G Model

YPHRS-2734; No. of Pages 5 ARTICLE IN PRESS

Pharmacological Research xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Pharmacological Research
journal homepage: www.elsevier.com/locate/yphrs

Review

Predicting post-vaccination autoimmunity: Who might be at risk?

Alessandra Soriano a , Gideon Nesher b,∗ , Yehuda Shoenfeld c
a
Department of Clinical Medicine and Rheumatology, Campus Bio-Medico University, Rome, Italy
b
Department of Internal Medicine A, Shaare Zedek Medical Center, and the Hebrew University Medical School, Jerusalem, Israel
c
The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Sackler Faculty of Medicine, Incumbent of the Laura Schwarz-Kip Chair for
Research of Autoimmune Diseases, Tel-Aviv University, Israel

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
G Model
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

described as ‘probably’ or ‘possibly’ related to administration of Smoking

hepatitis B vaccine.
Finally, antibiotics may also be responsible for anaphylactic Tobacco smoking is one of the most potent environmental
reactions. Thus, an accurate allergy history has to be taken in cases factors that influence autoimmune diseases. Smoking has been
with previous allergic reactions to antibiotics prior to administra- associated with SLE [42,43] and with an increased risk of RA,
tions of vaccines containing these agents. an effect that was more pronounced in males and in seroposi-
tive patients [43]. Studies documenting an increased prevalence of
smokers exist for many autoimmune disorders [43]. Smoking could
lead to autoimmunity by several mechanisms: it interacts with
Individuals who are prone to develop autoimmunity
genetic risk factors such as specific HLA-DR alleles, it induces tis-
sue damage, increases apoptosis, induces leukocytosis and elevates
Family history of autoimmune diseases and the genetic profile
levels of C-reactive protein, intercellular adhesion molecule-1 and
E-selectin, resulting in inflammation [44,45]. To date, no specific
Numerous studies have found that autoimmune diseases have
association was documented between smoking and vaccination-
a genetic predisposition. The abnormal immune response proba-
related ASIA.
bly depends upon interactions between susceptibility genes and
various environmental factors. Evidence for genetic predisposition
to autoimmunity includes increased concordance for disease in Hormonal factors
monozygotic compared to dizygotic twins, and an increased fre-
quency of autoimmunity in patients with affected family members. The hormonal panel, which affects the process leading to
Family history of autoimmunity was prevalent among patients autoimmunity, involves estrogen, prolactin and vitamin D [46,47].
developing SLE following HPV vaccination [8]. In another study, 19% Exposure of the immune system to estrogens may be exoge-
of 93 patients with autoimmune conditions following hepatitis B nous, in the form of oral contraceptives or hormone replacement
vaccination had a family history of autoimmunity [7]. therapy for post-menopausal women. Both forms may be asso-
Certain HLA profiles are associated with autoimmunity. The ciated with disease flare-up. Ovarian stimulation may also lead
most potent genetic influence on susceptibility to autoimmunity is to the development of SLE or induction of SLE flares [48]. The
the major histocompatibility complex (MHC). Different HLA alleles mechanisms by which other potential sources of environmental
are linked to different autoimmune diseases. Examples are DR2 and estrogens, such as phytoestrogens, pesticides and other chemicals,
increased risk for multiple sclerosis and Goodpasture’s syndrome; could alter the immune system are yet to be established. Estrogen
DR3 and increased risk for SLE, celiac disease, type 1 diabetes and leads to increased survival and activation of autoreactive B cells
