Pharmacological Research xxx (2014) xxx–xxx 3
contraindicated in immunosuppressed patients with autoimmune the study objectives. Because of such selection bias, the occurrence
conditions due to the risk of an uncontrolled viral replication [16]. of serious adverse reactions resulting from vaccinations in the real
Regarding inactivated or recombinant vaccines, these have the dis- life where vaccines are mandated to all individuals regardless of
advantage of inducing a suboptimal immune response, requiring their susceptibility factors may be considerably underestimated
sometimes the addition of adjuvants, which may be associated [24]. In particular, the number of true allergic reactions to vac-
with ASIA [6]. Several prospective controlled studies targeted safety cines is not known, with an estimated range from 1 per 50,000
issues of vaccination in patients with autoimmune conditions. In doses to 1 per 1,000,000 doses [25]. A higher rate of serious allergic
most studies, no increased risk for severe adverse events or increase reactions is probable if allergens such as gelatin (as in the case of
of activity of pre-existing disease was observed after vaccination. Japanese encephalitis vaccine) or egg proteins are included in the
HPV vaccine was well tolerated and reasonably effective in formulation.
patients with stable SLE and did not induce an increase in lupus Apart from infectious agents, vaccine components include
activity or flare. Disease flares in patients with SLE occurred at potential allergens such as animal-derived proteins or peptides
a similar frequency to that of 50 matched SLE controls (0.22 and (hen’s egg, horse serum, etc.), antibiotics (gentamycin, neomycin,
0.20/patient/year, respectively) [17]. streptomycin, polymyxin B), preservatives (aluminum, formalde-
The safety of hepatitis B vaccine has been assessed in prospec- hyde) and stabilizers like gelatin and lactose. In addition, exposure
tive studies in rheumatoid arthritis (RA) and SLE. In RA patients, to inadvertent allergenic contaminants such as latex (in vial stop-
hepatitis B vaccination was not associated with an appreciable pers and syringe plungers) may also occur.
deterioration in any clinical or laboratory measure of disease. The The classification of allergic reactions distinguishes mainly two
measures of disease activity of the patients and controls during categories: immediate, most likely IgE-mediated reactions, and
the study period did not differ significantly [18]. In SLE, hepatitis delayed reactions. IgE mediated reactions to vaccines may present
B vaccination was safe in patients in remission or mild disease. No with skin manifestations (urticaria, angioedema), respiratory signs
significant change in mean SLEDAI score was detected after vacci- (rhino-conjunctivitis or bronchospasm), gastrointestinal disorders
nation [19]. (diarrhea, abdominal pain and vomiting), and life-threatening car-
Several studies targeted the safety of influenza vaccination in diovascular complications such as hypotension and shock within
patients with autoimmune conditions. A large-scale study of 1668 minutes following the vaccination. It has been estimated that
patients with autoimmune rheumatic diseases and 234 controls immediate anaphylactic life-threatening reactions to vaccines are
evaluated the short-term (3 weeks) safety of non-adjuvanated a rare event, while reactions to vaccines limited to the injection site
Influenza A (H1N1) vaccination. Although no major relapses are more frequent [25].
occurred in this short period of follow up, patients with autoim- Delayed reactions comprise a wide spectrum of manifestations.
mune rheumatic diseases had significantly more arthralgia (9% Fever and local swelling are the most commonly observed, and usu-
compared to 3.8% in controls, p = 0.005), and fever (3.9% and 1.2%, ally are not considered a contraindication for future administration
respectively, p = 0.04) [20]. In another study, the autoantibody of the vaccine [26,27]. Less frequent delayed immunologic reac-
response to influenza vaccination in patients with autoimmune tions include serum sickness, polyarthritis and erythema nodosum.
rheumatic diseases was reported. Female patients had statistically These cases represent a contraindication for future vaccination
significant elevation in anti-nuclear antibody (ANA) titers follow- [28,29].
