Vaccination and autoimmune diseases: is prevention of adverse health effects on the horizon?

Abstract

Autoimmune diseases, including multiple sclerosis and type 1 diabetes mellitus, affect about 5% of the worldwide population. In the last decade, reports have accumulated on various autoimmune disorders, such as idiopathic thrombocytopenia purpura, myopericarditis, primary ovarian failure, and systemic lupus erythematosus (SLE), following vaccination. In this review, we discuss the possible underlying mechanisms of autoimmune reactions following vaccinations and review cases of autoimmune diseases that have been correlated with vaccination. Molecular mimicry and bystander activation are reported as possible mechanisms by which vaccines can cause autoimmune reactions. The individuals who might be susceptible to develop these reactions could be especially not only those with previous post-vaccination phenomena and those with allergies but also in individuals who are prone to develop autoimmune diseases, such as those with a family history of autoimmunity or with known autoantibodies, and the genetic predisposed individuals.
Further research is encouraged into the direct associations between vaccines and autoimmune conditions, and the biological mechanisms behind them.

Full text

1 23
EPMA Journal
A journal of predictive, preventive and
personalized medicine
ISSN 1878-5077
EPMA Journal
DOI 10.1007/s13167-017-0101-y
Vaccination and autoimmune diseases: is
prevention of adverse health effects on the
horizon?
Maria Vadalà, Dimitri Poddighe,
Carmen Laurino & Beniamino Palmieri

1 23
Your article is protected by copyright and
all rights are held exclusively by European
Association for Predictive, Preventive and
Personalised Medicine (EPMA). This e-offprint
is for personal use only and shall not be self-
archived in electronic repositories. If you wish
to self-archive your article, please use the
accepted manuscript version for posting on
your own website. You may further deposit
the accepted manuscript version in any
repository, provided it is only made publicly
available 12 months after official publication
or later and provided acknowledgement is
given to the original source of publication
and a link is inserted to the published article
on Springer's website. The link must be
accompanied by the following text: "The final
publication is available at link.springer.com”.

REVIEW
Vaccination and autoimmune diseases: is prevention of adverse
health effects on the horizon?
Maria Vadalà
1,2
&Dimitri Poddighe
3
&Carmen Laurino
1,2
&Beniamino Palmieri
1,2
Received: 11 May 2017 /Accepted: 31 May 2017
#European Association for Predictive, Preventive and Personalised Medicine (EPMA) 2017
Abstract Autoimmune diseases, including multiple sclerosis
and type 1 diabetes mellitus, affect about 5% of the worldwide
population. In the last decade, reports have accumulated on var-
ious autoimmune disorders, such as idiopathic thrombocytope-
nia purpura, myopericarditis, primary ovarian failure, and sys-
temic lupus erythematosus (SLE), following vaccination. In this
review, we discuss the possible underlying mechanisms of auto-
immune reactions following vaccinations and review cases of
autoimmune diseases that have been correlated with vaccination.
Molecular mimicry and bystander activation are reported as pos-
sible mechanisms by which vaccines can cause autoimmune
reactions. The individuals who might be susceptible to develop
these reactions could be especially not only those with previous
post-vaccination phenomena and those with allergies but also in
individuals who are prone to develop autoimmune diseases, such
as those with a family history of autoimmunity or with known
autoantibodies, and the genetic predisposed individuals.
Further research is encouraged into the direct associations
between vaccines and autoimmune conditions, and the biolog-
ical mechanisms behind them.
Keywords Vac c i ne .Predictive preventive personalized
medicine .Individualized patient profile .Diabetes .Multiple
sclerosis .Genetic test
Introduction
In the twentieth century, the vaccination is the most effective
prevention of epidemiologic infectious diseases, such as po-
liomyelitis, measles, mumps, and rubella [1]. So far, more
than 70 vaccines have been licensed on the market against
approximately 30 infectious agents: polio, for example, disap-
peared from the USA by 1979 after widespread vaccination
[2,3].
Although the vaccines are generally safe, with a low inci-
dence of serious systemic adverse events, numerous reports
highlighted the occurrence of neurological (Guillain Barre
syndrome, multiple sclerosis, autism), articular (arthritis, rheu-
matoid arthritis), and autoimmune untoward effects (systemic
lupus erythematosus, diabetes mellitus) after single or com-
bined multivaccine procedures (Table 1)[4].
In the 1994, Stratton and coworkers published the first
report on a causal relationship between several vaccines
(e.g., diphtheria, tetanus toxoids, oral polio vaccines) and au-
toimmune disorders (e.g., Guillain–Barre syndrome, type 1
diabetes, and multiple sclerosis) [5].
These autoimmune disorders (rheumatic, endocrinological,
and gastrointestinal diseases) are increased significantly over
the last 30 years and affect more than 5% of the individuals
worldwide at the age of vaccination programs, which is quite
different compared to the spontaneous autoimmune disease
incidence [6–9]. These observations raise the problem wheth-
er vaccination should be recommended or avoided in autoim-
mune risk patients [10].
The etiology and the trigger mechanism of autoimmune
disease are still unclear [11], but several studies suggest that
a vaccine component (inactive viral/bacterial agent or attenu-
ated living microorganism) or a wild superimposed infectious
agent can induce autoimmune disease in people with a genetic
predisposition [12,13]. For instance, Borrelia burgdorferi and
*Maria Vadalà
mary.vadala@gmail.com
1
Department of General Surgery and Surgical Specialties, Medical
School, Surgical Clinic, University of Modena and Reggio Emilia,
Modena, Italy
2
Network of the Second Opinion, Modena, MO, Italy
3
Department of Pediatrics, ASST Melegnano e Martesana,
Milano, Italy
EPMA Journal
DOI 10.1007/s13167-017-0101-y
Author's personal copy

group A-hemolytic streptococcus contained in the Lyme dis-
ease and S. pyogenes vaccines can cause chronic arthritis and
rheumatic heart disease, respectively [14,15].
The autoimmune reaction to specific self-antigens can be
tissue-specific (such as thyroid, β-cells of the pancreas),
where unique tissue-specific antigens are targeted, or system-
ic, with multiple tissues affected, and a variety of expressed
autoantigens are targeted [2].
The main pathogenic mechanisms of autoimmune disease
are the following: (1) Molecular mimicry by which viral or
bacterial agents trigger an immune response against
autoantigens: the susceptible host is infected by an agent car-
rying antigens immunologically similar to the host antigens
but trigger a different immune response when presented to T
cells. As a result, the tolerance to autoantigens breaks down,
and the pathogen-specific immune response causes tissue
damage [11,16]; (2) Bystander activation by which microbial
agents release sequestered self-antigens from host tissue that
activate antigen-presenting cells (APCs) and dormant
autoreactive T-helper cells. These auto-reactive T cells, along
with macrophages, secrete cytokines, and an additive effect
results in local inflammation and the recruitment of additional
T-helper cells.
We searched, Pubmed/Medline between 1980 and 2016,
the issue of immune disorders following vaccination in order
to review the state of the art and outline the possible patho-
genic link (see Table 1).
Influenza vaccine and Guillain-Barre syndrome
Guillain–Barré syndrome (GBS) affects the peripheral nerves,
with subsequent muscle weakness and loss of reflexes, in 2–8
cases per 100,000 person-years, mainly males [33,34]. It has
been detected after gastrointestinal or upper respiratory tract
infections, herpes virus [8], Epstein–Barr virus [9], cytomeg-
alovirus [10], measles [11], and also vaccination; expressing
autoimmune antibodies (including against GM1, GD1a,
GT1b, and GQ1b gangliosides) that cross-react with epitopes
on peripheral nerves, leading to demyelination and nerve dam-
age [35–38]. Approximately 20–30% of the cases of GBS is
positive to Campylobacter jejuni serologic markers [39,40].
More rarely Haemophilus influenzae type b (Hib) and respira-
tory or other microbic infections show an incidence rate of
0.6–4/100,000 person/year worldwide; GBS has been also
time related with different vaccines administration, such as
rabies, polio, tetanus, Bacillus Calmette-Guerin (BCG), small-
pox, mumps, rubella, hepatitis B, and diphtheria [25].
However, the association of GBS and the influenza vaccine
is more striking. Nachamkin and coworkers using Bswine
flu—influenza A (H1N1)^vaccine on 20 mice supposed the
responsibility of contaminants, such as sialic acid–hemagglu-
tinin (HA) complexes, or C. jejuni antigens mimicking GM1
ganglioside, leading to the high-titer-specific antibodies after
inoculation. In 1976, indeed, the H1N1 vaccination campaign
suddenly dropped in the USA due to an increase, within
6 weeks, of 500 cases of GBS (including 25 deaths) over 45
million vaccinated [41]. Laski et al. [27] recorded a 2% of
increase of GBS cases per million vaccinated persons and also
in the influenza vaccination program (1992–1993).
Hoshino et al. (2012) reported the first clinical case of acute
disseminated encephalomyelitis (ADEM) and GBS associated
to H1N1 vaccination in a 36-year-old man [42]. The man
developed acute urinary retention,weakness, limbs numb-
ness, and difficulty in walking within 10 days after the vaccine
inoculation. Positive anti-GM2 antibodies, which are fre-
quently found in GBS associated with cytomegalovirus infec-
tion [43] were detected. Furthermore, Terryberry et al. [44]
examined the cerebrospinal fluid (CSF) protein level (normal
range 125–150 mg/L) that is always elevated (>400 mg/L) in
GBS patients for the presence of antibodies against 18 myelin
autoantigens. These results suggest a multiinfectious etiology
of GBS or an increased susceptibility of GBS patients to in-
fection, supposing that GBS is probably both a humoral and a
cellular autoimmune disease induced by infection with multi-
ple microorganisms [45].
Tabl e 1 Autoimmune diseases
reported after vaccination Autoimmune disease Type of vaccine Ref
Systemic lupus erythematosus HBV, tetanus, anthrax [17]
Rheumatoid arthritis HBV, tetanus, typhoid/parathypoid, MMR [18]
Multiple sclerosis HBV [19–21]
Reactive arthritis BCG, typhoid, DPT, MMR, HBV influenza [22–24]
Polymiositis/ dermatomyositis BCG, smallpox, diphtheria, DPT [22,25]
Polyarteritis nodosa Influenza, pertussis, HBV [22,25]
Guillain-Barrè syndrome Influenza, polio, tetanus [26–28]
Diabetes mellitus-type I HIB [29–31]
Idiopathic thrombocytopenia MMR, HBV [22,25]
Hashimoto thyroiditis HBV [32]
EPMA Journal
Author's personal copy

