Autoimmune Diseases: The Role for Vaccines

C H A P T E R

22 Autoimmune Diseases: The Role for Vaccines S. Sohail Ahmed1 and Lawrence Steinman2 1

Translational Medicine, Galapagos GmbH, Basel, Switzerland 2Neurology and Neuroscience, Stanford University School of Medicine, Stanford, CA, United States

O U T L I N E Introduction

375

The Reality Facing Clinicians Currently

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Concerns for Autoimmune Diseases in the Context of Vaccination

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Crossfire and Coincidence

377

Certainty About Vaccines, Uncertainty About Compatibility of Administration in Certain Settings

379

Search and You Will Find

380

Conclusion

380

References

381

Further Reading

381

Example of an Animal Model Developed to Understand Acute Disseminated Encephalomyelitis Observed With Older Rabies Vaccine—The Experimental Autoimmune Encephalomyelitis Model

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Practical Approach to Vaccination in Patients With Autoimmune Disease

379

INTRODUCTION Vaccines are essential components of any public health program. Their beneficial effects have been largely recognized, and vaccination is generally considered the most cost-effective approach in preventive medicine. Therefore vaccines are used extensively, and coverage can reach over 90% in a given population. Since autoimmune diseases affect approximately 5% 10% of the population in Europe and North America, most people that develop an autoimmune disease are likely to be exposed to some vaccines at some time before or after the onset of the disease process. While earlier vaccines were mainly targeted for pediatric age-groups, the development of recent vaccines for adolescents [e.g., human papillomavirus vaccine (HPV)] and older individuals (e.g., pneumococcus and influenza) may increase the probability of coincidental associations of vaccination with autoimmune diseases. Two major questions are of particular relevance to vaccination and autoimmune diseases. First, can vaccination trigger or enhance autoimmune responses? This frequently expressed concern is based either on a putative mimicry between vaccines and host antigens or on the fact that vaccination is associated with a transitory and variable activation of innate immunity. The use of adjuvants exploiting the immunostimulatory effect of Toll-like receptors (TLRs) has also triggered concerns related to their possible role in autoimmune disease development. Indeed, TLR-related pathways are being independently studied by investigators for their role in autoimmune disease modulation. Second, should patients with chronic autoimmune diseases be routinely vaccinated? Since

The Autoimmune Diseases, 6th. DOI: https://doi.org/10.1016/B978-0-12-812102-3.00022-1

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Copyright © 2020 Elsevier Inc. All rights reserved.

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22. AUTOIMMUNE DISEASES: THE ROLE FOR VACCINES

several infections are known to enhance disease activity in some autoimmune diseases, one can expect that their prevention, when feasible, would be beneficial. However, activation of innate immunity with some vaccines may also bear a theoretical risk of enhancing disease activity. Therefore, it is of importance to define guidelines regarding the use of essential vaccines in patients with autoimmune diseases. Such guidelines have been proposed by the American College of Rheumatology and the European League Against Rheumatism and form the basis of recommendations to be discussed in subsequent sections in this chapter.