ing vaccination. In addition, a small subset of patients, especially Gelatin is one of the most common causes of allergic reactions to
ANA-positive patients, had a tendency to develop anti-extractable varicella, MMR, Japanese encephalitis vaccines and influenza vac-
nuclear antibodies (ENA). One month after vaccination 8% of pre- cine [30]. Egg protein is present in yellow fever, influenza, MMR
viously anti-cardiolipin (aCL)-negative patients presented with and some rabies vaccines. Influenza vaccination in patients with
elevated aCL IgG and 4% with elevated aCL IgM antibodies. There egg allergy is an important clinical issue and relevant guidelines
was significantly more aCL IgG/IgM induction after the H1N1 com- are frequently updated (see www.cdc.gov/vaccines). Currently, the
pared to seasonal influenza vaccine. Elevated aCL were mostly amounts of egg protein in most influenza vaccines are small (≤1 g
transient but one female patient developed persistent high levels of per 0.5 ml dose in most cases). In addition, egg-free influenza vac-
aCL IgM [21]. In another study on Influenza H1N1 safety in patients cines are now available for adults with egg allergy. Thus, influenza
with autoimmune rheumatic diseases, no change in disease activity vaccine can be safely administered to the vast majority of patients
scores was observed during a 4-week post vaccination period [22]. with egg allergy, as adverse reactions have generally been very rare
15 other studies on influenza vaccination (reviewed in [23]) did [31–33].
not report significant adverse effects in patients with autoimmune Thimerosal and phenoxyethanol, used as preservatives, have
conditions. been associated with delayed-type hypersensitivity reactions.
For the overwhelming majority of patients with established Thimerosal has been recently removed from vaccine formulations.
autoimmune diseases, vaccines carry no risk of significant disease Aluminum salts are contained in several vaccines, including diph-
flares. However, most studies did not address certain subsets of theria tetanus and pertussis, hepatitis A and B vaccine, human
patients with autoimmune diseases, such as vaccinating patients papilloma virus (HPV) and Haemophilus influenza vaccine. Alu-
with severe, active disease, or vaccination in conditions other than minum sensitization manifests as nodules at the injection site that
SLE or RA. In such subsets, the potential benefit of vaccination often regress after weeks of months, but may persist for years [34].
should be weighed against its potential risk. In subjects with suspected aluminum-induced granuloma a patch
test for aluminum may be used to confirm the sensitization.
Hepatitis B vaccine and anti-HPV vaccines are prepared by har-
Patients with a history of allergy vesting the antigens from cell cultures of recombinant strains of the
yeast Saccharomyces cerevisiae, also known as baker’s yeast. Yeast-
Historically, vaccine trials have routinely been excluded vulner- associated anaphylactic reactions have also been reported as rare
able individuals with a variety of pre-existing conditions. Some of events. DiMiceli et al. [35] reviewed the adverse events described
these include personal or immediate family history of developmen- in the Vaccine Adverse Event Reporting System (VAERS) focusing
tal delay or neurologic disorders (including convulsive disorders of on reports that mentioned a history of allergy to yeast and related
any origin), hypersensitivity to vaccine constituents and any con- anaphylactic reactions following vaccinations. Among 107 reports
dition that in the opinion of the investigators may interfere with of anaphylaxis in subjects with pre-existing yeast allergies, 11 were
Please cite this article in press as: Soriano A, et al. Predicting post-vaccination autoimmunity: Who might be at risk? Pharmacol Res
(2014), http://dx.doi.org/10.1016/j.phrs.2014.08.002
G Model
YPHRS-2734; No. of Pages 5 ARTICLE IN PRESS
4 A. Soriano et al. / Pharmacological Research xxx (2014) xxx–xxx
Please cite this article in press as: Soriano A, et al. Predicting post-vaccination autoimmunity: Who might be at risk? Pharmacol Res
(2014), http://dx.doi.org/10.1016/j.phrs.2014.08.002
G Model
YPHRS-2734; No. of Pages 5 ARTICLE IN PRESS
A. Soriano et al. / Pharmacological Research xxx (2014) xxx–xxx 5
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Please cite this article in press as: Soriano A, et al. Predicting post-vaccination autoimmunity: Who might be at risk? Pharmacol Res
(2014), http://dx.doi.org/10.1016/j.phrs.2014.08.002