Several mechanisms might explain this outcome: (1) The
epitopes of a vaccine could initiate the development of anti-
bodies and/or T cells that could cross-react with epitopes on
myelin or axonal glycoproteins; (2) Destruction of the axonal
or myelin membranes might be due directly by vaccine virus
or vaccine-associated products; (3) Possible genetic suscepti-
bility [42,46,47] might be the background. To date, there are
no epidemiologic studies that address the question of the risk
of GBS development after vaccination, delaying immuniza-
tion for a short period (e.g., one year) in all the patients with a
previous neurological illness is recommended bring some risk
(especially after tetanus toxoid) [48].
Influenza vaccine and diabetes
Type 1 diabetes is an organ-specific autoimmune disease char-
acterized by the selective destruction of pancreatic β-cells.
The pathology shows a decreased β-cell mass with infiltration
of mononuclear cells into Langerhans nests [49].
Currently, around 15 million people, especially young chil-
dren, are affected and epidemiologic studies evidenced an
increase of incidence of type 1 diabetes mellitus in developed
countries, among genetically similar populations (e.g. mono-
zygotic twins), supposing that environmental factors play a
significant role in the process [50–52].
Observational studies state a temporal link between child-
hood vaccinations and the development of type 1 diabetes.
Supposedly, any vaccination after 2 months age increases
the risk of type 1 diabetes but if practiced in the first month
of life, it protects against type 1 diabetes [53,54].
Investigators found a lower incidence of type 1 diabetes in
populations immunized with bacille Calmette–Guerin vaccine
at birth [55], while others found a higher incidence of the
disease in children who received four doses of Hib vaccine
at 3, 4, 6, and 14 months of age than in those who received one
dose of Hib vaccine at 14 months of age [55]. In addition,
21.421 children who received the Hib conjugate vaccine
(USA, 1988–1990) were followed for 10 years and the risk
of type 1 diabetes development was 0.78 when compared with
a group of 22.557 children who did not receive the vaccine
[55]. Hviid and coworkers compared the type 1 diabetes inci-
dence in routinely administered childhood vaccines (including
Hib, diphtheria, tetanus, poliovirus, pertussis, measles,
mumps, and rubella) in a cohort of 740 danish children (born
in the range 1990–2000) [56]. Type 1 diabetes was diagnosed
in 681 children who received at least one dose of vaccine, as
compared with unvaccinated children, with the consequent
rate ratio: 0.91 for Hib vaccine; 1.02 for diphtheria, tetanus,
and inactivated poliovirus vaccine; 1.06 for whole-cell pertus-
sis vaccine; 1.14 for measles, mumps, and rubella vaccine;
and 1.08 for oral poliovirus vaccine. The authors found that
the risk of type 1 diabetes increased among children who had
one or more siblings with diabetes, supposing also that any
association between vaccination and type 1 diabetes would be
more pronounced among children who were genetically
predisposed to diabetes. Classen and coworkers suggested that
the timing of vaccination could be meaningful and that some
vaccines, including Hib vaccine might increase the risk of type
1 diabetes if given at age 2 months or older [29,57].
Nevertheless, this hypothesis was not confirmed by a 10-
year follow-up study of more than 100,000 Finnish children
involved in a clinical trial of the Hib vaccine [30]. In this
study, there was no increased risk of diabetes when children
who had received four vaccine doses at 14–18 months, com-
pared with those who received a single dose at 2 years
[58–59]. Furthermore, the risk of diabetes did not differ be-
tween children in the latter two cohorts and those in a non-
concurrent unvaccinated group.
In Table 2, we reported a summary of epidemiologic stud-
ies, reviewed by specific scientific committee, on the associ-
ation between influenza vaccine and exacerbation of autoim-
mune disease.
HBV vaccine and multiple sclerosis
Multiple sclerosis (MS), also known as a Bchronic demyelin-
ating inflammatory disease,^is an autoimmune disease of the
central nervous system (CNS) with myelin destruction in the
CNs or nerve fibers coating sheath. The pathogenic mecha-
nism of MS is supposed to be an overactive or dysfunctional
immune response to self-antigen. The activated T cells induce
an inflammatory cascade and cell-mediated attack of CNS
myelin [69]. The potential association between the hepatitis
B virus (HBV) vaccination and MS development was first
recorded at the Hospital Paris (1995–1997) in 35 patients that
rose primary demyelinating events, including inflammatory
changes in the CSF protein level and lesions in the cerebral
white matter on T2-weighted MR images, within 8 weeks of
recombinant HBV vaccine injection [70,71], being the wom-
en patients with mean age around 30 years. They were at high
MS risk, because all had also over-representation of the HLA-
DR2 antigen and a positive family history of the disease.
About 200 cases of CNS demyelinating disorders within
2 months after HBV vaccination were reported to the French
pharmacovigilance system [72] and 2 years later, the French
government suspended routine immunization of preadoles-
cents in schools [73]. However, these studies were criticized
for methodological limitations, including methods used for
case ascertainment and control selection, the validation of
vaccination status, and limited statistical power, since the find-
ings of two large-scale studies have shown no significant as-
sociation between HBV vaccination and the MS occurrence
[74,75], but different opinions have also been formulated. For
instance, an unpublished study showed by the Bcapture–
EPMA Journal
Author's personal copy

recapture^method that the real number of MS cases linked to
HBV vaccine was 2–2.5 higher than the officially registered
number in the French pharmacology. Hernan and coworkers
performed a case-control study on 163 MS cases and 1604
matched controls, in the UK within the General Practice
Research Database, and found an increased odds ratios (OR)
for MS (OR 3.1; CI 1.5–6.3) within the 3 years following HBV
immunization [76]. Another epidemiological case-control
study was conducted to evaluate serious post-vaccination ad-
verse events registered in the USA through a spontaneous
reporting system in the VAERS database. Adults receiving
HBV immunization had significantly increased OR for MS
(OR 5.2; CI 1.9–20) in comparison with an age, sex, and
vaccine year-matched unexposed tetanus-containing vaccine
group [77]. In the same way, a French study on demyelination
in childhood [78] showed that Engérix B® vaccine adminis-
tration was associated with an increased trend of confirmed
MS after 3 years (OR 2.77; CI 1.23–6.24). Terney and co-
workers described a case report of a female patient (16 years)
that has neurological symptoms within 10 weeks after HBV
Tabl e 2 : Summary of the epidemiologic studies on relationship between Influenza vaccine and autoimmune diseases
Type vaccine Study design Patients Findings: primary effect size estimated
(95% CI or p value)
Ref
Studies included in the weight of epidemiologic evidence for Influenza Vaccine and Optic Neuritis
Influenza vaccine Case control study -108 patients with optic neuritis OR for optic neuritis onset any time after
influenza vaccination: 1.2 (95% CI,
0.6–2.3)
[60]
Case control study -1,131 patients with optic neuritis OR for optic neuritis onset within 18 weeks
of influenza vaccination: 1.01 (95% CI,
0.79–1.29)
[61]
-3,393 controls
Studies included in the weight of epidemiologic evidence for Influenza Vaccine and MS Relapse in Adults
Influenza vaccine Double-blind, randomized
controlled trial
-49 vaccinated Significant difference in MS relapse within 28
days or 6 months of influenza vaccination
[62]
-54 received placebo
Case-crossover controlled
study
-643 patients with definite or probable
MS diagnoses
RR of MS relapse within 2 months of influenza
vaccination: 1.08 (95% CI, 0.37–3.10)
[63]
Studies included in the weight of epidemiologic evidence for Influenza Vaccine and GBS
Influenza Vaccine Controlled study -12 vaccinated RR of GBS onset within 8 weeks of influenza
vaccination: 1.4 (95% CI, 0.7–2.1)
[64]
-393 unvaccinated
Controlled study 1979–1980 season: RR of GBS onset within 8 weeks of vaccination
during 1979–1980 season: 0.6 (95% CI,
0.45–1.32). RR of GBS onset within 8 weeks
of vaccination during 1980–1981 season: 1.4
(95% CI, 0.80–1.76)
[65]
-7 vaccinated
-412 unvaccinated
1980–1981 season:
-12 vaccinated
-347 unvaccinated
Influenza vaccine Self-controlled study -Three GBS cases in risk period
(42 days after vaccine)
Adjusted RR of GBS onset within 42 days of
influenza vaccination: 0.99 (95% CI,
0.32–3.12; p=.99)
[66]
-225 GBS cases in control period
Self-controlled study -51 GBS cases in risk period
(2-7 weeks after vaccine)
RR of hospitalization for GBS onset during the
2–7 weeks after influenza vaccination: 1.45
(95% CI, 1.05–1.99)
[67]
-141 GBS cases in control period
(26-43 weeks after vaccine)
Retrospective study 2005–2006: 12 events in risk period;
14.4 events in control period.
2006–2007: 17 events in risk period;
15.1 events in control period
2007–2008: 23 events in risk
period; 16.7 events in control period
RR of GBS onset (all ages) 1–42 days after
influenza vaccination during the 2005-2006
season: 0.83 RR of GBS onset (all ages) 1–42
days after influenza vaccination during the
2006–2007 season: 1.13 RR of GBS onset
(all ages) 1–42 days after influenza
vaccination during the 2007–2008
season: 1.37
[68]
EPMA Journal
Author's personal copy

immunization [79]. The laboratory assays and brain MRI con-
firmed acute disseminated encephalomyelitis, collagenosis,
sarcoidosis, and a first attack of MS [80]. The patient was
treated with immunoglobulin therapy for 10 times (1 g/kg/
day) and showed a marked improvement. This report indicates
a temporal link between the encephalomyelitis episode and
HBV vaccination. The mechanism of this link is unclear, but
Faure et al. hypothesize that it is due to molecular mimicry:
HBV polymerase (HBV-pol) protein, which could be a con-
taminant in the recombinant or plasma-derived vaccines,
could be co-purified with HBsAg during the manufacturing
process, and could act as autoantigen, triggering autoimmune
demyelinating disease, such as MS [81].
The controversy between the cited studies suggests the
need of further investigations of the relationship between
HBV vaccination and development of MS.
HBV vaccine and systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is a chronic,
multisystemic autoimmune inflammatory disease with multi-
factorial etiology, including genetic susceptibility, gender dif-
ferences, and immune system alterations triggered by environ-
mental factors, such as ultraviolet radiation (sunlight) as well
as infectious agents, primarily viruses [82,83]. SLE mortality
and morbidity significantly improved in the last decade, and
viral infections have been alleged in the onset or worsening of
symptoms of SLE (20–55%) [84].
Several studies reported the relationship between SLE and
HBV vaccine, with statistically significant temporal/causal
association, probably due to the low prevalence of post-
vaccination autoimmunity, low rate of reporting post-
vaccination adverse events, and various latency periods be-
tween vaccination and the onset of disease, as well as atypical
presentation of autoimmunity following vaccine [85,86].
For instance, a case control study of 265 SLE patients and
355 control subjects showed that the 95% of SLE individuals
reported a history of allergy to medications, particularly to
antibiotics. There was little association with history of mono-
nucleosis, a marker of late infection with Epstein–Barr virus,
implanted medical devices, or hepatitis B vaccination [87].
The first identified SLE case following the HBV vaccine is
recorded by Guiserix et al. [88]. A 26-year-old woman pre-
sented with fever; cutaneous eruption of the face, arms, and
legs; and chills after one week of a first recombinant HBV
vaccine (GenHevac-B) dose. The cutaneous biopsy and im-
munologic tests (antinuclear antibodies, complement compo-
nent C3, and C4 level), carried out 3 months later, confirmed
the SLE diagnosis. The authors supposed that Hb surface an-
tigen protein could play a significant pathogenic role and that
the patient with SLE clinical picture should stop the
immunization protocol, repeating the antinuclear antibody test
3 months later [89].
Agmon-Levin and coworkers analyzed retrospectively the
medical records of 10 SLE patients who developed the disease
following HBV vaccination (20% after the first dose, 20%
after the second dose, and 60% after the third dose) [90].
The mean latency period from the first HBV immunization
and onset of autoimmune symptoms was 56.3 days. The typ-
ical SLE manifestations included the joints (100%), skin
(80%), muscles (60%), and photosensitivity (30%). Seven pa-
tients (70%) followed the vaccination protocol although a
possible autoimmune adverse event was noticed with
follow-up period between 1 and 17 years. The clinical find-
ings showed positive ANAs and other autoantibodies in the
90% of patients, low levels of complement in three of the four
examined patients; and elevated cytokine levels [interleukin-2
(IL-2) receptor, interferon-alpha (INFa), and tumor necrosis
factor (TNF)] in one patient. Accordingly, with this study,
others reported a latency period of several days to 2 years
between immunization and the onset of SLE, since the Post-
HBV vaccine autoimmune conditions can be transient condi-
tions (e.g., vasculitis, arthritis, erythema nodosum) and onset
or relapse of a defined disease (e.g., rheumatoid arthritis, mul-
tiple sclerosis, SLE) [91].
The cause-and-effect interaction between HBV vaccine
and SLE is unclear, although the post-HBV vaccination auto-
immunity might be related to an increase in the number of
immune complexes as well as to the molecular mimicry be-
tween some components of the vaccine (e.g., aluminum,
yeast, thimerosal) and self-antigens [92]. This theory is sup-
ported by the study of Kowal et al. [93]thatprovedcross-
reactivity, at the molecular level, between pneumococcal anti-
bacterial antibodies and generation of antiDNA antibodies, in
SLE patients.
Individuals developing a post-vaccination chronic disease
are rare when compared with the number of vaccines admin-
istered. However, physicians and patients should be encour-
aged to routinely ask about prior vaccination and report such
possible association, as in most countries reporting vaccine
adverse events is based on voluntary rather than obligatory
notification.
Epidemiologic studies, reported in Table 3,hypothesized
that the vaccine could be the precipitating event but these
studies did not provide evidence linking these autoimmune
diseases to HBV vaccine.
MMR vaccine and idiopathic trombocytopenia
Another confirmed autoimmune adverse effect associated
with vaccination is the induction of idiopathic thrombocyto-
penia (ITP), also known as immune thrombocytopenia, fol-
lowing the measles–mumps rubella (MMR) vaccine, in
EPMA Journal
Author's personal copy

