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Vaccines, Adjuvants, and the Mosaic of Autoimmunity
Chapter 29
Vaccines, Adjuvants, and the Mosaic of Autoimmunity Abdulla Watad1,2,3, Nicola Luigi Bragazzi4 1Department
of Medicine ‘B’, Sheba Medical Center, Tel-Hashomer, Israel; 2Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel; 3Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 4Postgraduate School of Public Health, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy
INTRODUCTION The immune system is able to carefully distinguish between self- and non–self-components. Therefore, any small deviation of this balanced function may result in an autoimmune activity and harm against self-antigens (autoantigens). Various environmental factors have been described as possible triggers of autoimmune diseases, including drugs, infectious agents [1], smoking [2], vaccination, and adjuvants [3]. Genome-wide association studies have led to the discovery of more than 300 susceptibility loci for autoimmune diseases [4]. However, for almost all loci, understanding of the mechanisms leading to autoimmunity remains limited, and most variants that are likely to be causal are in noncoding regions of the genome. In the last century science donated humanity the gift of vaccines that have represented a Copernican Revolution by significantly reducing morbidity and virtually eliminating mortality due to infectious diseases [5]. The evidence that vaccines are fundamental for patients with autoimmune diseases has been recently addressed by a committee of experts of the European League Against Rheumatism (EULAR) [6]. These recommendations state that the initial evaluation of a patient with an autoimmune disease should include the assessment of the vaccination status. Other major recommendations include that vaccination should ideally be administered during stable disease, that influenza vaccination and pneumococcal vaccination should be strongly considered for patients with autoimmune rheumatic diseases, that vaccination can be administered during the use of DMARDs and anti-TNF agents but preferably before starting B cell– depleting therapy, and that attenuated live vaccines and BCG vaccination should be avoided whenever possible especially in immunosuppressed patients [7]. Because infections can trigger autoimmunity and may elicit a flare of an autoimmune disease, their prevention can reduce the incidence of the diseases as well as diseases flare-ups. In some instance, vaccine effect differs because of the genetic background of the recipient individual. Thus, the vaccination schedule would be better if personalized. Thomas et al. have revised this issue gathering a number of examples of genotype/gene polymorphisms mainly in the human leukocyte antigen (HLA) gene family, related to interindividual variation to vaccination [8]. Thus, we will discuss that vaccines and adjuvants may possibly act as triggers of autoimmune diseases in uniquely predisposed and susceptible individuals and report examples of autoimmune diseases induced by diverse vaccines either in clinical reports or experimental animal models. Our hope is that this information would help in advancing the research in the field, which, if properly implemented from a practical standpoint, could pave the way for the introduction of personalized medicine within the context of vaccination practices, considering individual-specific susceptibility factors (the so-called “personalized vaccinology”). The development of autoimmune diseases is a conundrum. In the book authored by Shoenfeld et al., in 1989 [9], entitled “The Mosaic of Autoimmunity,” the factors that may contribute to the development of a specific autoimmune disease in an individual were classified into four categories, namely, genetic factors, immune system dysregulation (complement system disorders, T cells dysfunction, etc.), hormonal factors (estrogen, progesterone, prolactin, vitamin D), and environmental factors [10,11], including viral and bacterial infections, UV exposure, and stress, among others. Furthermore, to develop an autoimmune disease, there needs to be an interplay or combination of these four categories of factors. For example, a single environmental trigger is unlikely to precipitate the development of autoimmunity in the absence of genetic predispositions. The wide diversity of these factors may also explain the presence of a large and heterogeneous group of 81 autoimmune diseases [12]. Additionally, the complexity and wide spectrum of possible interactions between susceptibility Mosaic of Autoimmunity. https://doi.org/10.1016/B978-0-12-814307-0.00029-3 Copyright © 2019 Elsevier Inc. All rights reserved.
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factors also explains why an individual may have more than one autoimmune disease. Thirty years’ after “The Mosaic of Autoimmunity,” additional important environmental factors were described, including dietary factors (salt, spicy foodprotective factor) [13] and obesity [14]. The genetic predisposition plays a pivotal role in all autoimmune diseases, as genetically predisposed individuals possess a very active immune system. It is possible to identify such individuals with a genetic predisposition to autoimmune diseases by the recognition of specific haplotypes of the HLA system [15]. Diverse HLA haplotypes have been described to be linked to the development of autoimmune diseases including (HLA-DRB1) [15], (HLA-DQB1) [16], (HLA-DRB1*07) [4], and several others. Female subjects are also at a higher risk for developing an autoimmune disease, sex hormones having a crucial role in this, with estrogens being a potent stimulators of autoimmunity and androgens playing a protective role [17]. Accumulating evidence further indicates that genetic, epigenetic, and environmental factors may also contribute to sex-related differences both in the risk and clinical course of autoimmune disease [17–20]. Moreover, pregnancy and postpartum periods are linked to autoimmune diseases, characterized by immune–endocrine imbalances, which occur to achieve immunosuppression and tolerance by the immune system to paternal and fetal antigens. These conditions may exacerbate some autoimmune disease and ameliorate others [21,22]. The impact of estrogens on the immune system is highly significant. Not only natural hormones but also endocrine disruptors, such as environmental estrogens, can act in conjunction with other factors to override immune tolerance to self-antigens [23,24]. Of all, probably the most important environmental factors are infections by microbial and viral agents [25–27]. There are five main mechanisms by which infections can lead to an autoimmune disease [10]. These mechanisms are as follows: (1) molecular mimicry, (2) “epitope spreading,” (3) polyclonal activation, (4) viral, and (5) bacterial superantigens that possess the ability to bind to the variable domain of the T cell receptor beta chain. Furthermore, environmental factors that possess an immune adjuvant or immune-potentiating activity such as infectious agents, aluminum, and other adjuvants have been associated with both clinically well-defined and nonspecific immune-mediated manifestations, both in animal models and in humans. These agents with immune adjuvant properties may affect diverse components of the immune system through the innate immune response by the activation of diverse toll-like receptors, the production of uric acid, and other molecules [28]. Adjuvants can be found in most vaccines and are added for the purpose of enhancing the host’s immune response to target antigens, and, therefore, genetically predisposed individuals may be at risk for developing an autoimmune disease because of vaccination. Altogether, these factors form the core basis underlying the description of the ASIA syndrome “autoimmune/inflammatory syndrome induced by adjuvants” [29–31], which will be discussed in a specific chapter.