Graves’ disease; DR4 and increased risk for RA, pemphigus and type [49]. Indeed, in large-scale reports of vaccination-induced ASIA,
1 diabetes; and DR5 and increased risk for Hashimoto’s thyroidi- females seem to be affected more frequently than males [7].
tis and pernicious anemia. HLA profiles were reported in only few Low vitamin D status has been implicated in the etiology of
patients with vaccination-triggered autoimmunity [36]. autoimmune diseases. There is an inverse relationship between
Non-HLA genes also play a role in the genetic etiology of autoim- vitamin D status and incidence of multiple sclerosis [50]. High
mune diseases. Non-HLA genes that have been associated with vitamin D intake was also associated with lower risk for type 1
autoimmunity can be divided into two groups: the first group diabetes mellitus, rheumatoid arthritis and inflammatory bowel
consists of immune-regulatory genes such as the cytotoxic T lym- diseases [51]. Vitamin D status has not been established in cases
phocyte antigen-4, or the protein tyrosine phosphatase gene, or with vaccination-related ASIA.
mutations leading to complement deficiencies or IgA deficiency
[37–40]. Deficiencies in the earlier components of the classical Summary
pathway (especially C4) have been linked to autoimmune diseases,
and autoimmune disorders occur more frequently in individuals Appropriate epidemiological studies should be undertaken to
with selective IgA deficiency. The second group of non-HLA genes confirm reports of individual cases or case series where familial,
that have been associated with autoimmunity consists of tissue- genetic, hormonal or other risk factors for autoimmune condi-
specific genes, such as polymorphisms associated with the insulin tions were found in patients who developed post-vaccination ASIA.
gene, the thyroglobulin gene and the thyroid-stimulating hormone However, it is important to remember that for the overwhelm-
receptor gene [reviewed in 37]. ing majority of individuals, vaccines carry no risk of systemic
autoimmune disease and should be administered according to cur-
rent recommendations. Reports on autoimmune reactions after
vaccination would constitute probably less than 0.01% of all vac-
Presence of autoantibodies cinations performed worldwide, although this rate may be biased
by under-reporting. In addition, many of those reactions are mild
Autoantibodies can be detected in the preclinical phase of and self-limited. Nevertheless we should be cautious, especially in
autoimmune diseases many years before the disease becomes cases with previous post-vaccination phenomena and those with
apparent. Examples are anti-citrullinated protein antibodies allergies, but also in individuals who are prone to develop autoim-
(ACPA) in RA, anti-mitochondrial antibodies (AMA) in primary bil- mune diseases, such as those with a family history of autoimmunity
iary cirrhosis, anti-thyroid antibodies in Hashimoto’s thyroiditis, or with known autoantibodies. In such subsets, the potential benefit
and anti-dsDNA in SLE [41]. Many autoantibodies have the ability of vaccination should be weighed against its potential risk.
to predict the development of an autoimmune disease in asymp-
tomatic persons. The progression towards an autoimmune disease
References
and its severity can be predicted from the type of antibody, its level,
and the number of different antibodies present. The ability to pre- [1] Shoenfeld E, Aron-Maor A. Vaccination and autoimmunity-vaccinosis: a dan-
dict the development of an autoimmune disease in asymptomatic gerous liaison. J Autoimmun 2000;14:1–10.
individuals is especially important when disease progression can be [2] Cohen AD, Shoenfeld Y. Vaccine-induced autoimmunity. J Autoimmun
1996;9:699–703.
prevented by avoiding environmental factors, such as vaccinations, [3] Shoenfeld Y, Agmon-Levin N. ‘ASIA’ – autoimmune/inflammatory syndrome
that may trigger or worsen the disease. induced by adjuvants. J Autoimmun 2011;36(1):4–8.