particular within 6 weeks of immunization [95–97]. ITP is an
autoimmune condition, clinically characterized by low platelet
count (less than 100,000 platelets per microliter) due to in-
creased destruction and impaired platelet production, and by
the presence of autoantibodies (IgG) directed toward platelet
membrane antigens (glycoproteins IIb–IIIa) [98]. The main
clinical manifestations include various degrees of cutaneous
and/or mucosal purpura; life-threatening hemorrhages occur
in less than 5% of adult patients [99]. ITP risk following the
MMR vaccine is seen highest in children, aged 12–19 months,
which is the estimated age when children would normally be
receiving the MMR vaccine.
The development of ITP after the administration of a live
attenuated measles vaccine was first described by Oski and
Naiman in 1966 [100]. Since then, epidemiological data have
clearly demonstrated higher incidence rates of ITP after MMR
vaccine, administered alone or in combination [101,102]; and
in 1993, the Vaccine Safety Committee of the Institute of
Medicine declared the potential relationship between the
MMR vaccine and ITP [103].
Miller and coworkers identified 35 cases (aged 12 to
23 months) of ITP after MMR vaccination and estimated that
the attributable risk of ITP within 6 weeks of MMR vaccina-
tion is 1 in 32,300 vaccinations [8]. These findings have been
Tabl e 3 : Summary of the epidemiologic studies on relationship between HBV vaccine and autoimmune diseases
Type vaccine Study design Patients Findings: primary effect size estimated (95% CI or
p value)
Ref
Studies included in the weight of epidemiologic evidence for HBV Vaccine and Optic Neuritis
HBV vaccine Case control study -108 patients with optic neuritis, OR for optic neuritis onset any time after hepatitis B
vaccination: 1.2 (95% CI, 0.5–3.1)
[60]
-228 controls
Case control study -1,131 patients with optic neuritis, OR for optic neuritis onset within 18 weeks of hepatitis
B vaccination: 1.02 (95% CI, 0.68–1.54)
[61]
-3,393 controls
Studies included in the weight of epidemiologic evidence for HBV Vaccine and MS onset in adults
HBV vaccine Case control study -190 patients with MS Age-adjusted RR of MS onset any time after hepatitis B
vaccination compared to healthy controls: 0.9
(95% CI, 0.5–1.6)
[19]
-534 healthy controls, Age-adjusted RR of MS onset within 2 years of hepatitis
B vaccination compared to healthy controls: 0.7 (95%
CI, 0.3–1.7)
-111 breast cancer controls Age-adjusted RR of MS onset any time after hepatitis B
vaccination compared to breast cancer controls: 1.2
(95% CI, 0.5–2.9)
Age-adjusted RR of MS onset within 2 years of hepatitis
B vaccination compared to breast cancer controls: 1.0
(95% CI, 0.3–4.2)
HBV vaccine Case control study -332 MS patients, OR for MS onset any time after hepatitis B vaccination:
0.8 (95% CI, 0.5–1.4
[60]
-722 controls
Case control -163 MS patients, OR for MS onset within 3 years of hepatitis B
vaccination: 3.1 (95% CI, 1.5–6.3)
[76]
-1,604 controls
Studies included in the weight of epidemiologic evidence for HBV Vaccine and first demyelinating event in adults
HBV vaccine Controlled study -440 patients with demyelinating disease; OR for demyelinating disease onset any time after
hepatitis B vaccination: 0.9 (95% CI, 0.6–1.5)
[60]
-950 controls
Controlled study -1,131 patients with optic neuritis; OR for optic neuritis onset within 18 weeks of hepatitis
B vaccination: 1.02 (95% CI, 0.68–1.54)
[61]
-3,393 controls
Self-controlled study -234 patients with a frst CNS demyelinating
event
RR of first demyelinating event 0–60 days after hepatitis
B vaccination: 1.68 (95% CI, 0.76–3.68). RR of first
demyelinating event 61–365 days after hepatitis B
vaccination: 1.33 (95% CI, 0.65–2.69). RR of first
demyelinating event indefinitely (maximum of
2.29 years) after hepatitis B vaccination: 1.35
(95% CI,0.61–3.01)
[94]
EPMA Journal
Author's personal copy

confirmed in the further case-control study: 23 children (aged
13–24 months) developed ITP after receiving their first MMR
dose inoculation, occurring symptoms between day 7 and day
28 after vaccination.
France and coworkers evaluated the risk of ITP after MMR
immunization in a large population (1,036,689 children, aged
12 months to 18 years) [104]. By using electronic databases,
they identified 1673 individuals as potential cases (low plate-
let count ≤50,000/μL). Of these, they excluded 532 who had a
known cause of thrombocytopenia (e.g., aplastic anemia, leu-
kemia) and 546 who were 30 days of age at the time of diag-
nosis. These data were similar in magnitude to the results of
Miller et al. (IRR: 3.27) and Black et al. (odds ratio: 6.10)
[105,106]. Furthermore, the authors found a significant asso-
ciation (IRR: 7.1) on children aged 12 to 15 months. The
hypothesis that MMR-related ITP may be due to a specific
immunological mechanism is supported by the recent findings
by Okazaki [109] who detected anti-measles and anti-rubella
virus IgG antibodies in platelets isolated from a case (aged
15 month) who developed ITP within4weeksof the sequen-
tial MMR vaccine. The antibodies were found on day 154 of
illness when the platelet count was very low but were no
longer detectable on day 298 (at the end of the period of
thrombocytopenia) or on day 373, when the disease was cured
[107]. Some ITP cases that can be negative for antiplatelet
antibodies can be due to other mechanisms: here, complemen-
tary T cell immune-mediated destruction or the reduction in
the formation of platelets is suspected and with presentationof
glycoprotein antigens to APCs, autoantibody generation is
stimulated, and ITP can occur [108,109].
Anyway, the ITP disappears in a few days or weeks in most
cases: more than 90% of children are completely cured within
6 months of diagnosis, and less than 10% develop chronic
disease [110].
In conclusion, although MMR vaccine is associated with
an increased ITP risk, the risk is lower compared to the wild
viruses, and the clinical picture is less severe. Children with
chronic ITP require a more cautious approach: for example,
the British Committee for Standards in Haematology advises
measuring measles titers before booster administration in or-
der to decide whether a further dose is indicated. If a child has
not been previously immunized, the risk–benefit ratio of
MMR should be weighed against the risk of measles in the
community at the time [111].
MMR vaccine and rheumatoid arthritis
Rheumatoid arthritis (RA) is a chronic autoimmune disease of
unknown etiology, characterized by inflammatory
polyarthritis affecting 1% of the adult population worldwide
[112,113]. RA is caused by a combination of genetic suscep-
tibility and environmental factors, including not only
increased antibody levels of measles virus but also by vaccine
strain [114]. A few case reports describe arthritis as a common
complication of wild rubella virus in adults, but it occurs less
often in children; that in several cases represents the first RA
clinical manifestation [115].
Nussinovitich and coworkers (1995) described the first
case of acute monoarthritis with effusion in a child (aged
19 months) within8daysafter mumps and measles vaccine,
most probably due to the mumps component [116]. The lab-
oratory findings confirmed the following (1) Mumps antibod-
ies (IgG) as measured 1 month later by complement fixation
assays were 1/64; (2) Measles antibodies were 1/16 (the titer
normally expected after vaccination was >1/8). The patient
was treated with intravenous cefuroxime for 5 days, followed
by cephalexin by mouth for another 21 days; and his joint
symptoms subsided within 24 h.
Another study evaluated the incidence of joint manifesta-
tions within 6 weeks after MMR immunization [117]: it in-
cluded 2658 vaccinated and 2359 non-vaccinated children,
confirming an increased risk of joint symptoms (arthralgia or
arthritis) in the immunized children.
Symmons et al. [23] suggest three possible explanations to
the potential association between immunization and the devel-
opment of arthritis: (1) it is due to the casual occurrence of two
common phenomena: immunization and arthritis; (2) the vac-
cine activates a specific form of arthritis that is distinct from
RA (post-immunization arthritis) and that is usually self-
limited; and (3) the vaccine is one of the factors which can
trigger the development of RA (so as the infections). A few
studies were identified, in the literature, from specific scien-
tific committee to evaluate the risk of autoimmune disease
after the administration of MMR vaccine (Table 4).
HPV vaccine and primary ovarian failure
The HPV vaccines (such as Gardasil® and Cervarix®) were
introduced to fight the cervical cancer; however, several cases
of onset or exacerbations of autoimmune diseases following
vaccination have been reported [128]. In 2013, Colafrancesco
reviewed three women (two of them are sisters, thus bringing
the relevance of genetics linkage) that developed primary
ovarian failure within 2 years by HPV vaccine [129]. All the
patients developed secondary amenorrhea, low estradiol, and
high follicle-stimulating hormone (FSH) and luteinizing hor-
mone (LH) following HPV vaccination, and elevated anti-
antibodies levels (e.g., anti-thyroid antibodies and anti-
ovarian antibodies). The authors suggested that the use of
adjuvants in the HPV vaccine could be a risk factor for
eliciting an autoimmune reaction to the vaccination: the
DNA fragments detected in 16 different Gardasil® vaccines
appeared to be bound to the aluminum used in the vaccine
formulation.
EPMA Journal
Author's personal copy