AUTOIMMUNE DISEASES INDUCED BY VACCINATION: CASE REPORTS AND SERIES The main limits discussing the association between vaccine and autoimmune conditions are that most of the data are case reports or case series, that large epidemiological data tend to exclude a causal association, and that most of the associations are reported within a short time from exposure, while the development of an autoimmune response may require a longer exposure. The first cue of possible insurgence of autoimmune events after vaccination dates to 1979, when a large, high-quality epidemiological survey showed a link between influenza vaccination and the emergence of the Guillain-Barré syndrome (GBS). Although disputed, this link has been replicated in further studies. Since then, the emergence of autoimmune disorders related to immunization practices has been described in many recent case reports and series (Table 29.1). Zafrir et al. [32] reported a case of a 4-month-old female patient who presented with bullous skin rash, 2 months following her second inoculation with the hepatitis B (HBV) vaccine. In addition, during the appearance of the rash she received a second dose of the hexavalent vaccine (containing diphtheria, tetanus, acellular pertussis-DTaP, HBV, inactivated polio, and Haemophilus influenzae b), which was followed by irritability and fever. According to the clinical picture, biopsy result, direct immune fluorescent, and indirect immune fluorescent, a diagnosis of infantile bullous pemphigoid was determined. The patient was resistant to most conventional therapies. Bizjak et al. [33] reported a case of pancreatitis after vaccination in a 20-year-old man. One week after being vaccinated with the first dose of quadrivalent human papillomavirus (HPV) vaccine, he developed severe abdominal pain. Despite ongoing symptoms of nausea and pain, he received the second dose of the vaccine. Only 10 days later, laboratory results revealed significantly elevated pancreatic enzymes, and, with a concomitant abdominal pain and vomiting, he was diagnosed with acute pancreatitis. This case of acute pancreatitis after HPV vaccination is not a novel entity. Although confirming the relationship between pancreatitis and vaccine is challenging, some factors suggest a possible link, including the positive rechallenge on repeated exposure to the vaccine, HPV vaccine relationship to other autoimmune diseases [34–39], and a probable mechanism of molecular mimicry. With regard to the latter, in conjunction with the aluminum adjuvant, the
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TABLE 29.1 Selected Recent Reports of Diverse Autoimmune Diseases Induced by Vaccines References
Vaccine
Autoimmune Disease
Description
Zafrir et al.
Hepatitis B vaccine (HBV)
Bullous pemphigoid
Case report of a 4-month-old child who developed bullous skin rash, 2 months following her second inoculation with HBV vaccine.
Bizjak et al.
Quadrivalent human papillomavirus (HPV)
Pancreatitis
Case report of a 20-year-old male, who developed nausea and pain 1 week after his first vaccine dose. Despite continuing symptoms he received the second dose and 10 days later, laboratory results revealed significantly elevated pancreatic enzymes and with concomitant abdominal pain and vomiting, he was diagnosed with acute pancreatitis.
Agmon-Levin et al.
HBV
Fibromyalgia, chronic fatigue syndrome
Observational study, 19 patients, all patients fulfilled the ASIA criteria.
Zafrir et al.
HBV
Immuno-mediated diseases
Retrospective 93 patients with neuropsychiatric (70%), fatigue (42%) mucocutaneous (30%), musculoskeletal (59%) and gastrointestinal (50%) complaints, elevated titers of autoantibodies were documented in 80%.
Cheng et al.
Influenza vaccine, which contains the MF59 adjuvant
Myositis and myocarditis
Case report of a 65-year-old previously healthy male who 5 days after the vaccination developed severe rhabdomyolysis. Elevated troponin-I and extensive cardiac investigations enabled the diagnosis of myocarditis.
Dansingani et al.
Quadrivalent HPV
Panuveitis
Case report of a 20-year-old woman, who developed panuveitis and exudative retinal detachments 3 weeks after her second dose of the quadrivalent HPV vaccine.
Anaya et al.
Quadrivalent HPV
ASIA syndrome (enthesitis-related arthritis, and systemic lupus erythematosus [SLE])
Three cases of HLA-B27 enthesitis-related arthritis, rheumatoid arthritis, and SLE. Fulfilled the criteria of ASIA.
Lai et al.
Varicella-zoster
Arthritis, alopecia
A case–control study, patients with zoster vaccination had 2.2 and 2.7 times the odds of developing arthritis and alopecia.
Becker et al.
H1N1
Acute disseminated encephalomyelitis
A case report of an 8-year-old boy, who had fever, headache, and somnolence 12 days after the first dose of vaccine against H1N1 influenza, followed by seizures and coma.
RuhrmanShahar et al.
Antitetanus
Dermatomyositis, SLE, type 1 diabetes mellitus, antiphospholipid syndrome
Temporal correlation between vaccination and the induction of the diseases. Other causes were excluded.
induction of immunity through molecular mimicry may potentially culminate in production of cytotoxic autoantibodies with a particular affinity for pancreatic acinar cells. We have reported the association between fibromyalgia, chronic fatigue syndrome (CFS), and HBV vaccination [40]. Nineteen patients with CFS and/or fibromyalgia following HBV vaccine immunization were analyzed. The mean age of the patients was 28.6 ± 11 years, of which 68.4% were female and 21.5% had either personal or familial background of autoimmune disease. The mean latency period from the last dose of HBV vaccine to the onset of the symptoms was 38.6 ± 79.4 days, ranging from days to a year. Eight (42.1%) patients continued with the immunization program despite experiencing adverse events. Manifestations that were commonly reported included neurological manifestations (84.2%), musculoskeletal (78.9%), psychiatric (63.1%), fatigue (63.1%), gastrointestinal complains (58%), and mucocutaneous manifestations (36.8%). Autoantibodies were detected in 71% of patients tested. All patients fulfilled the ASIA syndrome criteria [40].
