A b s t r a c t
Vaccinations have been used as an essential tool in the fight against infectious diseases, and succeeded inimproving public health. However, adverse effects, including autoimmune conditions may occur follow-ing vaccinations (autoimmune/inflammatory syndrome induced by adjuvants – ASIA syndrome). It hasbeen 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. Fortunately,vaccination-related ASIA is uncommon. Yet, by defining individuals at risk we may further limit the num-ber of individuals developing post-vaccination ASIA. In this perspective we defined four groups of individ-uals who might be susceptible to develop vaccination-induced ASIA: patients with prior post-vaccinationautoimmune phenomena, patients with a medical history of autoimmunity, patients with a history ofallergic reactions, and individuals who are prone to develop autoimmunity (having a family history ofautoimmune diseases; asymptomatic carriers of autoantibodies; carrying certain genetic profiles, etc.).
In the last two centuries, vaccinations have been used as anessential tool in the fight against infectious diseases, and suc-ceeded in improving public health and in eradicating or minimizingthe extent of several diseases around the world . However,adverse effects may occur following vaccinations, ranging from local reactions to systemic side effects, such as fever, flu-like symp-toms, and autoimmune conditions (autoimmune/inflammatorysyndrome induced by adjuvants – ASIA syndrome) [2,3].Considerable data have recently been gathered with regardto the involvement of the immune system following vaccination,although its precise role has not been fully elucidated . It hasbeen postulated that autoimmunity could be triggered or enhancedby the vaccine immunogen contents, as well as by adjuvants, whichare used to increase the immune reaction to the immunogen .The relationship between vaccines and autoimmunity isbi-directional . On one hand, vaccines prevent infectious condi-tions, therefore preventing the development of overt autoimmune diseases which in some individuals are triggered by infections.On the other hand, many reports that describe post-vaccinationautoimmunity strongly suggest that vaccines can indeed triggerautoimmunity. Defined autoimmune diseases that may occurfollowing vaccinations include arthritis, lupus (systemic lupus ery-thematosus, SLE), diabetes mellitus, thrombocytopenia, vasculitis,dermatomyositis, Guillain-Barré syndrome and demyelinatingdisorders . Almost all types of vaccines have been reported tobe associated with the onset of ASIA .It is important to emphasize that a temporal relationshipbetween autoimmunity and a specific vaccine is not always appar-ent. This matter is complicated by the fact that a specific vaccinemay cause more than one autoimmune phenomenon and, likewise,a particular immune process may be triggered by more than onetype of vaccine [2,3,6].Throughout our lifetime the normal immune system walks afine line between preserving normal immune reactions and devel-oping autoimmune diseases . The healthy immune system istolerant to self-antigens. When self-tolerance is disturbed, dysreg-ulation of the immune system follows, resulting in the emergenceof an autoimmune disease. Vaccination is one of the conditions thatmay disturb this homeostasis in susceptible individuals, resultingin autoimmune phenomena and ASIA.Fortunately, vaccination-related ASIA is uncommon. Yet, bydefining individuals at risk we may further limit the number ofindividuals developing post-vaccination ASIA. Who is suscepti-ble to develop vaccination-induced ASIA? It is assumed that fourgroups of individuals are at risk (Table 1): patients with priorpost-vaccination autoimmune phenomena, patients with a med-ical history of autoimmunity, patients with a history of allergicreactions, and individuals who are prone to develop autoimmunity(having a family history of autoimmune diseases; asymptomaticcarriers of autoantibodies; carrying certain genetic profiles, etc.).