Tabl e 4 : Summary of the epidemiologic studies on relationship between MMR vaccine and autoimmune diseases
Type vaccine Study design Patients Findings: primary effect size estimated (95% CI
or p value)
Ref
Studies included in the weight of epidemiologic evidence for MMR Vaccine and transient arthralgia in women and children
MMR vaccine Retrospective study - 485 vaccinated women; Vaccinated: 4 cases of arthralgia (0.8%).
Unvaccinated: 3 cases of arthralgia
(0.6%). Differences were not
statistically significant
[118]
- 493 unvaccinated women
Double-blind, randomized
controlled trial
-268 vaccinated, Acute arthralgia or arthritis within 12 months
of rubella vaccination: 1.73 (95% CI,
1.17–2.57)
[119]
-275 received placebo
Retrospective study -971 seronegative, vaccinated women, Vaccinated: 4 patients diagnosed as acute
arthralgias cases and 1 as indeterminate,
seropositive, unvaccinated.
Controls: one acute event
[120]
-2,421 seropositive, unvaccinated,
aged-matched controls;
-924 seronegative, unvaccinated,
unmatched controls
Double-blind, randomized,
controlled trial
Presence of Dominican Republic-2
(DR2) virus:
Acute arthralgia or arthritis within 12 months of
rubella vaccination in women expressing
DR2: 4.8 (95% CI, 1.2–18.8)
[121]
41 vaccinated;
38 received placebo
MMR vaccine Double-blind, controlled
crossover study
581 twin pairs Maximum difference rate of arthropathy
between MMR vaccine and placebo groups
at 7–9 days after vaccination: 0.8% (95% CI,
0.2–1.3%)
[122]
Double-blind, controlled
crossover study
581 twin pairs, separated into two age
groups: 14–18 months and
6 years of age
Adjusted OR of arthralgia in the 14–18 month
age group within 21 days of MMR
vaccination: 3.66 (95% CI, 1.74–7.70)
[123]
Double-blind, randomized
control trial
2,216 vaccinated with MMR II, 3,521
unvaccinated
MMR II group: 8 joint reactions (primarily
transient arthralgia) within 30 days of
vaccination
[124]
Case-control 125 patients with psoriatic arthritis;
163 patients with psoriasis
OR for psoriatic arthritis after rubella
vaccination: 12.4 (95% CI, 1.20–122.14)
[125]
Studies included in the weight of epidemiologic evidence for MMR Vaccine and Type 1 Diabetes
MMR vaccine Case-control -393 children with type 1 diabetes; OR for type 1 diabetes diagnosis; any time after
MMR vaccination: 0.95 (95% CI, 0.71–1.28)
OR for type 1 diabetes diagnosis any time after
measles vaccination: 0.74 (95% CI, 0.55–1.00)
OR for type 1 diabetes diagnosis any time after
mumps vaccination: 1.75 (95% CI,
0.54–5.70). OR for type 1 diabetes diagnosis
any time after rubella vaccination: 1.24 (95%
CI,0.41–3.73)
[126]
-786 controls matched on age, sex,
and county
Case-control -136 children with type 1 diabetes; OR for type 1 diabetes diagnosis any time after
MMR vaccination: 0.382 (95% CI,
0.201–0.798) OR for type 1 diabetes
diagnosis any time after measles
vaccination: 0.777 (95% CI,
0.403–1.498)
[127]
-272 controls matched on age and
registration with the same family
pediatrician
Retrospective cohort 739,694 children Rate ratio for type 1 diabetes diagnosis any
time after one dose of MMR vaccine
compared to the unexposed: 1.14 (95%
CI, 0.90–1.45)
[56]
EPMA Journal
Author's personal copy

HPV vaccine and SLE
In 2013, Gatto and coworkers investigated cases of SLE in
women following HPV vaccination [130]. The onset of SLE
occurred during the later doses of the HPV vaccination sched-
ule and all the women had family histories of autoimmune
disease. The major remitting patients with immunosuppres-
sion therapy had mild adverse effects to the vaccine immedi-
ately following the first dose of the HPV vaccine and then
developed heavier SLE symptoms within two months after
subsequent vaccine administration. In conclusion, the authors
hypothesized a potential causal link between HPV vaccination
and onset or relapse of SLE [130]. Thus, although for most
patients, the benefits of immunization outweigh its risks, cli-
nicians must be aware of the odds for an autoimmune disease
onset or exacerbation following HPV vaccination. A meticu-
lous pre-vaccination risk–benefits assessment, close follow-
up during and after each boost of vaccination, as well as as-
sessment of concomitant therapy with immune-modulating
agents such as hydroxychloroquine (HCQ), seems reasonable
for patients with an autoimmune disease. In 2013, Macartney
and colleague reviewed the literature of HPV vaccine-related
adverse effects and they reported almost mild reaction such as
local injection site swelling with local or generalized pain
[131]. Subjective reports are the primary source of vaccine
adverse event but a systematic approach to track vaccination
morbidity is required. In addition, the short follow-up institu-
tionally fixed by the health authorities miss mild and severe
long-term adverse reactions and large genetically different
vaccinated group would better outline the problem. Thus,
long-term surveillance of vaccines among interethnic popula-
tions groups would define more accurately their safety.
HPV vaccine and ASIA syndrome
Recently, several reports have suggested grouping different
autoimmune conditions that are triggered by external stimuli
(e.g., exposure to vaccine) as a single syndrome called auto-
immune syndrome induced by adjuvants (ASIA) [132]. This
syndrome is characterized by the appearance of myalgia, myo-
sitis, muscle weakness, arthralgia, arthritis, chronic fatigue,
sleep disturbances, cognitive impairment, and memory loss.
This term was introduced by Yehuda Shoenfeld, who
highlighted the pathogenic role of adjuvants in the induction
of autoimmune syndromes: these compounds mimic evolu-
tionarily conserved molecules (e.g., bacterial cell walls, LPS,
unmethylated CpG-DNA) and bind to toll-like receptors
(TLRs). They activate dendritic cells (DCs), lymphocytes,
and macrophages, increasing subsequently the release of
chemokines and cytokines from T-helper and mast cells
[133–137]. The adjuvants added into vaccines can induce a
non-specific activation of the immune system with a
subsequent expansion of autoreactive (in our case, myelin
specific) lymphocytes that may be further accelerated by de-
fective regulatory cells/circuits, in genetically susceptible in-
dividuals. Indeed, the main individuals at ASIA syndrome risk
are as follows: (1) patients with prior post-vaccination auto-
immune phenomena, (2) patients with a medical history of
autoimmunity, (3) patients with a history of allergic reactions,
and individuals who are prone to develop autoimmunity (hav-
ing a family history of autoimmune diseases, presence of au-
toantibodies, carrying certain genetic profiles, etc.) [138].
In the 2016, we retrospectively described a case series in-
cluding 18 girls (aged 12–24 years) for the evaluation of
Bneuropathy with autonomic dysfunction^immediately after
HPV vaccine [Gardasil® (9 girls) and Cervarix® (9 girls)]
[139]. All girls complained of long-lasting and invalidating
somatoform symptoms of the recently described ASIA syn-
drome (including asthenia, headache, cognitive dysfunctions,
myalgia, sinus tachycardia, and skin rashes) that have devel-
oped 1–5days(n=11),5–15 days (n= 5), and 15–20 days
(n= 2) after the last dose vaccination. The HPV vaccine for-
mula contains aluminum (225 e 500 μg/each dose in
Gardasil® and Cervarix®, respectively) but also high poly-
sorbate 80 (50 mcg) concentration that might also induce a
greater meningeal permeability leading to a facilitated en-
trance of many substances to the CNS. Based upon these
observations, it might be speculated that HPV vaccine could
induce some abnormal activation of immune competent cells
in the CNS, such as the glia.
Among the risk factors for ASIA syndrome, the metal hy-
persensitivity in girls, mainly genetically predisposed individ-
uals, exposed to immunization, has been suspected. We tested
five adjuvant metals (aluminum, mercury, nickel, methyl-
mercury, thimerosal) in our case series through in vitro blood
test and lymphocyte transformation test (MELISA®).
However, the study was frustrating, being the seven girls neg-
ative to each of the five metals tested, showing a metal-
hypersensitivity only in nine patients: toxicity to aluminum
(two girls), reactivity to nickel (seven girls), followed by mer-
cury (four girls) [140].
Case control and epidemiological studies and a detailed
genetic analysis of affected girls and their family might better
define the link between vaccination and CNS damage.
HPV Vaccine and transverse myelitis
Transverse myelitis (TM) is the paradigm of inflammatory
myelopathy, in which an immune-mediated process causes
neural injury to the spinal cord, resulting in varying degrees
of weakness, sensory alterations, and autonomic dysfunction.
TM may exist as part of a multifocal central nervous system
disease (e.g., multiple sclerosis), multisystemic disease (e.g.,
SLE),orasanisolatedidiopathicentity[141]. A recent review
EPMA Journal
Author's personal copy

(2014) summarizes nine published cases of CNS demyelin-
ation, including not only myelitis but also optic neuritis and
encephalitis, following HPV vaccination [142]. There are pre-
vious reports of CNS inflammatory syndromes following
HPV vaccination describing a 10-day to 5-month time lapse
from vaccination to symptom onset, with a minimum of a 21-
day interval in cases developing myelitis. For instance, a 14-
year-old immunocompetent girl noticed her left hand felt
weak and numb, after 3 days of a first dose of HPV vaccine
(Gardasil®) and these symptoms spread to the rest of her arm
and ipsilateral thoracic region, abdomen, and leg. On a med-
ical examination, the girl had bilateral diminished sensation to
light touch, pain, and vibration below C5 level; muscle weak-
ness of her left arm and leg; and hyperreflexia bilaterally with
nonsustained clonus and a left extensor plantar response.
Neurologic examination was otherwise normal. The relation-
ship between HPV vaccination and subsequent CNS inflam-
mation remains unclear. In the genesis of CNS inflammatory
disorders post-HPV vaccination, both molecular mimicry be-
tween vaccine antigen and myelin proteins and toxic materials
in vaccine components can represent potential causative fac-
tors [143]. Regarding etiology, the patient was immunocom-
petent and there were no systemic signs of infection. The
absence of cells in CSF analysis and the presence of
oligoclonal bands with an increased nonspecific immunoglob-
ulin M ratio suggested a background of a CNS inflammatory
condition; however, the mechanism of disease, whether viral-
induced or immune-mediated, remains to be determined.
Genetic basis for autoimmune diseases following
vaccination
Several studies identified genetic variants of the human leu-
kocyte antigen (HLA) gene family, significantly associated
with vaccine-induced autoimmune activation; some of these
HLA variants include HLA DRB1, HLA DRB2, HLA DR4,
HLA and DRQ8 that are implicated in autoimmune processes,
such as detection and removal of antigens during infection
[144–146].
A significant study, conducted in 2008, found statistical
correlations between six genetic variants [three variants of
interleukin 4 (IL4), two variants of interferon regulatory factor
(IRF1), and one variant of methylenetetrahydrofolate reduc-
tase (MTHFR), the C677T allele] and adverse event vaccine
following smallpox vaccine [147].
IL4 is an anti-inflammatory cytokine involved in the cell-
mediated inflammatory immune response, including inhibi-
tion of monocyte and dendritic cell migration to inflamed
tissue and promotion of Th2 effector pathways [148,149].
CD4+ T cell differentiation away from the Th1 pathway ren-
ders them unable to activate macrophages. Upon immunolog-
ical challenge by vaccination, the differentiation of CD4+ T
cells into armed Th1 versus Th2 cells plays a vital role in
determining whether the adaptive immune response will be
dominated by humoral effectors or macrophage activation
[150]. Thus, genetic polymorphisms related to inappropriate
regulation of IL-4 expression and/or activity of IL-4 cytokine
may over-stimulate inflammatory responses, leading to the
development of adverse events. IL-4 dysregulation may also
play a role in AEs resulting from the inappropriate clearance
of apoptotic immune effector cells after infection, as this func-
tion is normally carried out by macrophages.
IRF1 is a transcription factor involved in the release of
cytotoxic interferon, and cell apoptosis; it may push macro-
phage activity beyond the threshold of AE development [151].
Hyperactive IRF1 may also prolong the life of immune cells
that should be cleared following infection, protracting the pe-
riod of inflammation and leading to AEs.
The MTHFR 677 variant has been associated with many
phenotypes, including cardiovascular function, transplant
health, toxicity of immunosuppressive drugs, and systemic
inflammation [152,153]. Elevated plasma homocysteine
levels stimulate endothelial inflammatory responses, which
could contribute to adverse events. Alternatively, since vacci-
nation elicits 109 immune responses involving the rapid pro-
liferation of cells, demand for DNA synthesis metabolites
would be elevated, and alterations in the level or activity of
MTHFR enzyme may exert significant influence over this
process.
The results of this study evidence the utility of validation in
genetic studies of complex phenotypes. As with any statistical
association, follow-up studies are needed to identify the par-
ticular genetic susceptibility variants and examine the func-
tional consequences of polymorphisms in the AE-associated
genes. Since the authors found multiple AE-associated SNPs
in regions of IL-4 and IRF1, focused studies should be under-
taken to characterize the genetic variability in these candidate
regions. While the association of AEs with a non-synonymous
polymorphism in the gene 113 for MTHFR points toward
functional significance of this SNP, deep resequencing should
determine whether this is indeed the case. For all three candi-
date genes, functional studies are needed to connect genetic
polymorphisms to AEs following immunization.
Discussion
Most of the studies on vaccine-related adverse events reduce
to a 10–20 day follow-up analysis, the recruitment of putative-
ly linked autoimmune events. The analysis of potential corre-
lation between vaccine and autoimmune events/diseases is
puzzling, being not-specific and without a clear cut diagnosis,
not excluding other contemporary virus infections, environ-
mental factors, or nutrition imbalance. The adjuvants (e.g.,
aluminum, thimerosal) in vaccines were related to
EPMA Journal
Author's personal copy