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The link between HBV vaccine and autoimmune disease was also reported by analyzing medical records of 114 patients, from different centers in the United States, diagnosed with immune-mediated diseases following immunization with HBV vaccine [41]. The mean age of 93 patients was 26.5 ± 15 years; 69.2% were female and 21% were considered autoimmune-susceptible. The mean latency period from the last dose of HBV vaccine and onset of symptoms was 43.2 days. Of note, 47% of patients continued with the immunization program despite experiencing adverse events. Manifestations that were commonly reported included neuropsychiatric (70%), fatigue (42%) mucocutaneous (30%), musculoskeletal (59%), and gastrointestinal (50%) complaints. Elevated titers of autoantibodies were documented in 80% of sera tested. In this cohort, 80/93 patients (86%), comprising 57/59 (96%) adults and 23/34 (68%) children, fulfilled the required criteria for ASIA. Recently, a case report of ASIA syndrome was described in a previously healthy patient who received the seasonal influenza vaccine, which contains the MF59 adjuvant [42]. The patient was presented to the hospital with a profound weakness and was diagnosed with severe rhabdomyolysis. He had elevated troponin-I and extensive cardiac investigations enabled the diagnosis of myocarditis. His infectious and rheumatologic workups were negative. He responded well to conservative management and did not require immune suppressive therapy. He had received the influenza vaccine 5 days prior to the onset of symptoms and fulfilled the criteria of ASIA syndrome. A case of a panuveitis with exudative retinal detachments after vaccination against HPV in a 20-year-old white woman was reported recently [43]. The patient presented with a bilateral acute visual loss (visual acuity: 20/60), panuveitis, and exudative retinal detachments 3 weeks after a second dose of quadrivalent HPV vaccine. She was treated with oral prednisolone for 6 weeks and responded rapidly. By week four, the vision had normalized and the clinical signs have resolved. The association between uveitis and the HPV vaccination has been also reported by Holt et al. [44]. Anaya et al. [45] detailed three cases of patients with ASIA syndrome after quadrivalent HPV vaccination. All the patients were women. Diagnosis consisted of HLA-B27 enthesitis-related arthritis, rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE), respectively. These results highlight the risk of developing ASIA after HPV vaccination and may serve to increase the awareness of such complications. A case-control study has been performed and reported the association between Zoster vaccine and autoimmunity [46]. Compared with the unexposed subjects, patients with zoster vaccination had 2.2 and 2.7 times the odds of developing arthritis and alopecia, respectively (P < .001 and P = .015, respectively). A case of an acute disseminated encephalomyelitis was reported in a healthy 8-year-old boy, who had fever, headache, and somnolence 12 days after the first dose of vaccine against influenza H1N1 [47]. Ruhrman-Shahar et al. [48] described four cases with a temporal relation between antitetanus vaccination and the appearance of dermatomyositis, SLE, type 1 diabetes mellitus, and antiphospholipid syndrome. The first case was a 38-year-old man, previously healthy, with no known familial autoimmune disease, who was bitten by a black scorpion and received a booster dose of DTaP. According to the multicenter, international ASIA Web-based registry, up to December 2016, 300 cases of ASIA syndrome have been described, with a mean age at disease onset of 37 years and a mean duration of time latency between exposure to adjuvant and development of autoimmune conditions of 16.8 months (from 3 days to 5 years). Arthralgia, myalgia, and chronic fatigue were the most frequently reported symptoms. Eighty-nine percent of patients were also diagnosed with another defined and with the most frequent autoimmune disease related to ASIA syndrome being connective tissue disease [49].
AUTOIMMUNE DISEASES INDUCED BY VACCINATION: EPIDEMIOLOGICAL SURVEYS The emergence of autoimmune disorders after vaccination has been observed in several large, high-quality trials. Dodd and coauthors [50] have computed a relative incidence of GBS of 2.42 (95% confidence interval [CI] or CI 1.58–3.72) in the 42 days following exposure to pH1N1 influenza vaccine in an analysis of pooled data and 2.09 (95% CI 1.28–3.42) when carrying out a metaanalytic approach. Similarly, other collaborative groups have replicated this finding: in Italy by Galeotti and collaborators [51], in the United States by Souayah and coworkers [52], in South Korea by Park and collaborators [53], and in Canada by Juurlink and coauthors [54]. Narcolepsy is another autoimmune disorder documented after 2009 Pandemic H1N1 vaccine. Sarkanen and coauthors [55] recently performed a systematic review and metaanalysis and found a relative risk of narcolepsy related to administration increased 5–14-fold in children and adolescents and 2–7-fold in adults during the first year after vaccination. They computed a vaccine-attributable risk in children and adolescents of 1 per 18,400 vaccine doses. Donahue and coworkers [56] have computed an overall adjusted odds ratio of 2.0 (95% CI 1.1–3.6) in women who spontaneously aborted and received influenza-containing vaccine in the 28-day exposure window. Chambers and colleagues [57] analyzing data of a study from the cohort arm of the Vaccines and Medications in Pregnancy Surveillance System (VAMPSS) found a moderately elevated relative risk for major birth defects.
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ANIMAL MODELS OF AUTOIMMUNE DISEASES INDUCED BY ADJUVANTS A vaccine-related autoimmune reaction should meet a series of requirements to be actually considered vaccine-induced, including consistency, strength, specificity, and temporal relation [58]. In humans, adjuvants can induce nonspecific constitutional, musculoskeletal, or neurological clinical manifestations and, in certain cases, can lead to the appearance or acceleration of an autoimmune disease in a subject with genetic susceptibility. The link between vaccination and pathogenic immune reactions has been reported in animal models. Inbar et al. [59] assessed the behavioral and inflammatory parameters in female mice after the injection of aluminum and quadrivalent HPV vaccine. The C57BL/6 female mice were injected with qHPV, qHPV + pertussis toxin, aluminum hydroxide, or vehicle control in amounts equivalent to human exposure. The qHPV and aluminum-injected mice spent significantly more time floating in the forced swimming test in comparison to vehicle-injected mice (aluminum, P = .009; qHPV, P = .025; qHPV + pertussis toxin, P = .005). No significant differences were observed in the number of stairs climbed in the staircase test, which measures locomotor activity. This suggests that the abnormality observed in the forced swimming test was unlikely because of locomotor dysfunction, but rather because of depression. Other research in animal models showing toxicity of adjuvant compounds includes the work of Favoino et al. [60], who assessed the effect of diverse adjuvants (incomplete Freund’s adjuvant, complete Freund’s adjuvant, squalene, or aluminum hydroxide) in lupus-prone New Zealand black/New Zealand white (BW)F1 mice. In the aluminum group, weight decreased by almost half between weeks 29 and 31, indicating some toxic effect of aluminum in the late postimmunization period. Squalene was the least toxic adjuvant as it did not accelerate proteinuria onset compared with incomplete Freund’s adjuvant. Similarly, squalene did not induce toxicity compared with aluminum or elicit anti-RNP/Sm autoantibody as observed in the complete Freund’s adjuvant group. Quiroz-Rothe et al. [61] described a case of postvaccination polyneuropathy resembling human GBS in a Rottweiler dog. The dog suffered of two separated episodes of acute polyneuropathy after receiving two vaccines (both adjuvanted). Inactivated rabies vaccine was administered 15 days before clinical signs were first noted. Clinical remission was achieved with steroid therapy; however, 3 months later the dog had recurrence of polyneuropathy, following another vaccination administered 12 days earlier. The presence of antibodies against peripheral nerve myelin was demonstrated. Agmon-Levin et al. [62] examined the effects of immunization with HBV vaccine and aluminum on SLE-like disease in a murine model. NZBWF1 mice were immunized with HBV vaccine or aluminum hydroxide or phosphate-buffered saline (PBS) at 8 and 12 weeks of age. Mice were followed for weight, autoantibodies titers, blood counts, proteinuria, kidney histology, neurocognitive functions (novel object recognition, staircase, Y-maze, and the forced swimming tests), and brain histology. Immunization with HBV vaccine induced acceleration of kidney disease manifested by high anti-dsDNA antibodies (P < .01), early onset of proteinuria (P < .05), histological damage, and deposition of HBs antigen in the kidney. Mice immunized with HBV vaccine and/or aluminum had decreased cells counts mainly of the red cell lineage (P < .001), memory deficits (P < .01), and increased activated microglia in different areas of the brain in comparison with mice immunized with PBS. Anxiety-like behavior was more pronounced among mice immunized with aluminum. Aratani and collaborators [63], in a model of mice vaccinated with HPV and pertussis toxin, reported low responsiveness of the tail reflex and locomotive mobility because of apoptotic damage affecting the hypothalamus and circumventricular regions around the third ventricle. In summary, animal models are often used to study the relation between autoimmune, inflammatory diseases, and diverse triggers [28]. These are broadly classified as either spontaneous, where an animal’s genetic background results in a defined prevalence of disease, or induced, where disease is precipitated by exposure to defined antigens, adjuvants, or other experimental reagents [28]. Experimentally animal models of autoimmune diseases induced by adjuvants are currently widely used to understand the mechanisms and etiology and pathogenesis of these diseases and might thus promote the development of new diagnostic, predictive, and therapeutic methods.