Patients with prior post-vaccination autoimmunephenomena: “rechallenge” cases
The notion that there is a tendency of progression to full-blown immune-mediated disease in patients who experiencedinitial nonspecific symptoms (such as fever, arthralgia, transientskin 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 wouldhave been beneficial for some susceptible groups is still a matter ofdebate.In the analysis by Zafrir et al.  of 93 patients who experi-enced new immune-mediated phenomena following hepatitis Bvaccination, 47% continued with the vaccination protocol despiteexperiencing variable adverse events following the administrationof the first vaccine dose. Additionally, a personal or familial his-tory of immune-mediated diseases was documented in 21% of thecohort, which may have rendered this particular population moregenetically predisposed to developing immune-mediated adversereactions following vaccination. Gatto et al.  recently described6 cases of SLE following quadrivalent anti-human papilloma virus(HPV) vaccination (Gardasil®). In all six cases, several common fea-tures were observed, namely, a personal or familial susceptibilityto autoimmunity and an adverse response to a prior dose of thevaccine.In regard to quadrivalent anti-HPV vaccine, a case of suddendeath of a teenage girl approximately 6 months following herthird Gardasil®booster has been reported . The patient expe-rienced a range of non-specific symptoms shortly after the firstdose of Gardasil injection including dizziness spells, paresthesia inher hands, and memory lapses. After the second injection, her con-dition worsened, and she developed intermittent arm weakness,frequent tiredness requiring daytime naps, worsening paresthe-sia, night sweats, intermittent chest pain and sudden unexpectedpalpitations. A full autopsy analysis revealed no anatomical, histo-logical, toxicological, genetic or microbiological findings that mightbe linked to a potential cause of death. On the other hand, the post-mortem analysis of blood and splenic tissues revealed the presenceof HPV-16 L1 gene DNA fragments, thus implicating the vaccine as acausal factor . In particular, the sequence of the HPV DNA foundin both blood and spleen corresponded to that previously foundin 16 separate Gardasil®vials from different vaccine lots . Itwas also determined that these HPV 16L1 DNA contaminants werecomplexed with the aluminum adjuvant , which would explaintheir long-term persistence in the body of this teenager (morethan 6 months following her third injection). Adjuvants indeed canpersist in tissues for a long time (up to 8–10 years)  wherethey stimulate the immune system. This chronic stimulation maylead in certain cases to the development of a specific autoimmunedisease.Konstantinou et al.  reported two successive episodes ofleukoencephalitis associated with hepatitis B vaccination after theadministration of the second and the third vaccine dose in a pre-viously healthy 39-year-old woman. Soriano et al. , in theircase-series of giant cell arteritis and polymyalgia rheumatica (PMR)following influenza vaccination, described a patient who developedPMR 8 weeks after influenza vaccination; 2 years later, the patientwas in clinical remission when she received another influenza vac-cination, and experienced recurrence of PMR.Quiroz-Rothe et al.  also described a case of post-vaccinationpolyneuropathy resembling human Guillain-Barré syndrome in aRottweiler dog. The dog suffered two separated episodes of acutepolyneuropathy after receiving two vaccines (both adjuvanted).Inactivated rabies vaccine was administered 15 days before clin-ical signs were first noted. Clinical remission was achieved withsteroid therapy, but 3 months later the dog had recurrence of poly-neuropathy, following another vaccination administered 12 daysearlier. The presence of antibodies against peripheral nerve myelinwas demonstrated.Although data is limited, it seems preferable that individualswith prior autoimmune or autoimmune-like reactions to vaccina-tions, should not be immunized, at least not with the same type ofvaccine. If vaccination is of utmost importance, it might be given,but the patient should be followed closely and treated if necessary.