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

[4] Aron-Maor A, Shoenfeld Y. Vaccination and autoimmunity. In: Shoenfeld Y, [25] Wood RA, Berger M, Dreskin SC, Setse R, Engler RJ, Dekker CL, et al. Hypersen-
Rose NR, editors. Infection and autoimmunity. Amsterdam: Elsevier; 2004. p. sitivity Working Group of the Clinical Immunization Safety Assessment (CISA)
105–16. network. Pediatrics 2008;122:e771–7.
[5] Bijl M, Agmon-Levin N, Dayer JM, Israeli E, Gatto M, Shoenfeld Y. Vaccination of [26] Wood RA. Allergic reactions to vaccines. Pediatr Allergy Immunol
patients with auto-immune inflammatory rheumatic diseases requires careful 2013;24:521–6.
benefit-risk assessment. Autoimmun Rev 2012;11(8):572–6. [27] National Center for Immunization and Respiratory Diseases. General recom-
[6] Perricone C, Colafrancesco S, Mazor RD, Soriano A, Agmon-Levin N, Shoen- mendations on immunization–recommendations of the Advisory Committee
feld Y. Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) on Immunization Practice (ACIP). MMWR Recomm Rep 2011;60:1.
2013: unveiling the pathogenic, clinical and diagnostic aspects. J Autoimmun [28] Rogerson SJ, Nye FJ. Hepatitis B vaccine associated with erythema nodosum
2013:1–16. and polyarthritis. BMJ 1990;301:345.
[7] Zafrir Y, Agmon-Levin N, Paz Z, Shilton T, Shoenfeld Y. Autoimmunity [29] Kelso JM, Jones RT, Yunginger JW. Anaphylaxis to measles, mumps and rubella
following hepatitis B vaccine as part of the spectrum of ‘autoimmune (auto- vaccine mediated by IgE to gelatin. J Allergy Clin Immunol 1997;99:263.
inflammatory) syndrome induced by adjuvants’ (ASIA): analysis of 93 cases. [30] Lasley MV. Anaphylaxis after booster influenza vaccine due to gelatin allergy.
Lupus 2012;21:146–52. Pediatr Asthma Allergy Immunol 2007;20:201.
[8] Gatto M, Agmon-Levin N, Soriano A, Manna R, Maoz-Segal R, Kivity S, [31] Wood RA, Setse R, Halsey N, Clinical Immunization Safety Assessment (CISA)
et al. Human papillomavirus vaccine and systemic lupus erythematosus. Clin Network Hypersensitivity Working Group. Irritant skin test reactions to com-
Rheumatol 2013;32:1301–7. mon vaccines. J Allery Clin Immunol 2007;120:478.
[9] Lee SH. Detection of human papillomavirus L1 gene DNA fragments in post- [32] Centers for Disease Control and Prevention (CDC). Prevention and control
mortem blood and spleen after Gardasil® vaccination – a case report. Adv Biosci of influenza with vaccines: recommendations of the Advisory Committee on
Biotechnol 2012;3:1214–24. Immunization Practices (ACIP) – United States, 2012–13 influenza season.
[10] Lee SH. Detection of human papillomavirus (HPV) L1 gene DNA possibly bound MMWR Morb Mortal Wkly Rep 2012;61:613.
to particulate aluminum adjuvant in the HPV vaccine Gardasil. J Inorg Biochem [33] Committee on Infectious Diseases, American Academy of Pediatrics. Recom-
2012;112:85–92. mendations for prevention and control of influenza in children, 2012–2013.
[11] Lee SH. Topological conformational changes of human papillomavirus (HPV) Pediatrics 2012;130:780.
DNA bound to an insoluble aluminum salt – a study by low temperature PCR. [34] Barbaud A, Deschildre A, Waton J, Raison-Peyron N, Trechot P. Hypersensitivity
Adv Biol Chem 2013;3:76–85. and vaccines: an update. Eur J Dermatol 2013;23:135–41.
[12] Gherardi RK, Coquet M, Cherin P, Belec L, Moretto P, Dreyfus PA, et al. [35] DiMiceli L, Pool V, Kelso JM, Shadomy SV, Iskander J, VAERS Team. Vaccination
Macrophagic myofasciitis lesions assess long-term persistence of vaccine- of yeast sensitive individuals: review of safety data in the US vaccine adverse
derived aluminium hydroxide in muscle. Brain 2001;124:1821–31. event reporting system (VAERS). Vaccine 2006;24:703–7.
[13] Konstantinou D, Paschalis C, Maraziotis T, Dimopoulos P, Bassaris H, Skoutelis [36] Santoro D, Vita G, Vita R, Mallamace A, Savica V, Bellinghieri G, et al. HLA hap-
A. Two episodes of leukoencephalitis associated with recombinant hepatitis B lotype in a patient with systemic lupus erythematosus triggered by hepatitis B
vaccination in a single patient. Clin Infect Dis 2001;33:1772–3. vaccine. Clin Nephrol 2010;74(2):150–3.
[14] Soriano A, Verrecchia E, Marinaro A, Giovinale M, Fonnesu C, Landolfi R, et al. [37] Jacobson EM, Tomer Y. The CD40, CTLA-4, thyroglobulin, TSH receptor and