autoantibodies levels, such as raised anticardiolipin antibodies
after influenza vaccination in patients with lupus, anti-
Epstein–Barr antibodies after HPV vaccine [139,154–156].
The adjuvants enhance and prolong the immune response,
promoting physical protection against the pathogen and facil-
itating its translocation to lymph nodes [157]. The develop-
ment of an inactivated vaccine would be a solution for the
immunosuppressed individuals. However, killed vaccines
may have disadvantages as risk of incomplete inactivation,
change in immunogenic properties of the virus, and the use
of multiple doses [158,159]. The relationship between vac-
cines and autoimmunity is bidirectional. On the one hand, the
immunization prevents infectious diseases, and thus in turn
prevents the development of an overt autoimmune disease
which in some individuals is triggered by infections.
Furthermore, Singh et al. [160] suggest that immunization
with certain vaccines may stimulate the immune system to
modulate or prevent the generation of pathogenic cells by
the induction of regulatory cells, and thus prevent autoimmu-
nity. The post-vaccination adverse events strongly suggest that
vaccinations can trigger autoimmunity in a similar way to the
infections to be prevented. In this way, vaccination should be
considered as part of the mosaic of autoimmunity, in which
abrogation of an autoimmune disease (and in the case of vac-
cination, the prevention of an autoimmune disease) could con-
comitantly induce another autoimmune disease.
During the vaccination process, only a comprehensive and
multidisciplinary strategy can help to reduce the risk that a new
one will induce autoimmune reactions: (1) the question whether
clinical manifestations of an autoimmune nature are known to
be associated with the infectious disease that will be the target
of the new vaccine has to be raised. If such events have been
Tabl e 5 A summary of the
epidemiologic assessments and
causality conclusions for hepatitis
Avaccine
Typ e
vaccine
Adverse event Epidemiologic
assessment
Studies contributing
to epidemiologic
assessment
Causality
conclusion
Hepatitis A
vaccine
Transverse myelitis Insufficient None Inadequate
MS Insufficient None Inadequate
Guillain–Barré syndrome Insufficient None Inadequate
Chronic inflammatory disseminated
polyneuropathy
Insufficient None Inadequate
Autoimmune hepatitis insufficient None Inadequate
Tabl e 6 A summary of the
epidemiologic assessments and
causality conclusions for hepatitis
B vaccine
Typ e
vaccine
Adverse event Epidemiologic
assessment
Studies contributing
to epidemiologic
assessment
Causality
conclusion
Hepatitis B
vaccine
Transverse myelitis Insufficient None inadequate
Optic neuritis Limited 2 Inadequate
MS onset in adults Limited 4 Inadequate
MS onset in children Limited 1 Inadequate
MS relapse in adults Limited 1 Inadequate
MS relapse in children Limited 1 Inadequate
First demyelinating event in
adults
Moderate 3 Inadequate
First demyelinating event in
children
Limited 1 Inadequate
Guillain–Barré syndrome Insufficient None Inadequate
Chronic Inflammatory
Disseminated
Polyneuropathy
Insufficient None Inadequate
Onset or exacerbation of
rheumatoid arthritis
Limited 1 Inadequate
Type 1 diabetes Moderate 1 Inadequate
Fibromyalgia Insufficient None Inadequate
EPMA Journal
Author's personal copy

reported, e.g., for group A streptococcal diseases, attention
should be given to avoid reproducing the natural pathogenic
process; this process might include the identification and exclu-
sion of naturally pathogenic epitopes; (2) potential molecular
and immunological mimicry between vaccine antigens and host
components should be extensively analyzed through a combi-
nation of bioinformatics and immunological studies.
Information should be gathered on the relative ability of such
epitopes to bind to MHC molecules, to be processed by
antigen-presenting cells, and to be recognized by autoreactive
T cells. Molecular mimicry in itself is not sufficient to trigger
autoimmune pathology, and other factors intrinsic to infections,
such as tissue damage and long-lasting inflammatory reaction,
might be required as well. For example, a new Lyme disease
vaccine contains an immunodominant epitope of the outer sur-
face protein A of Borrelia burgdorferi that displays great ho-
mology to human lymphocyte function-associated antigen-1,
an adhesion molecule of the two integrin family [161].
Although this homology raised concern about the safety of this
vaccine, there was no evidence for an increased frequency of
arthritis in individuals who received the Lyme vaccine [162];
(3) indicative information can be obtained through the use of ad
hoc experimental models of autoimmune diseases. Different
vaccine formulations and adjuvants can be compared with re-
spect to their potential capacity to induce or enhance the ex-
pression of pathology in relevant models; (4) appropriate im-
munological investigations, e.g., autoimmune serology, can be
systematically included in phase I–III clinical trials.
In conclusion, clinical surveillance of potential autoim-
mune adverse effects and appropriate laboratory tests
should be considered for inclusion in the monitoring pro-
tocol. Such surveillance should be extended through the
postmarketing stage if specific rare events have to be
ruled out [10].
Reports on autoimmune reactions after vaccination would
constitute probably less than 0.01% of all vaccinations per-
formed worldwide, although this rate may be biased by under-
reporting.
We reported a summary of epidemiologic assessments, and
causality conclusions for the main vaccines described in this
review, including hepatitis A, hepatitis B, influenza, MMR,
HPV vaccine (Tables 5,6,7,8,and9).
In addition, many of those reactions are mild and self-limited.
Nevertheless, we should be cautious, especially not only in cases
Tabl e 7 A summary of the
epidemiologic assessments,
mechanistic assessments, and
causality conclusions for
influenza vaccine
Typ e
vaccine
Adverse event Epidemiologic
assessment
Studies contributing to
epidemiologic assessment
Causality
conclusion
Influenza
vaccine
Transverse myelitis Insufficient None inadequate
Optic neuritis Limited 2 Inadequate
MS onset in adults Limited 2 Inadequate
Guillain-Barré Syndrome Moderate 9 Inadequate
Chronic inflammatory
disseminated
polyneuropathy
Insufficient None Inadequate
Fibromyalgia Insufficient None Inadequate
Tabl e 8 A summary of the epidemiologic assessments, mechanistic assessments, and causality conclusions for MMR vaccine
Type vaccine Adverse event Epidemiologic assessment Studies contributing
to epidemiologic assessment
Causality conclusion
MMR
vaccine
Transverse myelitis Insufficient None Inadequate
Optic neuritis Limited 1 Inadequate
MS onset in adults Limited 2 Inadequate
MS onset in Children Limited 1 Inadequate
Guillain-Barré Syndrome Insufficient None Inadequate
Chronic Inflammatory
Disseminated
Polyneuropathy
Insufficient None Inadequate
Chronic arthritis in Women Limited 2 Inadequate
Type 1 Diabetes High 5 Favors rejection
Fibromyalgia Insufficient None Inadequate
EPMA Journal
Author's personal copy

with previous post-vaccination phenomena and those with aller-
gies but also in individuals who are prone to develop autoim-
mune diseases, such as those with a family history of autoimmu-
nity or with known autoantibodies, and in genetic predisposed
individuals. In such subsets, the potential benefit of vaccination
should be weighed against its potential risk [138].
In the 2015, Soriano et al. supposed that four groups of
individuals are at risk: (1) patients with prior post-
vaccination autoimmune phenomena, such as patients who
showed initial clinical manifestations (fever, arthralgia) after
dose vaccination; (2) immunosuppressed patients with auto-
immune conditions: indeed, live vaccines including BCG,
MMR vaccines, and vaccines against herpes zoster, and yel-
low fever are generally contraindicated in these patients due to
the risk of an uncontrolled viral replication [163]; (3) patients
with a history of allergic reactions: the vaccine components
include potential allergens such as animal-derived proteins
like egg (present in yellow fever, influenza, and MMR vac-
cines), adjuvants like aluminum (present in HPV, HNI, and
HBVand vaccines) and thimerosal (HPV vaccine), antibiotics
like gentamycin, neomycin, streptomycin, polymyxin B, and
stabilizers like gelatin (present in varicella, and MMR vac-
cines) and lactose; (4) patients who are prone to develop au-
toimmunity, including patients having a family history of au-
toimmune diseases; asymptomatic carriers of autoantibodies,
such as high levels of anti-citrullinated protein antibodies
(ACPA) in RA, anti-mitochondrial antibodies (AMA) in pri-
mary biliary cirrhosis, anti-thyroid antibodies in Hashimoto’s
thyroiditis, and anti-dsDNA in SLE [164]; carrying certain
genetic profiles, including patients with polymorphisms asso-
ciated with the insulin gene, the thyroglobulin gene and the
thyroid-stimulating hormone receptor gene [165].
Conclusions and expert recommendations
The vaccination might display autoimmune side effects
and potentially even trigger a full-blown autoimmune
disease. This susceptibility to vaccine-induced autoimmu-
nity is probably determined also by genetic predisposi-
tion, which further emphasizes the importance of Bthe
mosaic of autoimmunity^[4]. The vaccination decreases
the morbidity and mortality of the individuals, especially
children. Nevertheless, the dilemma of whom and when to
vaccinate remains unresolved and further research is need-
ed to explain the action mechanism.
Finally, we believe that our commitment should be to
plan genetic investigations on the post-vaccination auto-
immune-affected patients in order to clarify the pathogen-
ic background and the physiopathology of vaccine-related
autoimmune response. Hopefully, this approach might
lead to outline a screen-test (patch test?) for this risk
and, eventually, to prevention of adverse reactions by vac-
cination. It could represent a Bpersonalized medicine^that
could potentially improve preventive methods and thera-
peutic options, accordingly with the recommendations of
the BEuropean Association for Predictive, Preventive and
Personalised Medicine^[166].
Compliance with ethical standards
Funding This study is not funded.
Conflict of interest The authors declare that they have no conflict of
interest.
References
1. Nabel GJ. Designing tomorrow’s vaccines. N Engl J Med.
2013;368(6):551–60.
2. Ansakorpi H, et al. Lambert-Eaton myasthenic syndrome follow-
ing H1N1-influenza vaccination: a case report. Acta Neurol
Scand. 2012;126(5):e25–8.
3. Beeler J, Varricchio F, Wise R. Thrombocytopenia after immunization
with measles vaccines: review of the vaccine adverse events reporting
system (1990 to 1994). Pediatr Infect Dis J. 1996;15(1):88–90.
Tabl e 9 A summary of the
epidemiologic assessments,
mechanistic assessments, and
causality conclusions for HPV
vaccine
Typ e
vaccine
Adverse event Epidemiologic
assessment
Studies contributing to
epidemiologic assessment
Causality
conclusion
HPV
vaccine
Transverse myelitis Insufficient None Inadequate
Neuromyelitis optica Insufficient None Inadequate
MS Insufficient None Inadequate
Guillain–Barré
syndrome
Insufficient None Inadequate
Chronic inflammatory
disseminated
polyneuropathy
Insufficient None Inadequate
Amyotrophic lateral
sclerosis
insufficient None Inadequate
Transient arthralgia limited 1 Inadequate
EPMA Journal
Author's personal copy