Patients with established autoimmune conditions
The efficacy of vaccination in patients with autoimmunity maybe reduced. On the other hand it is important to realize that theimmune system is stimulated by vaccinations (especially whenadjuvants are added), and therefore the chance of side effects isincreased, in particular for patients with autoimmune diseases,where the immune system is already stimulated. There is a poten-tial risk of flares following vaccination in such cases. Adjuvantedvaccines have been reported to trigger autoantibodies and ASIA[3,6]. Live vaccines including Bacillus Calmette-Guérin (BCG) and vac-cines against herpes zoster, yellow fever (YF) and measles, andmumps measles and rubella triple vaccine (MMR) are generallycontraindicated in immunosuppressed patients with autoimmuneconditions due to the risk of an uncontrolled viral replication .Regarding inactivated or recombinant vaccines, these have the dis-advantage of inducing a suboptimal immune response, requiringsometimes the addition of adjuvants, which may be associatedwith ASIA . Several prospective controlled studies targeted safetyissues of vaccination in patients with autoimmune conditions. Inmost studies, no increased risk for severe adverse events or increaseof activity of pre-existing disease was observed after vaccination.HPV vaccine was well tolerated and reasonably effective inpatients with stable SLE and did not induce an increase in lupusactivity or flare. Disease flares in patients with SLE occurred ata similar frequency to that of 50 matched SLE controls (0.22 and0.20/patient/year, respectively) .The safety of hepatitis B vaccine has been assessed in prospec-tive studies in rheumatoid arthritis (RA) and SLE. In RA patients,hepatitis B vaccination was not associated with an appreciabledeterioration in any clinical or laboratory measure of disease. Themeasures of disease activity of the patients and controls duringthe study period did not differ significantly . In SLE, hepatitisB vaccination was safe in patients in remission or with mild dis-ease. No significant change in mean SLEDAI score was detected aftervaccination .Several studies targeted the safety of influenza vaccination inpatients with autoimmune conditions. A large-scale study of 1668patients with autoimmune rheumatic diseases and 234 controlsevaluated the short-term (3 weeks) safety of non-adjuvanatedInfluenza A (H1N1) vaccination. Although no major relapsesoccurred in this short period of follow up, patients with autoim-mune rheumatic diseases had significantly more arthralgia (9%compared to 3.8% in controls, p = 0.005), and fever (3.9% and 1.2%,respectively, p = 0.04) . In another study, the autoantibodyresponse to influenza vaccination in patients with autoimmunerheumatic diseases was reported. Female patients had statisticallysignificant elevation in anti-nuclear antibody (ANA) titers follow-ing vaccination. In addition, a small subset of patients, especiallyANA-positive patients, had a tendency to develop anti-extractablenuclear antibodies (ENA). One month after vaccination 8% of pre-viously anti-cardiolipin (aCL)-negative patients presented withelevated aCL IgG and 4% with elevated aCL IgM antibodies. Therewas significantly more aCL IgG/IgM induction after the H1N1 com-pared to seasonal influenza vaccine. Elevated aCL were mostlytransient but one female patient developed persistent high levels ofaCL IgM . In another study on Influenza H1N1 safety in patientswith autoimmune rheumatic diseases, no change in disease activityscores was observed during a 4-week post vaccination period .15 other studies on influenza vaccination (reviewed in ) didnot report significant adverse effects in patients with autoimmuneconditions.For the overwhelming majority of patients with establishedautoimmune diseases, vaccines carry no risk of significant diseaseflares. However, most studies did not address certain subsets ofpatients with autoimmune diseases, such as vaccinating patientswith severe, active disease, or vaccination in conditions other thanSLE or RA. In such subsets, the potential benefit of vaccinationshould be weighed against its potential risk.
Patients with a history of allergy
Historically, vaccine trials have routinely excluded vulnerableindividuals with a variety of pre-existing conditions. Some of theseinclude personal or immediate family history of developmentaldelay or neurological disorders (including convulsive disorders ofany origin), hypersensitivity to vaccine constituents and any con-dition that in the opinion of the investigators may interfere withthe study objectives. Because of such selection bias, the occurrenceof serious adverse reactions resulting from vaccinations in the reallife where vaccines are mandated to all individuals regardless oftheir susceptibility factors may be considerably underestimated. In particular, the number of true allergic reactions to vac-cines is not known, with an estimated range from 1 per 50,000doses to 1 per 1,000,000 doses . A higher rate of serious allergicreactions is probable if allergens such as gelatin (as in the case ofJapanese encephalitis vaccine) or egg proteins are included in theformulation.Apart from infectious agents, vaccine components includepotential allergens such as animal-derived proteins or peptides(hen’s egg, horse serum, etc.), antibiotics (gentamycin, neomycin,streptomycin, polymyxin B), preservatives (aluminum, formalde-hyde) and stabilizers like gelatin and lactose. In addition, exposureto inadvertent allergenic contaminants such as latex (in vial stop-pers and syringe plungers) may also