CONCERNS FOR AUTOIMMUNE DISEASES IN THE CONTEXT OF VACCINATION Under the generic term of “vaccines,” there is a whole range of products that include complex live-attenuated microorganisms as well as purified proteins or polysaccharides. The common purpose of vaccination is to trigger a protective immune response in the host (similar to that seen with naturally acquired infection). Some vaccines are associated with a transient fever, and some vaccines commonly result in inflammation at the site of injection. Whether a vaccine can trigger or contribute to the initiation or worsening of autoimmune disease is a subject that is widely discussed. Fear of adverse reactions versus the immense known benefit of approved vaccines continues to be a topic of lively debate. In the United States, the National Childhood Vaccine Injury Act of 1986 (42 U.S.C. yy 300aa-1 to 300aa-34) was established under President Ronald Reagan as federal law (https://www.nytimes.com/1986/11/15/us/reagansigns-bill-on-drug-exports-and-payment-for-vaccine-injuries.html) to provide a legal basis for contesting whether or not a particular individual may have suffered harm from a given vaccine. The fund is financed by a tax on vaccines and is administered by the Federal Courts in the United States. The legal standard is the “preponderance of evidence”—a standard that is accepted in civil litigation in the United States. The standard is often at variance with the vague standards established for scientific review where “statistical significance” is usually invoked. Both in the previous decades for live or nonadjuvanted vaccines and more recently for adjuvanted vaccines, a major safety concern has centered on the possibility of potent stimulators of the immune response increasing the risk of developing an autoimmune disease. The old rabies vaccine that was produced using rabbit brain tissue was associated with the occasional (0.33/1000) development of immune-mediated encephalitis and antimyelin T-cell responses (Swaddiwuthipong et al., 1998). This is no longer observed with modern rabies vaccines produced with cell lines. Measles vaccination is also occasionally associated with a transitory immune thrombocytopenic purpura like thrombocytopenia. However, this syndrome is observed 6 10 times more frequently after natural measles infection (Beeler et al., 1996; Wraith et al., 2003). The swine influenza vaccine that was used in 1976 was associated with a significant increase in the frequency of Guillain Barre´ syndrome (incidence of 1 in 100,000) in the weeks following vaccination (Wraith et al., 2003), but this risk was significantly reduced with refinements in the manufacturing process of subsequent seasonal vaccines (risk of Guillain Barre´ reduced to 1 in 1,000,000) (Schonberger et al., 1979; Chen et al., 2001). In 2011, an epidemiological association of narcolepsy with the use of an AS03-adjuvanted H1N1 pandemic influenza vaccine was reported in Finland (National Narcolepsy Task Force Interim Report, 2011; Statement on Narcolepsy and Vaccination, 2011). The incidence of narcolepsy was 9.0 in the vaccinated as compared to 0.7/100,000 person years in the unvaccinated individuals, the rate ratio being 12.7. This H1N1 pandemic wave was shown in China to also be associated with a 3 4 rise of narcolepsy in the absence of vaccination (Han et al., 2011). A study published in 2015 may have established an immunologic link between the influenza virus and narcolepsy through antigenic molecular mimicry. Specifically, molecular mimicry was identified between a fragment of one of the influenza antigens (nucleoprotein) contained in the AS03-adjuvanted pandemic vaccine and a portion of the human brain, hypocretin receptor 2, that is responsible for promoting wakefulness (Ahmed et al., 2015). Using mass spectrometry, influenza nucleoprotein was demonstrated to be present in significant amounts in the AS03-adjuvanted inactivated split-virion pandemic vaccine compared to the MF59-adjuvanted inactivated subunit pandemic vaccine (that was not associated with narcolepsy and contained 73% less influenza nucleoprotein). The authors additionally demonstrated the presence of antibodies capable of cross-reacting with both influenza nucleoprotein and the hypocretin receptor that could, theoretically, disrupt wakefulness that is normally triggered by binding of hypocretin protein to the hypocretin receptor 2. These findings and the association of narcolepsy with influenza infection make the role of adjuvants, by themselves, in triggering autoimmune disease in genetically susceptible subjects less likely. However, both Guillain Barre´ and narcolepsy should serve as reminders that vaccine antigen formulations need to be carefully selected to avoid potential autoimmune disease development in a percentage of the population receiving vaccines, and that disease development may, rarely, be potentiated by adjuvants in the presence of a cross-reactive antigen.

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CROSSFIRE AND COINCIDENCE

CROSSFIRE AND COINCIDENCE The associations described previously underscore the extent of our current capabilities in identifying risks associated with vaccines—that is, through statistical associations. While identifying causation would be ideal (e.g., a clear and unequivocal link between vaccination and rare adverse events, such as autoimmune disease), this is difficult given the individual, environmental, and temporal variables that occur during the window of immunization. While disease incidence in the setting of vaccination can be identified using statistical tools, this analysis can be confounded by the occurrence of “coincidental” associations. There is a background rate of these events that occur despite vaccination and a risk of such event occurring at the same time as the vaccine, by chance alone, which can confound the interpretation of vaccine safety. One possible but not always a practical solution is to collect autoimmune disease prevalence and incidence data in a given population before vaccination to illustrate these coincidental associations. Such an approach was utilized prior to the large-scale introduction of the HPV vaccine where a cohort study of 214,896 female adolescents and 221,472 young adults was carried out to monitor the prevalence of autoimmune disease before vaccine introduction (Siegrist et al., 2007). This elegant approach collected data on the frequency of immune-mediated conditions leading to outpatient visits, the number of women hospitalized, and the most frequently diagnosed autoimmune disease. These data were then used to model temporal associations that would have occurred theoretically had the vaccine been used with 80% coverage. One can quickly appreciate how such population-based efforts enable one to identify, in advance, confounding issues affecting safety perception to avoid a negative impression of an inherently safe vaccine. Table 22.1 has been adapted primarily from autoimmune disease epidemiological data reported in a systematic review (Jacobson et al., 1997); in which, four additional categories were added from a study published in 2003 (Cooper and Stroehla, 2003). These combined data represent, to our knowledge, the most comprehensive and conservative estimates to date. Table 22.1 intentionally focuses on the incidence of autoimmune diseases more commonly occurring in adults because the adult population is traditionally enrolled in first-in-human clinical trials with vaccines (the rates of autoimmunity in pediatric patients, though limited, suggest that they are quite different and reflect the contributions of time and environmental exposure to disease development). These autoimmune diseases, based on previously reported estimates of incidence (Jacobson et al., 1997; Cooper and Stroehla, 2003), would have been responsible for 204,789 new cases of autoimmune disease in a population .18 years of age in the United States based on the 2010 US Census (US Census Bureau, 2011). With this extrapolated