4. Shoenfeld Y, Aharon-Maor A, Sherer Y. Vaccination as an addi-
tional player in the mosaic of autoimmunity. Clin Exp Rheumatol.
2000;18(2):181–4.
5. Stratton KR, Howe CJ, Johnston RB Jr. Adverse events associated
with childhood vaccines other than pertussis and rubella.
Summary of a report from the Institute of Medicine. JAMA.
1994;271(20):1602–5.
6. Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and
estimated population burden of selected autoimmune diseases in the
United States. Clin Immunol Immunopathol. 1997;84(3):223–43.
7. Onkamo P, Väänänen S, Karvonen M, Tuomilehto J. Worldwide
increase in incidence of type I diabetes—the analysis of the data on
published incidence trends. Diabetologia. 1999;42(12):1395–403.
8. Variation and trends in incidence of childhood diabetes in Europe.
EURODIAB ACE Study Group. Lancet. 2000;355(9207):873–6.
9. Lerner A, Jeremias P, Matthias T. The world incidence and prev-
alence of autoimmune diseases is increasing. Int J Celiac Dis.
2015;3(4):151–5.
10. Wraith DC, Goldman M, Lambert PH. Vaccination and autoimmune
disease: what is the evidence? Lancet. 2003;362(9396):1659–66.
11. Albert LJ, Inman RD. Molecular mimicry and autoimmunity. N
Engl J Med. 1999;341(27):2068–74.
12. Langridge WH. Edible vaccines. Sci Am. 2000;283(3):66–71.
13. Todd JA, Wicker LS. Genetic protection from the inflammatory
disease type 1 diabetes in humans and animal models. Immunity.
2001;15(3):387–95.
14. Steere AC, et al. Lyme arthritis: an epidemic of oligoarticular
arthritis in children and adults in three Connecticut communities.
Arthritis Rheum. 1977;20(1):7–17.
15. Zabriskie JB, Freimer EH. An immunological relationship be-
tween the group. A streptococcus and mammalian muscle. J Exp
Med. 1966;124(4):661–78.
16. Regner M, Lambert PH. Autoimmunity through infection or im-
munization? Nat Immunol. 2001;2(3):185–8.
17. Tudela P, Marti S, Bonal J. Systemic lupus erythematosus and
vaccination against hepatitis B. Nephron. 1992;62(2):236.
18. Symmons DP, Chakravarty K. Can immunisation trigger rheuma-
toid arthritis? Ann Rheum Dis. 1993;52(12):843–4.
19. Ascherio A, et al. Hepatitis B vaccination and the risk of multiple
sclerosis. N Engl J Med. 2001;344(5):327–32.
20. Tourbah A, et al. Encephalitis after hepatitis B vaccination: recurrent
disseminated encephalitis or MS? Neurology. 1999;53(2):396–401.
21. Contavreux C, Suissa S, Saddier P, Bourdes V, et al. Vaccination
and the risk of relapse in multiple sclerosis. N Engl J Med.
2001;344:319–26.
22. Aharon-Maor A, Shoenfeld Y. The good, the bad and the ugly of
vaccination. Isr Med Assoc J. 2000;2(3):225–7.
23. Symmons DP, Chakravarty K. Can immunization trigger rheuma-
toid arthritis. Ann. Rheum. Dis. 1993;52:843–4.
24. Tishler M, Shoenfeld Y. Vaccination may be associated with au-
toimmune diseases. Isr Med Assoc J. 2004;6:430–2.
25. Schonberger LB, Bregman DJ, Sullivan-Bolyai JZ, Keenlyside
RA, Ziegler DW, Retailliau HF, et al. Guillain-Barre syndrome
following vaccination in the National Influenza Immunization
Program, United States, 1976–1977. Am J Epidemiol.
1979;110(2):105–23.
26. Shoenfeld Y, Aron-Maor A. Vaccination and autoimmunity-
‘vaccinosis’: a dangerous liaison? J Autoimmun. 2000;14:1–10.
27. Lasky T, Magder TG. The Guillain-Barre syndrome and the 1992-
1993 and 1993-1994 influenza vaccines. N Engl J Med. 1998;339:
1797–801.
28. Geier MR, Geier DA, Zahalsky AC. Influenza vaccination and
Guillain Barre syndrome. Clin Immunol. 2003;107(2):116–21.
29. Classen JB, Classen DC. Association between type I diabetes and
Hib vaccine: causal relation is likely. BMJ. 1999;319:1133.
30. Karvonen M, Cepaitis Z, Tuomilehto J. Association between type
1 diabetes and Haemophilus influenzae type b vaccination: birth
cohort study. BMJ. 1999;318:1169–72.
31. Wakeberg J, Fredriksson J, Vaarala O, Ludvigsson J. Vaccinations
may induce diabetes-related autoantibodies in one-year-old chil-
dren. Ann N YAcad Sci. 2003;1005:404–8.
32. Yu O, Bohlke K, Hanson CA, Delaney K, Rees TG, Zavitkovsky
A, et al. Hepatitis B vaccine and risk of autoimmune thyroid dis-
ease: a vaccine safety datalink study. Pharmacoepidemiol Drug
Saf. 2007;16(7):736–45.
33. Sejvar JJ, Baughman AL, Wise M, Morgan OW. Population inci-
dence of Guillain-Barre syndrome: a systematic review and meta-
analysis. Neuroepidemiology. 2011;36(2):123–33.
34. Shui IM, Rett M, Weintraub E, Marcy M, Amato AA, Sheikh SI,
et al. Vaccine safety datalink research team. Guillain-Barré syn-
drome incidence in a large United States cohort (2000-2009).
Neuroepidemiology. 2012;39(2):109–15.
35. Lehmann HC, Hartung HP, Kieseier BC, Hughes RA. Guillain-
Barre syndrome after exposure to influenza virus. Lancet Infect
Dis. 2010;10(9):643–51.
36. Tam CC, O'Brien SJ, Petersen I, Islam A, Hayward A, Rodrigues
LC. Guillain-Barre syndrome and preceding infection with cam-
pylobacter, influenza and Epstein-Barr virus in the general practice
research database. PLoS One. 2007;2(4):e344.
37. Stowe J, Andrews N, Wise L, Miller E. Investigation of the tem-
poral association of Guillain-Barre syndrome with influenza vac-
cine and influenza like illness using the United Kingdom General
Practice Research Database. Am J Epidemiol. 2009;169(3):382–8.
38. Hardy TA, Blum S, McCombe PA, Reddel SW. Guillain-Barr
syndrome: modern theories of etiology. Curr Allergy Asthma
Rep. 2011;11(3):197–204.
39. McCarthy N, Giesecke J. Incidence of Guillain-Barré syndrome
following infection with Campylobacter jejuni. Am J Epidemiol.
2001;153:610–4.
40. Offit PA. Thimerosal and vaccines—acautionarytale.NEnglJ
Med. 2007;357:1278–9.
41. Schonberger LB, Bregman DJ, Sullivan-Bolyai JZ, Keenlyside RA,
Ziegler DW, Retailliau HF, et al. Guillain-Barré syndrome following
vaccination in the National Influenza Immunization Program,
United States, 1976–1977. Am J Epidemiol. 1979;110:105–23.
42. Hoshino T, Uchiyama Y, Ito E, Osawa S, Ohashi T. Simultaneous
development of acute disseminated encephalomyelitis and
Guillain-Barré syndrome associated with H1N1 09 influenza vac-
cination. Intern Med. 2012;51:1595–158.
43. Hughes RA, Cornblath DR. Guillain-Barré syndrome. Lancet.
2005;366:1653–66.
44. Terryberry J, Sutjita M, Shoenfeld Y, Gilburd B, Tanne D, Lorber
M, et al. Myelin- and microbe-specific antibodies in Guillian–
Barre syndrome. J. Clin. Lab. Analysis. 1995;9:308–19.
45. Shoenfeld Y, Isenberg D. Natural autoantibodies eds. Boca-Raton:
CRC; 1993: p. 15–33.
46. Nachamkin I, Shadomy S, Moran AP, Cox N, Fitzgerald C, Ung H,
et al. Anti-ganglioside antibody induction by swine (A/NJ/1976/
H1N1) and other influenza vaccines: insights into vaccine-associated
Guillain-Barré syndrome. J Infect Dis. 2008;198(2):226–33.
47. Lei T, Sutjita K, Kok KH, Chan KH, Chan EY, Hung IF. Anti-
ganglioside antibodies were not detected in human subjects infect-
ed with or vaccinated against 2009 pandemic influenza A (H1N1)
virus. Vaccine. 2012;30(16):2605–10.
48. Hughes RA, Choudhary PP, Osborn M, Rees JH, Sanders EA.
Immunization and risk of relapse of Guillain–Barre syndrome or
chronic inflammatory demyelinating polyradiculoneuropathy.
Muscle Nerve. 1996;19:1230–1.
49. Opie EL. On the relation of chronic interstitial pancreatitis to the
islands of Langerhans and to diabetes melutus. J Exp Med.
1901;5:397–428.
EPMA Journal
Author's personal copy