THE CONCEPT OF PERSONALIZED VACCINOLOGY Vaccination is a pivotal tool to prevent serious infections. In some cases vaccination may lead to adverse events. These are classified in local and systemic events such as allergy, fever, and possibly autoimmune diseases in genetically predisposed individuals [64]. It is important to highlight the fact that a temporal relationship between the induction of an autoimmune phenomenon and a specific vaccine is not always notable. Moreover, a specific vaccine may cause more than one autoimmune disease [65]; likewise, a particular immune process may be induced by diverse vaccines [3]. It is essential to recognize individuals with high risk and prone to develop autoimmunity before the exposure to diverse adjuvants through routine vaccinations. Soriano et al. [66] classified four groups of individuals in which vaccination may represent a risk factor for
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the induction of autoimmune phenomena. These groups include the following: (1) individuals with prior postvaccination autoimmune phenomena; (2) persons with a medical history of autoimmunity; (3) individuals with a history of allergic reactions (especially vaccination-related reactions); and (4) individuals who are prone to develop autoimmunity (having a family history of autoimmune diseases and presence of specific autoimmune disease markers such as elevated autoantibodies, certain genetic profiles, etc.). The HLA genes encode mostly immune-associated proteins whose main effect is the presentation of antigens to the immune cells. As such, HLA-related protein products are essential for the proper function of the immune response against pathogens; however, their variants are also strongly implicated in the development of autoimmune diseases [66], likewise, the positive correlation between SLE and the allotypes DR2 and DR3 of HLA class II [67], RA and HLA-DRB1 [68], and several others. In conclusion, physicians should be aware of the rare but possible adverse events to vaccinations, especially not only in cases with previous postvaccination phenomena and those with allergies but also in individuals who might be more prone to develop autoimmune diseases, due to a family history of autoimmune diseases, presence of specific HLA haplotypes and/ or autoantibodies, and other risk factors for autoimmunity (smoking, obesity, etc.). Factors that are predictive of developing autoimmune diseases should be examined at the population level to establish preventive measures in at-risk individuals for whom health care should be personalized. We do not stress enough that nowadays the benefits of vaccination overweight its potential risks. Surely, big data–based epidemiological surveys, metaanalytical approaches, and omics-based studies (exploiting, for instance, new cutting edge high-throughput technologies, such as “adversomics,” that is to say the systematic, holistic, data-driven “study of vaccine adverse reactions using immunogenomics and systems biology approaches”) [69] can pave the way toward personalized vaccinology.
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Panuveitis with exudative retinal detachments after vaccination against human papilloma virus. Ophthalmic Surg Lasers Imaging Retin 2015;46:967–70. [44] Holt HD, Hinkle DM, Falk NS, Fraunfelder FT, Fraunfelder FW. Human papilloma virus vaccine associated uveitis. Curr Drug Saf 2014;9:65–8. [45] Anaya JM, Reyes B, Perdomo-Arciniegas AM, Camacho-Rodríguez B, Rojas-Villarraga A. Autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA) after quadrivalent human papillomavirus vaccination in Colombians: a call for personalised medicine. Clin Exp Rheumatol 2015;33:545–8. [46] Lai YC, Yew YW. Severe autoimmune adverse events post herpes zoster vaccine: a case-control study of adverse events in a national database. J Drugs Dermatol 2015;14:681–4. [47] Becker MM, Ranzan J, Magalhães LV, Ohlweiler L, Winckler MI, Ramos MS, et al. Post-H1N1 vaccine acute disseminated encephalomyelitis. Pediatr Int 2014;56:437–8. [48] Ruhrman-Shahar N, Torres-Ruiz J, Rotman-Pikielny P, Levy Y. Autoimmune reaction after anti-tetanus vaccination---description of four cases and review of the literature. Immunol Res 2016;1–7. [49] Watad A, Quaresma M, Bragazzi NL, Cervera R, Tervaert JWC, Amital H, et al. The autoimmune/inflammatory syndrome induced by adjuvants (ASIA)/Shoenfeld’s syndrome: descriptive analysis of 300 patients from the international ASIA syndrome registry. Clin Rheumatol Feb 2018;37(2):483–93. [50] Dodd CN, Romio SA, Black S, Vellozzi C, Andrews N, Sturkenboom M, et al. International collaboration to assess the risk of Guillain Barré Syndrome following Influenza A (H1N1) 2009 monovalent vaccines. Vaccine 2013;31(40):4448–58. 6. [51] Galeotti F, Massari M, D’Alessandro R, Beghi E, Chiò A, Logroscino G, et al. Risk of Guillain-Barré syndrome after 2010–2011 influenza vaccination. Eur J Epidemiol 2013;28(5):433–44. [52] Souayah N, Michas-Martin PA, Nasar A, Krivitskaya N, Yacoub HA, Khan H, et al. Guillain-barre syndrome after gardasil vaccination: data from vaccine adverse event reporting system 2006-2009. Vaccine 2011;29(5):886–9. [53] Park Y-S, Lee K-J, Kim SW, Kim KM, Suh BC. Clinical features of post-vaccination Guillain-Barré syndrome (GBS) in Korea. J Kor Med Sci 2017;32(7):1154.