occur.The classification of allergic reactions distinguishes mainly twocategories: immediate, most likely IgE-mediated reactions, anddelayed reactions. IgE mediated reactions to vaccines may presentwith skin manifestations (urticaria, angioedema), respiratory signs(rhino-conjunctivitis or bronchospasm), gastrointestinal disorders(diarrhea, abdominal pain and vomiting), and life-threatening car-diovascular complications such as hypotension and shock withinminutes following the vaccination. It has been estimated thatimmediate anaphylactic life-threatening reactions to vaccines area rare event, while reactions to vaccines limited to the injection siteare more frequent .Delayed reactions comprise a wide spectrum of manifestations.Fever and local swelling are the most commonly observed, and usu-ally are not considered a contraindication for future administrationof the vaccine [26,27]. Less frequent delayed immunologic reac-tions include serum sickness, polyarthritis and erythema nodosum.These cases represent a contraindication for future vaccination[28,29].Gelatin is one of the most common causes of allergic reactions tovaricella, MMR, Japanese encephalitis vaccines and influenza vac-cine . Egg protein is present in yellow fever, influenza, MMRand some rabies vaccines. Influenza vaccination in patients withegg allergy is an important clinical issue and relevant guidelinesare frequently updated (see www.cdc.gov/vaccines). Currently, theamounts of egg protein in most influenza vaccines are small (≤1 gper 0.5 ml dose in most cases). In addition, egg-free influenza vac-cines are now available for adults with egg allergy. Thus, influenzavaccine can be safely administered to the vast majority of patientswith egg allergy, as adverse reactions have generally been very rare[31–33].Thimerosal and phenoxyethanol, used as preservatives, havebeen associated with delayed-type hypersensitivity reactions.Thimerosal has been recently removed from vaccine formulations.Aluminum salts are contained in several vaccines, including diph-theria tetanus and pertussis, hepatitis A and B vaccine, humanpapilloma virus (HPV) and Haemophilus influenza vaccine. Alu-minum sensitization manifests as nodules at the injection site thatoften regress after weeks or months, but may persist for years .In subjects with suspected aluminum-induced granuloma a patchtest for aluminum may be used to confirm the sensitization.Hepatitis B vaccine and anti-HPV vaccines are prepared by har-vesting the antigens from cell cultures of recombinant strains of theyeast Saccharomyces cerevisiae, also known as baker’s yeast. Yeast-associated anaphylactic reactions have also been reported as rareevents. DiMiceli et al.  reviewed the adverse events describedin the Vaccine Adverse Event Reporting System (VAERS) focusingon reports that mentioned a history of allergy to yeast and related anaphylactic reactions following vaccinations. Among 107 reportsof anaphylaxis in subjects with pre-existing yeast allergies, 11 weredescribed as ‘probably’ or ‘possibly’ related to the administrationof hepatitis B vaccine.Finally, antibiotics may be responsible for anaphylactic reac-tions. Thus, an accurate allergy history has to be taken in cases withprevious allergic reactions to antibiotics prior to administrations ofvaccines containing these agents.
Individuals who are prone to develop autoimmunity
Family history of autoimmune diseases and the genetic profile
Numerous studies have found that autoimmune diseases havea genetic predisposition. The abnormal immune response proba-bly depends upon interactions between susceptibility genes andvarious environmental factors. Evidence for genetic predispositionto autoimmunity includes increased concordance for disease inmonozygotic compared to dizygotic twins, and an increased fre-quency of autoimmunity in patients with affected family members.Family history of autoimmunity was prevalent among patientsdeveloping SLE following HPV vaccination . In another study, 19%of 93 patients with autoimmune conditions following hepatitis Bvaccination had a family history of autoimmunity .Certain HLA profiles are associated with autoimmunity. Themost potent genetic influence on susceptibility to autoimmunity isthe major histocompatibility complex (MHC). Different HLA allelesare linked to different autoimmune diseases. Examples are DR2 andincreased risk for multiple sclerosis and Goodpasture’s syndrome;DR3 and increased risk for SLE, celiac disease, type 1 diabetes andGraves’ disease; DR4 and increased risk for RA, pemphigus and type1 diabetes; and DR5 and increased risk for Hashimoto’s thyroidi-tis and pernicious anemia. HLA profiles were reported in only fewpatients with vaccination-triggered autoimmunity .Non-HLA genes also play a role in the genetic etiology of autoim-mune diseases. Non-HLA genes that have been associated withautoimmunity can be divided into two groups: the first groupconsists of immune-regulatory genes such as the cytotoxic T lym-phocyte antigen-4, or the protein tyrosine phosphatase gene, ormutations leading to complement deficiencies or IgA deficiency[37–40]. Deficiencies in the earlier components of the classical com-plement pathway (especially C4) have been linked to autoimmunediseases, and autoimmune disorders occur more frequently in indi-viduals with selective IgA deficiency. The second group of non-HLAgenes that have been associated with autoimmunity consists oftissue-specific genes, such as polymorphisms associated with theinsulin gene, the thyroglobulin gene and the thyroid-stimulatinghormone receptor gene [reviewed in 37].