Giant cell arteritis and polymyalgia rheumatica after influenza vaccination: PTPN22 gene quintet and its contribution to thyroid autoimmunity: back to
report of 10 cases and review of the literature. Lupus 2012;21:153–7. the future. J Autoimmun 2007;28:85–98.
[15] Quiroz-Rothe E, Ginel PJ, Pérez J, Lucena R, Rivero JLL. Vaccine-associated [38] Tomer Y, Davies TF. Searching for the autoimmune thyroid disease susceptibil-
acute polyneuropathy resembling Guillain-Barré syndrome in a dog. EJCAP ity genes: from gene mapping to gene function. Endocr Rev 2003;24:694–717.
2005;15(2). [39] Walport MJ, Davies KA, Morley BJ, Botto M. Complement deficiency and autoim-
[16] van Assen S, Agmon-Levin N, Elkayam O, Cervera R, Doran MF, Dougados M, munity. Ann N Y Acad Sci 1997;815:267–81.
et al. EULAR recommendations for vaccination in adult patients with autoim- [40] Liblau R, Bach JF. Selective IgA deficiency and autoimmunity. Int Arch Allergy
mune inflammatory rheumatic diseases. Ann Rheum Dis 2011;70(3):414–22. Immunol 1992;99:16–27.
[17] Mok CC, Ho LY, Fong LS, To CH. Immunogenicity and safety of a quadrivalent [41] Bizzaro N, Tozzoli R, Shoenfeld Y. Are we at a stage to predict autoimmune
human papillomavirus vaccine in patients with systemic lupus erythematosus: rheumatic diseases. Arthritis Rheum 2007;56:1736–44.
a case–control study. Ann Rheum Dis 2013;72(5):659–64. [42] Costenbader KH, Kim DJ, Peerzada J, Lockman S, Nobles-Knight D, Petri M,
[18] Elkayam O, Yaron M, Caspi D. Safety and efficacy of vaccination against hepatitis et al. Cigarette smoking and the risk of systemic lupus erythematosus: a meta-
B in patients with rheumatoid arthritis. Ann Rheum Dis 2002;61(7):623–5. analysis. Arthritis Rheum 2004;50:849–57.
[19] Kuruma KA, Borba EF, Lopes MH, de Carvalho JF, Bonfá E. Safety and efficacy of [43] Harel-Meir M, Sherer Y, Shoenfeld Y. Tobacco smoking and autoimmune
hepatitis B vaccine in systemic lupus erythematosus. Lupus 2007;16(5):350–4. rheumatic diseases. Nat Clin Pract Rheumatol 2007;3:707–12.
[20] Saad CG, Borba EF, Aikawa NE, Silva CA, Pereira RM, Calich AL, et al. [44] George J, Levy Y, Shoenfeld Y. Smoking and immunity. An additional player in
Immunogenicity and safety of the 2009 non-adjuvanted influenza A/H1N1 the mosaic of autoimmunity. Scand J Immunol 1997;45:1–6.
vaccine in a large cohort of autoimmune rheumatic diseases. Ann Rheum Dis [45] Costenbader KH, Karlson EW. Cigarette smoking and autoimmune disease:
2011;70(6):1068–73. what can we learn from epidemiology? Lupus 2006;15:737–45.
[21] Perdan-Pirkmajer K, Thallinger GG, Snoj N, Cucnik S, Zigon P, Kveder T, [46] Orbach H, Shoenfeld Y. Hyperprolactinemia and autoimmune diseases.
et al. Autoimmune response following influenza vaccination in patients with Autoimmun Rev 2007;6:537–42.
autoimmune inflammatory rheumatic disease. Lupus 2012;21:175–83. [47] Arnson Y, Amital H, Shoenfeld Y. Vitamin D and autoimmunity: new etiological
[22] Elkayam O, Amir S, Mendelson E, Schwaber M, Grotto I, Wollman J, et al. and therapeutic considerations. Ann Rheum Dis 2007;66:1137–42.
Efficacy and safety of vaccination against pandemic 2009 influenza A [48] Zandman-Goddard G, Peeva E, Shoenfeld Y. Gender and autoimmunity.
(H1N1) virus among patients with rheumatic diseases. Arthritis Care Res Autoimmun Rev 2007;6:366–72.
2011;63(7):1062–7. [49] Grimaldi CM, Michaels DJ, Diamond B. Cutting edge: expansion and activation
[23] van Assen S, Elkayam O, Agmon-Levin N, Cervera R, Doran MF, Douga- of a population of autoreactive marginal zone B cells in a model of estrogen-
dos M, et al. Vaccination in adult patients with auto-immune inflammatory induced lupus. J Immunol 2001;167:1886–90.
rheumatic diseases: a systematic literature review for the European League [50] Munger KL, Zhang SM, Oreilly E, Hernan MA, Olek MJ, Willett WG, et al. Vitamin
Against Rheumatism evidence-based recommendations for vaccination in D intake and the incidence of multiple sclerosis. Neurology 2004;62:60–5.
adult patients with auto-immune inflammatory rheumatic diseases. Autoim- [51] Cantorna MT, Mahon BD. Mounting evidence for vitamin D as an envi-
mun Rev 2011;10(6):341–52. ronmental factor affecting autoimmune disease prevalence. Exp Biol Med
[24] Fritsche PJ, Helbling A, Ballmer-Weber BK. Vaccine hypersensitivity – update 2004;229:1136–42.
and overview. Swiss Med Wkly 2010;140:238–46.

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