50. Institute for Vaccine Safety Diabetes Workshop Panel. Childhood
immunizations and type 1 diabetes: summary of an Institute for
vaccine safety workshop. The Institute for Vaccine Safety Diabetes
Workshop Panel. Pediatr Infect Dis J. 1999;18(3):217–22.
51. Atkinson MA, Maclaren NK. The pathogenesis of insulin-
dependent diabetes mellitus. N Engl J Med. 1994;331(21):1428–36.
52. Bach JF. The effect of infections on susceptibility to autoimmune
and allergic diseases. N Engl J Med. 2002;347(12):911–20.
53. Classen DC, Classen JB. The timing of pediatric immunization
and the risk of insulin-dependent diabetes mellitus. Infect Dis Clin
Pract. 1997;6:449–54.
54. Classen JB. The timing of immunization affects the development
of diabetes in rodents. Autoimmunity. 1996;24:137–45.
55. Institute for Vaccine Safety Diabetes Workshop Panel. Childhood
immunizations and type 1 diabetes: summary of an Institute for
Vaccine Safety Workshop. Pediatr Infect Dis J. 1999;18:217–22.
56. Hviid A, Stellfeld M, Wohlfahrt J, Melbye M. Childhood vaccina-
tion and type 1 diabetes. N Engl J Med. 2004;350(14):1398–404.
57. Classen JB, Classen DC. Immunization in the first month of life
may explain decline in incidence of IDDM in The Netherlands.
Autoimmunity. 1999;31:43–5.
58. Wynn DR, Rodriguez M, O’Fallon WM, Kurland LT. A reapprais-
al of the epidemiology of multiple sclerosis in Olmsted County
Minnesota. Neurology. 1990;40:780–6.
59. Todd JA, Wicker LS. Genetic protection from the inflammatory
disease type 1 diabetes in humans and animal models. Immunity.
2001;15:387–95.
60. DeStefano F, Verstraeten T, Jackson LA, Okoro CA, Benson P,
Black SB, et al. Vaccinations and risk of central nervous system
demyelinating diseases in adults. Arch Neurol. 2003;60(4):504–9.
61. Payne DC, Rose CE, Kerrison J, Aranas A, Duderstadt S, McNeil
MM. Anthrax vaccination and risk of optic neuritis in the United
States military, 1998-2003. Arch Neurol. 2006;63(6):871–5.
62. Miller AE, Morgante LA, Buchwald LY, Nutile SM, Coyle PK,
Krupp LB, et al. A multicenter, randomized, double-blind,
placebo-controlled trial of influenza immunization in multiple
sclerosis. Neurology. 1997;48(2):312–4.
63. Confavreux C, Suissa S, Saddier P, Bourdes V, Vukusic S.
Vaccinations and the risk of relapse in multiple sclerosis. N Engl
J Med. 2001;344(5):319–26.
64. Hurwitz ES, Schonberger LB, Nelson DB, Holman RC. Guillain-
Barré syndrome and the 1978-1979 influenza vaccine. N Engl J
Med. 1981;304(26):1557–61.
65. Kaplan JE, Katona P, Hurwitz ES, Schonberger LB. Guillain-Barre
syndrome in the United States, 1979-19 and 1980-1981. Lack of an
association with influenza vaccination. JAMA. 1982;248(6):698–700.
66. Hughes RA, Charlton J, Latinovic R, Gulliford MC. No association
between immunization and Guillain-Barre syndrome in the United
Kingdom, 1992 to 2000. Arch Intern Med. 2006;166(12):1301–4.
67. Juurlink DN, Stukel TA, Kwong J, Kopp A, McGeer A, Upshur RE.
Guillain-Barre syndrome after influenza vaccination in adults: a
population-based study. Arch Intern Med. 2006;166(20):2217–21.
68. Greene SK, Kulldorff M, Lewis EM, Li R, Yin R, Weintraub ES,
et al. Near real-time surveillance for influenza vaccine safety:
proof-of-concept in the Vaccine Safety Datalink Project. Am J
Epidemiol. 2010;171(2):177–88.
69. Cohen JA. The future of multiple sclerosis treatment. J Neurol Sci.
2009;277(1):S55–61.
70. Tourbah A, Gout O, Liblau R, Lyon-Caen O, Bougniot C, Iba-Zizen
MT, et al. Encephalitis after hepatitis B vaccination: recurrent dis-
seminated encephalitis or MS? Neurology. 1999;53:396–401.
71. Gout O, Lyon-Caen O. Sclerotic plaques and vaccination against
hepatitis B. Rev Neurol (Paris). 1998;154:205–7.
72. Fourrier A, Bégaud B, Alpérovitch A, Verdier-Taillefer MH,
Touzè E, Decker N, et al. Hepatitis B vaccine and first episodes
of central nervous system demyelinating disorders: a comparison
between reported and expected number of cases. Br J Clin
Pharmacol. 2001;51:489–49.
73. Dittmann S. Special address: safety of hepatitis B vaccination.
Vaccine. 2000;18:S10–1.
74. Confavreux C, Suissa S, Saddier P, Bourdès V, Vukusic S.
Vaccinations and the risk of relapse in multiple sclerosis.
Vaccines in Multiple Sclerosis Study Group. N Engl J Med.
2001;344:319–26.
75. Ascherio A, Zhang SM, Hernàn MA, Olek MJ, Coplan PM,
Brodovicz K, et al. Hepatitis B vaccination and the risk of multiple
sclerosis. N Engl J Med. 2001;344:327–32.
76. Hernàn MA, Jick SS, Olek MJ, Jick H. Recombinant hepatitis B
vaccine and the risk of multiple sclerosis. Neurology; 2004; 63(5):
838-42
77. Geier DA, Geier MR. A case-control study of serious autoimmune
adverse events following hepatitis B immunization.
Autoimmunity. 2005;38(4):295–301.
78. Mikaeloff Y, Caridade G, Suissa S, Tardieu M. Hepatitis B vaccine
and the risk of CNS inflammatory demyelination in childhood.
Neurology. 2009;72(10):873–80.
79. Terney D, Beniczky S, Barsi P, Kondàkor I, Perènyi J, Faludi B,
et al. Multiple sclerosis after hepatitis B vaccination in a 16- year-
old patient. Chin Med J. 2006;119(1):77–9.
80. Atlas SW. Magnetic resonance imaging of the brain and spine.3rd
edition. Lippincott, Williams and Wilkins; 2003; 1-2200
81. Faure E. Multiple sclerosis and hepatitis B vaccination: could
minute contamination of the vaccine by partial hepatitis B virus
polymerase play a role through molecular mimicry? Med
Hypotheses. 2005;65(3):509–20.
82. James JA, Kaufman KM, Farris AD, Taylor-Albert E, Lehman TJ,
Harley JB. An increased prevalence of Epstein-Barr virus infec-
tion in young patients suggests a possible etiology for systemic
lupus erythematosus. J Clin Investig. 1997;100(12):3019–26.
83. Vaughan JH. The Epstein-Barr virus and systemic lupus erythe-
matosus. J Clin Invest. 1997;100(12):2939–40.
84. Ippolito A, Petri M. An update on mortality in systemic lupus ery-
thematosus. Clin Exp Rheumatol. 2008;26(5 (suppl 51):S72–9.
85. Aron-Maor A, Shoenfeld Y. Vaccination and systemic lupus erythe-
matosus: the bidirectional dilemmas. Lupus. 2001;10(3):237–40.
86. Older SA, Battafarano DF, Enzenauer RJ, Krieg AM. Can immu-
nization precipitate connective tissue disease? Report of five cases
of systemic lupus erythematosus and review of the literature.
Semin Arthritis Rheum. 1999;29(3):131–9.
87. Cooper GS, Dooley MA, Treadwell EL, St Clair EW, Gilkeson
GS. Risk factors for development of systemic lupus erythemato-
sus: allergies, infections, and family history. J Clin Epidemiol.
2002;55(10):982–9.
88. Guiserix J. Systemic lupus erythematosus following hepatitis B
vaccine. Nephron. 1996;74(441):1.
89. Borisova VV, Krel’VV. Systemic lupus erythematosus etiologi-
cally due to the hepatitis B and C viruses. Ter Arkh. 1992;64:92–3.
90. Agmon-Levin N, Zafrir Y, Paz Z, Shilton T, Zandman-Goddard G,
Shoenfeld Y. Ten cases of systemic lupus erythematosus related to
hepatitis B vaccine. Lupus. 2009;18(13):1192–7.
91. Maillefert JF, Sibilia J, Toussirot E, Vignon E, Eschard JP,
Lorcerie B, et al. Rheumatic disorders developed after hepatitis
B vaccination. Rheumatology (Oxford). 1999;38(10):978–83.
92. Santoro D, Stella M, Montalto G, Castellino S. Lupus nephritis
after hepatitis B vaccination: an uncommon complication. Clin
Nephrol. 2007;67(1):61–3.
93. Kowal C, Weinstein A, Diamond B. Molecular mimicry between
bacterial and self antigen in a patient with systemic lupus erythe-
matosus. Eur J Immunol. 1999;29(6):1901–11.
94. Hocine MN, Farrington CP, Touze E, Whitaker HJ, Fourrier A,
Moreau T, et al. Hepatitis B vaccination and frst central nervous
system demyelinating events: reanalysis of a case-control study
EPMA Journal
Author's personal copy