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[54] Juurlink DN, Stukel TA, Kwong J, Kopp A, McGeer A, Upshur RE, et al. Guillain-Barre syndrome after influenza vaccination in adults: a population-based study. Arch Intern Med 2006;166(20):2217–21. [55] Sarkanen TO, Alakuijala APE, Dauvilliers YA, Partinen MM. Incidence of narcolepsy after H1N1 influenza and vaccinations: systematic review and meta-analysis. Sleep Med Rev Apr 2018;38:177–86. [56] Donahue JG, Kieke BA, King JP, DeStefano F, Mascola MA, Irving SA, et al. Association of spontaneous abortion with receipt of inactivated influenza vaccine containing H1N1pdm09 in 2010-11 and 2011-12. Vaccine 2017;35(40):5314–22. [57] Chambers CD, Johnson D, Xu R, Luo Y, Louik C, Mitchell AA, et al. Risks and safety of pandemic h1n1 influenza vaccine in pregnancy: birth defects, spontaneous abortion, preterm delivery, and small for gestational age infants. Vaccine 2013;31(44):5026–32. [58] Salemi S, D’Amelio R. Could autoimmunity be induced by vaccination? Int Rev Immunol 2010;29:247–69. [59] Inbar R, Weiss R, Tomljenovic L, Arango M-T, Deri Y, Shaw CA, et al. Behavioral abnormalities in female mice following administration of aluminum adjuvants and the human papillomavirus (HPV) vaccine Gardasil. Immunol Res 2016;1–14. [60] Favoino E, Favia EI, Digiglio L, Racanelli V, Shoenfeld Y, Perosa F. Effects of adjuvants for human use in systemic lupus erythematosus (SLE)prone (New Zealand black/New Zealand white) F(1) mice. Clin Exp Immunol 2014;175:32–40. [61] Quiroz-Rothe E, Ginel PJ, Perez J, Lucena R, Rivero JLL. Vaccine-associated acute polyneuropathy resembling Guillain-Barré syndrome in a dog. Eur J Companion Anim Pr 2005;15(2):155–9. [62] Agmon-Levin N, Arango MT, Kivity S, Katzav A, Gilburd B, Blank M, et al. Immunization with hepatitis B vaccine accelerates SLE-like disease in a murine model. J Autoimmun 2014;54:21–32. [63] Aratani S, Fujita H, Kuroiwa Y, Usui C, Yokota S, Nakamura I, et al. Murine hypothalamic destruction with vascular cell apoptosis subsequent to combined administration of human papilloma virus vaccine and pertussis toxin. Sci Rep November 11, 2016;6:36943. [64] Cruz-Tapias P, Agmon-Levin N, Israeli E, Anaya J-M, Shoenfeld Y. Autoimmune (auto-inflammatory) syndrome induced by adjuvants (ASIA)-animal models as a proof of concept. Curr Med Chem 2013;20:4030–6. [65] Soriano A, Nesher G, Shoenfeld Y. Predicting post-vaccination autoimmunity: who might be at risk? Pharmacol Res 2015;92:18–22. [66] Shoenfeld Y, Agmon-Levin N, Tomljenovic L. Vaccines and autoimmunity. 1st ed. New Jersey: Wiley-Blackwell; 2015. [67] Relle M, Weinmann-Menke J, Scorletti E, Cavagna L, Schwarting A. Genetics and novel aspects of therapies in systemic lupus erythematosus. Autoimmun Rev 2015;14:1005–18. [68] Perricone C, Ceccarelli F, Valesini G. An overview on the genetic of rheumatoid arthritis: a never-ending story. Autoimmun Rev 2011;10:599–608. [69] Whitaker JA, Ovsyannikova IG, Poland GA. Adversomics: a new paradigm for vaccine safety and design. Expert Rev Vaccines July 2015;14(7):935–47.
Vaccines, Adjuvants, and the Mosaic of Autoimmunity Abdulla Watad1,2,3, Nicola Luigi Bragazzi4 1Department
of Medicine ‘B’, Sheba Medical Center, Tel-Hashomer, Israel; 2Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel; 3Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 4Postgraduate School of Public Health, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy
INTRODUCTION The immune system is able to carefully distinguish between self- and non–self-components. Therefore, any small deviation of this balanced function may result in an autoimmune activity and harm against self-antigens (autoantigens). Various environmental factors have been described as possible triggers of autoimmune diseases, including drugs, infectious agents [1], smoking [2], vaccination, and adjuvants [3]. Genome-wide association studies have led to the discovery of more than 300 susceptibility loci for autoimmune diseases [4]. However, for almost all loci, understanding of the mechanisms leading to autoimmunity remains limited, and most variants that are likely to be causal are in noncoding regions of the genome. In the last century science donated humanity the gift of vaccines that have represented a Copernican Revolution by significantly reducing morbidity and virtually eliminating mortality due to infectious diseases [5]. The evidence that vaccines are fundamental for patients with autoimmune diseases has been recently addressed by a committee of experts of the European League Against Rheumatism (EULAR) [6]. These recommendations state that the initial evaluation of a patient with an autoimmune disease should include the assessment of the vaccination status. Other major recommendations include that vaccination should ideally be administered during stable disease, that influenza vaccination and pneumococcal vaccination should be strongly considered for patients with autoimmune rheumatic diseases, that vaccination can be administered during the use of DMARDs and anti-TNF agents but preferably before starting B cell– depleting therapy, and that attenuated live vaccines and BCG vaccination should be avoided whenever possible especially in immunosuppressed patients [7]. Because infections can trigger autoimmunity and may elicit a flare of an autoimmune disease, their prevention can reduce the incidence of the diseases as well as diseases flare-ups. In some instance, vaccine effect differs because of the genetic background of the recipient individual. Thus, the vaccination schedule would be better if personalized. Thomas et al. have revised this issue gathering a number of examples of genotype/gene polymorphisms mainly in the human leukocyte antigen (HLA) gene family, related to interindividual variation to vaccination [8]. Thus, we will discuss that vaccines and adjuvants may possibly act as triggers of autoimmune diseases in uniquely predisposed and susceptible individuals and report examples of autoimmune diseases induced by diverse vaccines either in clinical reports or experimental animal models. Our hope is that this information would help in advancing the research in the field, which, if properly implemented from a practical standpoint, could pave the way for the introduction of personalized medicine within the context of vaccination practices, considering individual-specific susceptibility factors (the so-called “personalized vaccinology”). The development of autoimmune diseases is a conundrum. In the book authored by Shoenfeld et al., in 1989 [9], entitled “The Mosaic of Autoimmunity,” the factors that may contribute to the development of a specific autoimmune disease in an individual were classified into four categories, namely, genetic factors, immune system dysregulation (complement system disorders, T cells dysfunction, etc.), hormonal factors (estrogen, progesterone, prolactin, vitamin D), and environmental factors [10,11], including viral and bacterial infections, UV exposure, and stress, among others. Furthermore, to develop an autoimmune disease, there needs to be an interplay or combination of these four categories of factors. For example, a single environmental trigger is unlikely to precipitate the development of autoimmunity in the absence of genetic predispositions. The wide diversity of these factors may also explain the presence of a large and heterogeneous group of 81 autoimmune diseases [12]. Additionally, the complexity and wide spectrum of possible interactions between susceptibility Mosaic of Autoimmunity. https://doi.org/10.1016/B978-0-12-814307-0.00029-3 Copyright © 2019 Elsevier Inc. All rights reserved.