Presence of autoantibodies
Autoantibodies can be detected in the preclinical phase ofautoimmune diseases many years before the disease becomesapparent. Examples are anti-citrullinated protein antibodies(ACPA) in RA, anti-mitochondrial antibodies (AMA) in primary bil-iary cirrhosis, anti-thyroid antibodies in Hashimoto’s thyroiditis,and anti-dsDNA in SLE . Many autoantibodies have the abilityto predict the development of an autoimmune disease in asymp-tomatic persons. The progression towards an autoimmune diseaseand its severity can be predicted from the type of antibody, its level,and the number of different antibodies present. The ability to pre-dict the development of an autoimmune disease in asymptomaticindividuals is especially important when the disease progressioncan be prevented by avoiding environmental factors, such as vac-cinations, that may trigger or worsen the disease.
Tobacco smoking is one of the most potent environmentalfactors that influence autoimmune diseases. Smoking has beenassociated with SLE [42,43] and with an increased risk of RA,an effect that was more pronounced in males and in seroposi-tive patients . Studies documenting an increased prevalence ofsmokers exist for many autoimmune disorders . Smoking couldlead to autoimmunity by several mechanisms: it interacts withgenetic risk factors such as specific HLA-DR alleles, it induces tis-sue damage, increases apoptosis, induces leukocytosis and elevateslevels of C-reactive protein, intercellular adhesion molecule-1 andE-selectin, resulting in inflammation [44,45]. To date, no specificassociation was documented between smoking and vaccination-related ASIA.
The hormonal panel, which affects the process leading toautoimmunity, involves estrogen, prolactin and vitamin D [46,47].Exposure of the immune system to estrogens may be exoge-nous, in the form of oral contraceptives or hormone replacementtherapy for post-menopausal women. Both forms may be asso-ciated with disease flare-up. Ovarian stimulation may also leadto the development of SLE or induction of SLE flares . Themechanisms by which other potential sources of environmentalestrogens, such as phytoestrogens, pesticides and other chemicals,could alter the immune system are yet to be established. Estrogenleads to increased survival and activation of autoreactive B cells. Indeed, in large-scale reports of vaccination-induced ASIA,females seem to be affected more frequently than males .Low vitamin D status has been implicated in the etiology ofautoimmune diseases. There is an inverse relationship betweenvitamin D status and incidence of multiple sclerosis . Highvitamin D intake was also associated with lower risk for type 1diabetes mellitus, rheumatoid arthritis and inflammatory boweldiseases . Vitamin D status has not been established in caseswith vaccination-related ASIA.
Appropriate epidemiological studies should be undertaken toconfirm reports of individual cases or case series where familial,genetic, hormonal or other risk factors for autoimmune condi-tions were found in patients who developed post-vaccination ASIA.However, it is important to remember that for the overwhelm-ing majority of individuals, vaccines carry no risk of systemicautoimmune disease and should be administered according to thecurrent recommendations. Reports on autoimmune reactions aftervaccination would constitute probably less than 0.01% of all vac-cinations performed worldwide, although this rate may be biasedby under-reporting. In addition, many of those reactions are mildand self-limited. Nevertheless, we should be cautious, especially incases with previous post-vaccination phenomena and in those withallergies, but also in individuals who are prone to develop autoim-mune diseases, such as those with a family history of autoimmunityor with known autoantibodies. In such subsets, the potential benefitof vaccination should be weighed against its potential risk.
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