using the self-controlled case series method. Vaccine.
2007;25(31):5938–43.
95. Vlacha V, Forman EN, Miron D, Peter G. Recurrent thrombocy-
topenic purpura after repeated measles-mumps-rubella vaccina-
tion. Pediatrics. 1996;97:738–9.
96. Jonville-Bera AP, Autret E, Galy-Eyraud C, Hessel L.
Thrombocytopenic purpura after measles, mumps and rubella
vaccination: a retrospective survey by the French regional
pharmacovigilance centres and pasteurmerieux serums et vac-
cines. Pediatr Infect Dis J. 1996;15:44–8.
97. Cecinati V, Principi N, Brescia L, Giordano P, Esposito S. Vaccine
administration and the development of immune thrombocytopenic
purpura in children. Hum Vaccin Immunother. 2013;9:1158–62.
98. Izak M, Bussel JB. Management of thrombocytopenia.
F1000Prime Rep. 2014;6(45).
99. Cines DB, Liebman H, Stasi R. Pathobiology of secondary immune
thrombocytopenia. Semin Hematol. 2009;46(1 Suppl 2):S2–14.
100. Oski FA, Naiman JL. Effect of live measles vaccine on the platelet
count. N Engl J Med. 1966;275(7):352–6.
101. Autret E,Jonville-Béra AP, Galy-Eyraud C, Hessel L.
Thrombocytopenic purpura after isolated or combined vaccination
against measles, mumps and rubella. Therapie. 1996;51(6):677–80.
102. Jonville-Bera AP, Autret E, Galy-Eyraud C, Hessel L.
Thrombocytopenic purpura after measles, mumps and rubella
vaccination: a retrospective survey by the French regional
pharmacovigilance centres and pasteur-merieux serums et
vaccins. Pediatr Infect Dis J. 1996;15(1):44–8.
103. Institute of Medicine (US) Vaccine Safety Committee; Stratton KR,
Howe CJ, Johnston RB Jr., editors. Adverse events associated with
childhood vaccines: evidence bearing on causality.1994;118–186.
104. France EK, Glanz J, Xu S, Hambidge S, Yamasaki K, Black SB, et al.
Risk of immune thrombocytopenic purpura after measles-mumps-
rubella immunization in children. Pediatrics. 2008;121(3):e687–92.
105. Miller E, Waight P, Farrington CP, Andrews N, Stowe J, Taylor B.
Idiopathic thrombocytopenic purpura and MMR vaccine. Arch
Dis Child. 2001;84(3):227–9.
106. Black C, Kaye JA, Jick H. MMR vaccine and idiopathic
thrombocytopaenic purpura. Br J Clin Pharmacol. 2003;55(1):107–11.
107. Okazaki N, Takeguchi M, Sonoda K, Handa Y, Kakiuchi T,
Miyahara H, et al. Detection of platelet-binding anti-measles and
anti-rubella virus IgG antibodies in infants with vaccine-induced
thrombocytopenic purpura. Vaccine. 2011;29(31):4878–80.
108. Toltl LJ, Nazi I, Jafari R, Arnold DM. Piecing together the humor-
al and cellular mechanisms of immune thrombocytopenia. Semin
Thromb Hemost. 2011;37:631–9.
109. Kuwana M, Okazaki Y, Ikeda Y. Splenic macrophages maintain
the antiplatelet autoimmune response via uptake of opsonized
platelets with immune thrombocytopenic purpura. J Thromb
Haemost. 2009;7(2):322–9.
110. Nieminen U, Peltola H, Syrjälä MT, Mäkipernaa A, Kekomäki R.
Acute thrombocytopenic purpura following measles, mumps and
rubella vaccination. A report on 23 patients. Acta Paediatr.
1993;82(3):267–70.
111. British Committee for Standards in Haematology General
Haematology Task Force. Guidelines for the investigation and
management of idiopathic thrombocytopenic purpura in adults,
children and in pregnancy. Br J Haematol. 2003;120(4):574–96.
112. Raychaudhuri S, Thomson BP, Remmers EF, Eyre S, Hinks A,
Guiducci C, et al. Genetic variants at CD28, PRDM1 and CD2/
CD58 are associated with rheumatoid arthritis risk. Nat Genet.
2009;41(12):1313–8.
113. Cerhan JR, Saag KG, Merlino LA, Mikuls TR, Criswell LA.
Antioxidant micronutrients and risk of rheumatoid arthritis in a
cohort of older women. Am J Epidemiol. 2003;157(4):345–54.
114. Plenge RM, Seielstad M, Padyukov L, Lee AT, Remmers EF, Ding
B, et al. TRAF1-C5 as a risk locus for rheumatoid arthritis—a
genomewide study. N Engl J Med. 2007;357(12):1199–209.
115. Grasland A, Vinceneux P. Rheumatic manifestations of vaccina-
tion. R Rheumat Eur. 1999;28:25–7.
116. Nussinovitch M, Harel L, Varsano I. Arthritis after mumps and
measles vaccination. Arch Dis Child. 1995;72(4):348–9.
117. Benjamin CM, Chew CG, Silman AJ. Joint and limb symptoms in
children after immunization with measles, mumps and rubella
vaccine. BMJ. 1992;304:1075–7.
118. Slater PE, Ben-Zvi T, Fogel A, Ehrenfeld M, Ever-Hadani S. Absence
of an association between rubella vaccination and arthritis in
underimmune postpartum women. Vaccine. 1995;13(16):1529–32.
119. Tingle AJ, Mitchell LA, Grace M, Middleton P, Mathias R,
MacWilliam L, et al. Randomised double-blind placebo-con-
trolled study on adverse effects of rubella immunisation in sero-
negative women. Lancet. 1997;349(9061):1277–81.
120. Ray P, Black S, Shinefeld H, Dillon A, Schwalbe J, Holmes S,
et al. Risk of chronic arthropathy among women after rubella
vaccination. J Am Med Assoc. 1997;278(7):551–6.
121. Mitchell LA, Tingle AJ, MacWilliam L, Home C, Keown P, Gaur
LK, et al. HLA-DR class II associations with rubella vaccine-
induced joint manifestations. J Infect Dis. 1998;177(1):5–12.
122. Peltola H, Heinonen OP. Frequency of true adverse reactions to
measles-mumps-rubella vaccine. Lancet. 1986;327(8487):939–42.
123. Virtanen M, Peltola H, Paunio M, Heinonen OP. Day-to-day
reactogenicity and the healthy vaccinee effect of measles-
mumps-rubella vaccination. Pediatrics 2000;106(5):E62
124. dos Santos BA, Ranieri TS, Bercini M, Schermann MT, Famer S,
Mohrdieck R, et al. An evaluation of the adverse reaction potential
of three measles-mumps-rubella combination vaccines. Rev
Panam Salud Publica. 2002;12(4):240–6.
125. Pattison E, Harrison BJ, Griffths CEM, Silman AJ, Bruce IN.
Environmental risk factors for the development of psoriatic arthritis:
results from a case-control study. Ann Rheum Dis. 2008;67(5):672–6.
126. Blom L, Nystrom L, Dahlquist G. The Swedish childhood diabe-
tes study. Vaccinations and infections as risk determinants for di-
abetes in childhood. Diabetologia. 1991;34(3):176–81.
127. Altobelli E, Petrocelli R, Verrotti A, Valenti M. Infections and risk
of type I diabetes in childhood: a population-based case-control
study. Eur J Epidemiol. 2003;18(5):425–30.
128. Pellegrino P, Carnovale C, Perrone V, Salvati D, Gentili M,
Brusadelli T, Pozzi M, Antoniazzi S, Clementi E, Radice S. On
the association between human papillomavirus vaccine and pri-
mary ovarian failure. American Journal of Reproductive
Immunology. Am J Reprod Immunol. 2014;71:293–4.
129. Colafrancesco S, Perricone C, Tomljenovic L, Shoenfeld Y.
Human papilloma virus vaccine and primary ovarian failure: an-
other facet of the autoimmune/inflammatory syndrome induced
by adjuvants. Am J Reprod Immunol. 2013;70:309–16.
130. Gatto M, Agmon-Levin N, Soriano A, Manna R, Maoz-Segal R,
Kivity S, et al. Human papillomavirus vaccine and systemic lupus
erythematosus. Clin Rheumatol. 2013;32:1301–7.
131. Macartney KK, Chiu C, Georgousakis M, Brotherton JM. Safety
of human papillomavirus vaccines: a review. Drug Saf. 2013;36:
393–412.
132. Cojocaru M, Chicos B. ASIA or Shoenfeld's syndrome—an auto-
immune syndrome induced by adjuvants. Rom J Intern Med.
2013;51(3–4):131–4.
133. Israeli E, Agmon-Levin N, Blank M, Shoenfeld Y. Adjuvants and
autoimmunity. Lupus. 2009;18(13):1217–25.
134. Agmon-Levin N, Hughes GR, Shoenfeld Y. The spectrum of
ASIA: ‘autoimmune (auto-inflammatory) syndrome induced by
adjuvants’. Lupus. 2012;21(2):118–20.
135. Vera-Lastra O, Medina G, Cruz-Dominguez Mdel P, Jara LJ,
Shoenfeld Y. Autoimmune/inflammatory syndrome induced by
EPMA Journal
Author's personal copy

adjuvants (Shoenfeld’s syndrome): clinical and immunological
spectrum. Expert Rev Clin Immunol. 2013;9(4):361–73.
136. Marrack P, McKee AS, Munks MW. Towards an understanding of the
adjuvant action of aluminium. Nat Rev Immunol. 2009;9(4):287–93.
137. McKee AS, Munks MW, MacLeod MK, Fleenor CJ, Van Rooijen
N, Kappler JW, et al. Alum induces innate immune responses
through macrophage and mast cell sensors, but these sensors are
not required for alum to act as an adjuvant for specific immunity. J
Immunol. 2009;183(7):4403–14.
138. Soriano A, Nesher G, Shoenfeld Y. Predicting post-vaccination au-
toimmunity: who might be at risk? Pharmacol Res. 2015;92:18–22.
139. Palmieri B, Poddighe D, Vadalà M, Laurino C, Carnovale C,
Clementi E. Severe somatoform and dysautonomic syndromes
after HPV vaccination: case series and review of literature.
Immunol Res. 2017;65(1):106-16.
140. Poddighe D, Vadalà M, Laurino C, Palmieri B. Somatoform and
neurocognitive syndromes after HPV immunization are not asso-
ciated to cell-mediated hypersensitivity to aluminum. Toxicol
In vitro. 2017; 43:58-61
141. Garcia Allende N, Garcia Posada MJ, Radosta MF, Sánchez AV,
Mayer Wolf M, Rodriguez V. Acute transverse myelitis in a trav-
eler. Medicina (B Aires). 2016;76(4):242–4.
142. Karussis D, Petrou P. The spectrum of post-vaccination inflamma-
tory CNS demyelinating syndromes. Autoimmun Rev.
2014;13(3):215–24.
143. Sutton I, Lahoria R, Tan I, Clouston P, Barnett M. CNS demye-
lination and quadrivalent HPV vaccination. Mult Scler.
2009;15(1):116–9.
144. Poland GA, Ovsyannikova IG, Jacobson RM. Personalized vac-
cines: the emerging field of vaccinomics. Expert Opin Biol Ther.
2008;8(11):1659–67.
145. Poland GA, Ovsyannikova IG, Jacobson RM. Adversomics: the
emerging field of vaccine adverse event immunogenetics. Pediatr
Infect Dis J. 2009;28(5):431–2.
146. Stern LJ, Calvo-Calle JM. HLA-DR: molecular insights and vac-
cine design. Curr Pharm Des. 2009;15(28):3249–61.
147. Reif M, McKinney BA, Motsinger AA, Chanock SJ, Edwards
KM, Rock MT, et al. Genetic basis for adverse events after small-
pox vaccination. J Infect Dis. 2008;198(1):16–22.
148. Mangan DF, Robertson B, Wahl SM. IL-4 enhances programmed
cell death (apoptosis) in stimulated human monocytes. J Immunol.
1992;148(6):1812–6.
149. Soruri A, Kiafard Z, Dettmer C, Riggert J, Kohl J, Zwirner J. IL-4
downregulates anaphylatoxin receptors in monocytes and dendrit-
ic cells and impairs anaphylatoxin-induced migration in vivo. J
Immunol. 2003;170:3306–14.
150. Janeway CA, Travers P, Walport M, Shlomchik MJ.
Immunobiology: The immune system in health and disease,
vol. 5. 5th ed. New York: Garland Publishing; 2001.
151. Goodbourn S, Didcock L, Randall RE. Interferons: cell signalling,
immune modulation, antiviral response and virus countermea-
sures. J Gen Virol. 2000;81(Pt 10):2341–64.
152. Dedoussis GV, Panagiotakos DB, Pitsavos C, Chrysohoou C,
Skoumas J, Choumerianou D, et al. An association between the
methylenetetrahydrofolate reductase (MTHFR) C677T mutation
and inflammation markers related to cardiovascular disease. Int J
Cardiol. 2005;100(3):409–14.
153. Urano W, Taniguchi A, Yamanaka H, Tanaka E, Nakajima H,
Matsuda Y, et al. Polymorphisms in the methylenetetrahydrofolate
reductase gene were associated with both the efficacy and the
toxicity of methotrexate used for the treatment of rheumatoid ar-
thritis, as evidenced by single locus and haplotype analyses.
Pharmacogenetics. 2002;12(3):183–90.
154. Lerner A. Aluminum as an adjuvant in Crohn’s disease induction.
Lupus. 2012;21(2):231–8.
155. Dimitrijevic L, ŽivkovićI, StojanovićM, PetrušićV, Živančević-
SimonovićS. Vaccine model of antiphospholipid syndrome in-
duced by tetanus vaccine. Lupus. 2012;21(2):195–202.
156. Vista ES, Crowe SR, Tompson LF, Air GM, Robertson JM,
Guthridge JM, et al. Influenza vaccination can induce new-onset
anticardiolipins but not 2-glycoprotein-I antibodies among patients
with systemic lupus erythematosus. Lupus. 2012;21(2):168–74.
157. Shoenfeld Y, Agmon-Levin N. BASIA^—autoimmune/inflammato-
ry syndrome induced by adjuvants. J Autoimmun. 2011;36(1):4–8.
158. Gaspar LP, Mendes YS, Yamamura MY, Almeida LF, Caride E,
Gonçalves RB, et al. Pressure-inactivated yellow fever 17DD vi-
rus: implications for vaccine development. J Virol Methods.
2008;150(1–2):57–62.
159. Monath TP, Fowler E, Johnson CT, Balser J, Morin MJ, Sisti M,
et al. An inactivated cell culture vaccine against yellow fever. N
Engl J Med. 2011;364(14):1326–33.
160. Singh B. Stimulation of the developing immune system can pre-
vent autoimmunity. Autoimmunity. 2000;14:15–22.
161. Gross DM, Forsthuber T, Tary-Lehmann M, Etling C, Ito K, Nagy
ZA, et al. Identification of LFA-1 as a candidate autoantigen in
treatment-resistant Lyme arthritis. Science. 1998;281:703–6.
162. Chen RT, Pless R, Destefano F. Epidemiology of autoimmune
reactionsinduced by vaccination. J Autoimmun. 2001;16:309–18.
163. van Assen S, Agmon-Levin N, Elkayam O, Cervera R, Doran MF,
Dougados M. EULAR recommendations for vaccination in adult
patients with autoimmune inflammatory rheumatic diseases. Ann
Rheum Dis. 2011;70(3):414–22.
164. Bizzaro N, Tozzoli R, Shoenfeld Y. Are we at a stage to predict
autoimmune rheumatic diseases. Arthritis Rheum. 2007;56:1736–44.
165. Jacobson EM, Tomer Y. The CD40, CTLA-4, thyroglobulin, TSH
receptor and PTPN22 gene quintet and its contribution to thyroid
autoimmunity: back to the future. J Autoimmun. 2007;28:85–98.
166. Golubnitschaja O, Baban B, Boniolo G, Wang W, Bubnov R,
Kapalla M, et al. Medicine in the early twenty-first century: para-
digm and anticipation—EPMA position paper 2016. EPMA J.
2016;7:23.
EPMA Journal
Author's personal copy