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factors also explains why an individual may have more than one autoimmune disease. Thirty years’ after “The Mosaic of Autoimmunity,” additional important environmental factors were described, including dietary factors (salt, spicy foodprotective factor) [13] and obesity [14]. The genetic predisposition plays a pivotal role in all autoimmune diseases, as genetically predisposed individuals possess a very active immune system. It is possible to identify such individuals with a genetic predisposition to autoimmune diseases by the recognition of specific haplotypes of the HLA system [15]. Diverse HLA haplotypes have been described to be linked to the development of autoimmune diseases including (HLA-DRB1) [15], (HLA-DQB1) [16], (HLA-DRB1*07) [4], and several others. Female subjects are also at a higher risk for developing an autoimmune disease, sex hormones having a crucial role in this, with estrogens being a potent stimulators of autoimmunity and androgens playing a protective role [17]. Accumulating evidence further indicates that genetic, epigenetic, and environmental factors may also contribute to sex-related differences both in the risk and clinical course of autoimmune disease [17–20]. Moreover, pregnancy and postpartum periods are linked to autoimmune diseases, characterized by immune–endocrine imbalances, which occur to achieve immunosuppression and tolerance by the immune system to paternal and fetal antigens. These conditions may exacerbate some autoimmune disease and ameliorate others [21,22]. The impact of estrogens on the immune system is highly significant. Not only natural hormones but also endocrine disruptors, such as environmental estrogens, can act in conjunction with other factors to override immune tolerance to self-antigens [23,24]. Of all, probably the most important environmental factors are infections by microbial and viral agents [25–27]. There are five main mechanisms by which infections can lead to an autoimmune disease [10]. These mechanisms are as follows: (1) molecular mimicry, (2) “epitope spreading,” (3) polyclonal activation, (4) viral, and (5) bacterial superantigens that possess the ability to bind to the variable domain of the T cell receptor beta chain. Furthermore, environmental factors that possess an immune adjuvant or immune-potentiating activity such as infectious agents, aluminum, and other adjuvants have been associated with both clinically well-defined and nonspecific immune-mediated manifestations, both in animal models and in humans. These agents with immune adjuvant properties may affect diverse components of the immune system through the innate immune response by the activation of diverse toll-like receptors, the production of uric acid, and other molecules [28]. Adjuvants can be found in most vaccines and are added for the purpose of enhancing the host’s immune response to target antigens, and, therefore, genetically predisposed individuals may be at risk for developing an autoimmune disease because of vaccination. Altogether, these factors form the core basis underlying the description of the ASIA syndrome “autoimmune/inflammatory syndrome induced by adjuvants” [29–31], which will be discussed in a specific chapter.
AUTOIMMUNE DISEASES INDUCED BY VACCINATION: CASE REPORTS AND SERIES The main limits discussing the association between vaccine and autoimmune conditions are that most of the data are case reports or case series, that large epidemiological data tend to exclude a causal association, and that most of the associations are reported within a short time from exposure, while the development of an autoimmune response may require a longer exposure. The first cue of possible insurgence of autoimmune events after vaccination dates to 1979, when a large, high-quality epidemiological survey showed a link between influenza vaccination and the emergence of the Guillain-Barré syndrome (GBS). Although disputed, this link has been replicated in further studies. Since then, the emergence of autoimmune disorders related to immunization practices has been described in many recent case reports and series (Table 29.1). Zafrir et al. [32] reported a case of a 4-month-old female patient who presented with bullous skin rash, 2 months following her second inoculation with the hepatitis B (HBV) vaccine. In addition, during the appearance of the rash she received a second dose of the hexavalent vaccine (containing diphtheria, tetanus, acellular pertussis-DTaP, HBV, inactivated polio, and Haemophilus influenzae b), which was followed by irritability and fever. According to the clinical picture, biopsy result, direct immune fluorescent, and indirect immune fluorescent, a diagnosis of infantile bullous pemphigoid was determined. The patient was resistant to most conventional therapies. Bizjak et al. [33] reported a case of pancreatitis after vaccination in a 20-year-old man. One week after being vaccinated with the first dose of quadrivalent human papillomavirus (HPV) vaccine, he developed severe abdominal pain. Despite ongoing symptoms of nausea and pain, he received the second dose of the vaccine. Only 10 days later, laboratory results revealed significantly elevated pancreatic enzymes, and, with a concomitant abdominal pain and vomiting, he was diagnosed with acute pancreatitis. This case of acute pancreatitis after HPV vaccination is not a novel entity. Although confirming the relationship between pancreatitis and vaccine is challenging, some factors suggest a possible link, including the positive rechallenge on repeated exposure to the vaccine, HPV vaccine relationship to other autoimmune diseases [34–39], and a probable mechanism of molecular mimicry. With regard to the latter, in conjunction with the aluminum adjuvant, the
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TABLE 29.1 Selected Recent Reports of Diverse Autoimmune Diseases Induced by Vaccines References
Vaccine
Autoimmune Disease
Description
Zafrir et al.
Hepatitis B vaccine (HBV)
Bullous pemphigoid
Case report of a 4-month-old child who developed bullous skin rash, 2 months following her second inoculation with HBV vaccine.
Bizjak et al.
Quadrivalent human papillomavirus (HPV)
Pancreatitis
Case report of a 20-year-old male, who developed nausea and pain 1 week after his first vaccine dose. Despite continuing symptoms he received the second dose and 10 days later, laboratory results revealed significantly elevated pancreatic enzymes and with concomitant abdominal pain and vomiting, he was diagnosed with acute pancreatitis.
Agmon-Levin et al.
HBV
Fibromyalgia, chronic fatigue syndrome
Observational study, 19 patients, all patients fulfilled the ASIA criteria.
Zafrir et al.
HBV
Immuno-mediated diseases
Retrospective 93 patients with neuropsychiatric (70%), fatigue (42%) mucocutaneous (30%), musculoskeletal (59%) and gastrointestinal (50%) complaints, elevated titers of autoantibodies were documented in 80%.
Cheng et al.
Influenza vaccine, which contains the MF59 adjuvant
Myositis and myocarditis
Case report of a 65-year-old previously healthy male who 5 days after the vaccination developed severe rhabdomyolysis. Elevated troponin-I and extensive cardiac investigations enabled the diagnosis of myocarditis.
Dansingani et al.
Quadrivalent HPV
Panuveitis
Case report of a 20-year-old woman, who developed panuveitis and exudative retinal detachments 3 weeks after her second dose of the quadrivalent HPV vaccine.
Anaya et al.