TABLE 22.1

Autoimmune Disease Epidemiological Data Reported in a Systematic Review Expected new diagnosesb (persons .18 years of age)

Autoimmune diseasea

Incidencea (per 100,000 persons per year)

Adult rheumatoid arthritis

23.7

55,092

Thyroiditis (hypothyroidism)

21.8

50,675

Graves’ disease (hyperthyroidism)

13.9

32,311

Type 1 diabetes (age 20 years)

8.1

18,829

Systemic lupus erythematosus

7.3

16,969

Sjo¨gren disease

3.9

9065

Multiple sclerosis

3.2

7438

Primary systemic vasculitis

2.0

4649

Polymyositis/Dermatomyositis

1.8

4184

Systemic sclerosis

1.4

3254

Addison disease

0.6

1394

Myasthenia gravis

0.4

929

Total

204,789

a

The table is obtained with permission from Ahmed, S., Plotkin, S.A., Black, S., Coffman, R.L., 2011. Assessing the safety of adjuvanted vaccines. Sci. Transl. Med. 3, 93rv2. Expected new diagnoses in the United States were extrapolated using the 2009 US Census data for population .18 years of age.

b

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378 TABLE 22.2

22. AUTOIMMUNE DISEASES: THE ROLE FOR VACCINES

Incidence Data From Autoimmune Diseases Study sample size N 5 200

N 5 1000

N 5 2000

N 5 3000

N 5 10,000

a

Probability to observe at least one case Autoimmune diseasea Adult rheumatoid arthritis (%)

4.6

21.1

37.8

50.9

90.7

Thyroiditis (hypothyroidism) (%)

4.3

19.6

35.3

48.0

88.7

Graves’ disease (hyperthyroidism) (%)

2.7

13.0

24.3

34.1

75.1

Type 1 diabetes (age .20 years) (%)

1.6

7.8

15.0

21.6

55.5

Systemic lupus erythematosus (%)

1.4

7.0

13.6

19.7

51.8

Sjo¨gren disease (%)

0.8

3.8

7.5

11.0

32.3

Multiple sclerosis (%)

0.6

3.1

6.2

9.2

27.4

Primary systemic vasculitis (%)

0.4

2.0

3.9

5.8

18.1

Polymyositis/dermatomyositis (%)

0.4

1.8

3.5

5.3

16.5

Systemic sclerosis (%)

0.3

1.4

2.8

4.1

13.1

Addison disease (%)

0.1

0.6

1.2

1.8

5.8

Myasthenia gravis (%)

0.1

0.4

0.8

1.2

3.9

15.0

55.5

80.2

91.2

100.0

Total (%) a

The table is obtained with permission from Ahmed, S., Plotkin, S.A., Black, S., Coffman, R.L., 2011. Assessing the safety of adjuvanted vaccines. Sci. Transl. Med. 3, 93rv2.

table, one rapidly gains a perspective on the risk of coincidental association that can occur when an autoimmune disease is diagnosed in a subject immunized during a vaccine clinical trial (independent of the vaccine’s effect). Table 22.2 uses the incidence data from these autoimmune diseases and calculates the probability of observing at least one case of autoimmune disease in clinical trials ranging from 200 to 10,000 subjects. As demonstrated, there is an increase in the probability of observing one patient with autoimmune disease when examining a trial with 200 subjects (15%) versus 3000 subjects (91%), which illustrates why coincidental associations occasionally occur during large phase III vaccine studies and even more during postlicensure monitoring of vaccination adverse events. Whether a given case of new onset autoimmune disease is “expected” statistically or due to an underlying predisposition to susceptibility is a recurrent issue. Sample sets, such as the Department of Defense serum repository, may help us to design studies to analyze who may be at substantial risk from a given immunization (Arbuckle et al., 2003).