Quadrivalent HPV
ASIA syndrome (enthesitis-related arthritis, and systemic lupus erythematosus [SLE])
Three cases of HLA-B27 enthesitis-related arthritis, rheumatoid arthritis, and SLE. Fulfilled the criteria of ASIA.
Lai et al.
Varicella-zoster
Arthritis, alopecia
A case–control study, patients with zoster vaccination had 2.2 and 2.7 times the odds of developing arthritis and alopecia.
Becker et al.
H1N1
Acute disseminated encephalomyelitis
A case report of an 8-year-old boy, who had fever, headache, and somnolence 12 days after the first dose of vaccine against H1N1 influenza, followed by seizures and coma.
RuhrmanShahar et al.
Antitetanus
Dermatomyositis, SLE, type 1 diabetes mellitus, antiphospholipid syndrome
Temporal correlation between vaccination and the induction of the diseases. Other causes were excluded.
induction of immunity through molecular mimicry may potentially culminate in production of cytotoxic autoantibodies with a particular affinity for pancreatic acinar cells. We have reported the association between fibromyalgia, chronic fatigue syndrome (CFS), and HBV vaccination [40]. Nineteen patients with CFS and/or fibromyalgia following HBV vaccine immunization were analyzed. The mean age of the patients was 28.6 ± 11 years, of which 68.4% were female and 21.5% had either personal or familial background of autoimmune disease. The mean latency period from the last dose of HBV vaccine to the onset of the symptoms was 38.6 ± 79.4 days, ranging from days to a year. Eight (42.1%) patients continued with the immunization program despite experiencing adverse events. Manifestations that were commonly reported included neurological manifestations (84.2%), musculoskeletal (78.9%), psychiatric (63.1%), fatigue (63.1%), gastrointestinal complains (58%), and mucocutaneous manifestations (36.8%). Autoantibodies were detected in 71% of patients tested. All patients fulfilled the ASIA syndrome criteria [40].
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The link between HBV vaccine and autoimmune disease was also reported by analyzing medical records of 114 patients, from different centers in the United States, diagnosed with immune-mediated diseases following immunization with HBV vaccine [41]. The mean age of 93 patients was 26.5 ± 15 years; 69.2% were female and 21% were considered autoimmune-susceptible. The mean latency period from the last dose of HBV vaccine and onset of symptoms was 43.2 days. Of note, 47% of patients continued with the immunization program despite experiencing adverse events. Manifestations that were commonly reported included neuropsychiatric (70%), fatigue (42%) mucocutaneous (30%), musculoskeletal (59%), and gastrointestinal (50%) complaints. Elevated titers of autoantibodies were documented in 80% of sera tested. In this cohort, 80/93 patients (86%), comprising 57/59 (96%) adults and 23/34 (68%) children, fulfilled the required criteria for ASIA. Recently, a case report of ASIA syndrome was described in a previously healthy patient who received the seasonal influenza vaccine, which contains the MF59 adjuvant [42]. The patient was presented to the hospital with a profound weakness and was diagnosed with severe rhabdomyolysis. He had elevated troponin-I and extensive cardiac investigations enabled the diagnosis of myocarditis. His infectious and rheumatologic workups were negative. He responded well to conservative management and did not require immune suppressive therapy. He had received the influenza vaccine 5 days prior to the onset of symptoms and fulfilled the criteria of ASIA syndrome. A case of a panuveitis with exudative retinal detachments after vaccination against HPV in a 20-year-old white woman was reported recently [43]. The patient presented with a bilateral acute visual loss (visual acuity: 20/60), panuveitis, and exudative retinal detachments 3 weeks after a second dose of quadrivalent HPV vaccine. She was treated with oral prednisolone for 6 weeks and responded rapidly. By week four, the vision had normalized and the clinical signs have resolved. The association between uveitis and the HPV vaccination has been also reported by Holt et al. [44]. Anaya et al. [45] detailed three cases of patients with ASIA syndrome after quadrivalent HPV vaccination. All the patients were women. Diagnosis consisted of HLA-B27 enthesitis-related arthritis, rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE), respectively. These results highlight the risk of developing ASIA after HPV vaccination and may serve to increase the awareness of such complications. A case-control study has been performed and reported the association between Zoster vaccine and autoimmunity [46]. Compared with the unexposed subjects, patients with zoster vaccination had 2.2 and 2.7 times the odds of developing arthritis and alopecia, respectively (P < .001 and P = .015, respectively). A case of an acute disseminated encephalomyelitis was reported in a healthy 8-year-old boy, who had fever, headache, and somnolence 12 days after the first dose of vaccine against influenza H1N1 [47]. Ruhrman-Shahar et al. [48] described four cases with a temporal relation between antitetanus vaccination and the appearance of dermatomyositis, SLE, type 1 diabetes mellitus, and antiphospholipid syndrome. The first case was a 38-year-old man, previously healthy, with no known familial autoimmune disease, who was bitten by a black scorpion and received a booster dose of DTaP. According to the multicenter, international ASIA Web-based registry, up to December 2016, 300 cases of ASIA syndrome have been described, with a mean age at disease onset of 37 years and a mean duration of time latency between exposure to adjuvant and development of autoimmune conditions of 16.8 months (from 3 days to 5 years). Arthralgia, myalgia, and chronic fatigue were the most frequently reported symptoms. Eighty-nine percent of patients were also diagnosed with another defined and with the most frequent autoimmune disease related to ASIA syndrome being connective tissue disease [49].
AUTOIMMUNE DISEASES INDUCED BY VACCINATION: EPIDEMIOLOGICAL SURVEYS The emergence of autoimmune disorders after vaccination has been observed in several large, high-quality trials. Dodd and coauthors [50] have computed a relative incidence of GBS of 2.42 (95% confidence interval [CI] or CI 1.58–3.72) in the 42 days following exposure to pH1N1 influenza vaccine in an analysis of pooled data and 2.09 (95% CI 1.28–3.42) when carrying out a metaanalytic approach. Similarly, other collaborative groups have replicated this finding: in Italy by Galeotti and collaborators [51], in the United States by Souayah and coworkers [52], in South Korea by Park and collaborators [53], and in Canada by Juurlink and coauthors [54]. Narcolepsy is another autoimmune disorder documented after 2009 Pandemic H1N1 vaccine. Sarkanen and coauthors [55] recently performed a systematic review and metaanalysis and found a relative risk of narcolepsy related to administration increased 5–14-fold in children and adolescents and 2–7-fold in adults during the first year after vaccination. They computed a vaccine-attributable risk in children and adolescents of 1 per 18,400 vaccine doses. Donahue and coworkers [56] have computed an overall adjusted odds ratio of 2.0 (95% CI 1.1–3.6) in women who spontaneously aborted and received influenza-containing vaccine in the 28-day exposure window. Chambers and colleagues [57] analyzing data of a study from the cohort arm of the Vaccines and Medications in Pregnancy Surveillance System (VAMPSS) found a moderately elevated relative risk for major birth defects.
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ANIMAL MODELS OF AUTOIMMUNE DISEASES INDUCED BY ADJUVANTS A vaccine-related autoimmune reaction should meet a series of requirements to be actually considered vaccine-induced, including consistency, strength, specificity, and temporal relation [58]. In humans, adjuvants can induce nonspecific constitutional, musculoskeletal, or neurological clinical manifestations and, in certain cases, can lead to the appearance or acceleration of an autoimmune disease in a subject with genetic susceptibility. The link between vaccination and pathogenic immune reactions has been reported in animal models. Inbar et al. [59] assessed the behavioral and inflammatory parameters in female mice after the injection of aluminum and quadrivalent HPV vaccine. The C57BL/6 female mice were injected with qHPV, qHPV + pertussis toxin, aluminum hydroxide, or vehicle control in amounts equivalent to human exposure. The qHPV and aluminum-injected mice spent significantly more time floating in the forced swimming test in comparison to vehicle-injected mice (aluminum, P = .009; qHPV, P = .025; qHPV + pertussis toxin, P = .005). No significant differences were observed in the number of stairs climbed in the staircase test, which measures locomotor activity. This suggests that the abnormality observed in the forced swimming test was unlikely because of locomotor dysfunction, but rather because of depression. Other research in animal models showing toxicity of adjuvant compounds includes the work of Favoino et al. [60], who assessed the effect of diverse adjuvants (incomplete Freund’s adjuvant, complete Freund’s adjuvant, squalene, or aluminum hydroxide) in lupus-prone New Zealand black/New Zealand white (BW)F1 mice. In the aluminum group, weight decreased by almost half between weeks 29 and 31, indicating some toxic effect of aluminum in the late postimmunization period. Squalene was the least toxic adjuvant as it did not accelerate proteinuria onset compared with incomplete Freund’s adjuvant. Similarly, squalene did not induce toxicity compared with aluminum or elicit anti-RNP/Sm autoantibody as observed in the complete Freund’s adjuvant group. Quiroz-Rothe et al. [61] described a case of postvaccination polyneuropathy resembling human GBS in a Rottweiler dog. The dog suffered of two separated episodes of acute polyneuropathy after receiving two vaccines (both adjuvanted). Inactivated rabies vaccine was administered 15 days before clinical signs were first noted. Clinical remission was achieved with steroid therapy; however, 3 months later the dog had recurrence of polyneuropathy, following another vaccination administered 12 days earlier. The presence of antibodies against peripheral nerve myelin was demonstrated. Agmon-Levin et al. [62] examined the effects of immunization with HBV vaccine and aluminum on SLE-like disease in a murine model. NZBWF1 mice were immunized with HBV vaccine or aluminum hydroxide or phosphate-buffered saline (PBS) at 8 and 12 weeks of age. Mice were followed for weight, autoantibodies titers, blood counts, proteinuria, kidney histology, neurocognitive functions (novel object recognition, staircase, Y-maze, and the forced swimming tests), and brain histology. Immunization with HBV vaccine induced acceleration of kidney disease manifested by high anti-dsDNA antibodies (P < .01), early onset of proteinuria (P < .05), histological damage, and deposition of HBs antigen in the kidney. Mice immunized with HBV vaccine and/or aluminum had decreased cells counts mainly of the red cell lineage (P < .001), memory deficits (P < .01), and increased activated microglia in different areas of the brain in comparison with mice immunized with PBS. Anxiety-like behavior was more pronounced among mice immunized with aluminum. Aratani and collaborators [63], in a model of mice vaccinated with HPV and pertussis toxin, reported low responsiveness of the tail reflex and locomotive mobility because of apoptotic damage affecting the hypothalamus and circumventricular regions around the third ventricle. In summary, animal models are often used to study the relation between autoimmune, inflammatory diseases, and diverse triggers [28]. These are broadly classified as either spontaneous, where an animal’s genetic background results in a defined prevalence of disease, or induced, where disease is precipitated by exposure to defined antigens, adjuvants, or other experimental reagents [28]. Experimentally animal models of autoimmune diseases induced by adjuvants are currently widely used to understand the mechanisms and etiology and pathogenesis of these diseases and might thus promote the development of new diagnostic, predictive, and therapeutic methods.
THE CONCEPT OF PERSONALIZED VACCINOLOGY Vaccination is a pivotal tool to prevent serious infections. In some cases vaccination may lead to adverse events. These are classified in local and systemic events such as allergy, fever, and possibly autoimmune diseases in genetically predisposed individuals [64]. It is important to highlight the fact that a temporal relationship between the induction of an autoimmune phenomenon and a specific vaccine is not always notable. Moreover, a specific vaccine may cause more than one autoimmune disease [65]; likewise, a particular immune process may be induced by diverse vaccines [3]. It is essential to recognize individuals with high risk and prone to develop autoimmunity before the exposure to diverse adjuvants through routine vaccinations. Soriano et al. [66] classified four groups of individuals in which vaccination may represent a risk factor for
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the induction of autoimmune phenomena. These groups include the following: (1) individuals with prior postvaccination autoimmune phenomena; (2) persons with a medical history of autoimmunity; (3) individuals with a history of allergic reactions (especially vaccination-related reactions); and (4) individuals who are prone to develop autoimmunity (having a family history of autoimmune diseases and presence of specific autoimmune disease markers such as elevated autoantibodies, certain genetic profiles, etc.). The HLA genes encode mostly immune-associated proteins whose main effect is the presentation of antigens to the immune cells. As such, HLA-related protein products are essential for the proper function of the immune response against pathogens; however, their variants are also strongly implicated in the development of autoimmune diseases [66], likewise, the positive correlation between SLE and the allotypes DR2 and DR3 of HLA class II [67], RA and HLA-DRB1 [68], and several others. In conclusion, physicians should be aware of the rare but possible adverse events to vaccinations, especially not only in cases with previous postvaccination phenomena and those with allergies but also in individuals who might be more prone to develop autoimmune diseases, due to a family history of autoimmune diseases, presence of specific HLA haplotypes and/ or autoantibodies, and other risk factors for autoimmunity (smoking, obesity, etc.). Factors that are predictive of developing autoimmune diseases should be examined at the population level to establish preventive measures in at-risk individuals for whom health care should be personalized. We do not stress enough that nowadays the benefits of vaccination overweight its potential risks. Surely, big data–based epidemiological surveys, metaanalytical approaches, and omics-based studies (exploiting, for instance, new cutting edge high-throughput technologies, such as “adversomics,” that is to say the systematic, holistic, data-driven “study of vaccine adverse reactions using immunogenomics and systems biology approaches”) [69] can pave the way toward personalized vaccinology.
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