EXAMPLE OF AN ANIMAL MODEL DEVELOPED TO UNDERSTAND ACUTE DISSEMINATED ENCEPHALOMYELITIS OBSERVED WITH OLDER RABIES VACCINE—THE EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS MODEL Animal models have played a major role in understanding how vaccines might induce damage. As mentioned in the Introduction, the old rabies vaccine that was produced using rabbit brain tissue was associated with the occasional (0.33/1000) development of immune-mediated encephalitis and antimyelin T-cell responses (Swaddiwuthipong et al., 1998). The model known as experimental allergic or experimental autoimmune encephalomyelitis (both now abbreviated EAE) was actually developed in the 1930s by Thomas Rivers and colleagues at the Rockefeller to help understand acute disseminated encephalomyelitis that was seen following rabies vaccine used at that time (Rivers et al., 1933). The EAE model comes in many forms these days and no longer requires adjuvant for induction. EAE has directly contributed to six new therapies for multiple sclerosis. It has provided a fertile test system for exploring how vaccines might induce neuroinflammatory damage in susceptible hosts (Steinman, 2003; Steinman and Zamvil, 2006).

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CERTAINTY ABOUT VACCINES, UNCERTAINTY ABOUT COMPATIBILITY OF ADMINISTRATION IN CERTAIN SETTINGS

379

PRACTICAL APPROACH TO VACCINATION IN PATIENTS WITH AUTOIMMUNE DISEASE What is frequently forgotten, but is commonly observed by clinicians managing patients with autoimmune diseases, is that natural infection, unlike vaccination, is a more likely and proven risk factor for triggering (flare) and augmenting severity of autoimmune diseases. For example, an influenza vaccine study with 69 patients with systemic lupus erythematosus (SLE) and 54 patients with rheumatoid arthritis demonstrated that every viral and bacterial infection (seen predominantly in the nonvaccinated cohort) resulted in worsening of the main disease (Stojanovich, 2006). Similarly, a case report described a severe flare of SLE in a patient infected with parvovirus B19 (Hemauer et al., 1999). A meta-analysis arrived at a similar conclusion that several vaccine-preventable infections occurred more often in patients with autoimmune disease, that vaccines were efficacious in these patients, and that there did not appear to be an increase in vaccination-related harm compared to nonvaccinated patients (van Assen et al., 2011). Influenza and other acute respiratory infections are also commonly associated with an increased frequency of relapses in patients with relapsing multiple sclerosis (Oikonen et al., 2011). This risk is markedly reduced in patients that received the seasonal influenza vaccine (De Keyser et al., 1998).

THE REALITY FACING CLINICIANS CURRENTLY The last 10 years have ushered in several new vaccines which rheumatologists caring for their patients should be familiar with. Some of these vaccines may be live-attenuated versus being inactivated (thus not capable of replication) and thus need to be considered carefully depending on the clinical interventions being considered for the patient. These vaccines include those for cholera (live oral), meningitis (quadrivalent conjugate and serogroup B recombinant), pneumococcus (conjugate), papillomavirus (alum and TLR4 adjuvanted), rotavirus, and, lastly, the DTaP vaccine (diphtheria, tetanus, and acellular pertussis). A shingles vaccine (containing varicella zoster virus (VZV) glycoprotein with AS01B T-cell boosting adjuvant) has been submitted in 2016 for evaluation by the FDA and has now been approved by the FDA (https://www.fda.gov/BiologicsBloodVaccines/Vaccines/ ApprovedProducts/ucm581491.htm). Yet despite evidence of the impact and benefits of vaccinations, clinicians are not adequately vaccinating their patients according to established guidelines. The most significant barrier to vaccination identified by the Centers for Disease Control is the lack of knowledge about vaccines among adult patients and providers (Kroger et al., 2011). This section will provide guidance to the practicing rheumatologist regarding the role for vaccines in the patients that they treat based on Vaccine Recommendation and Guidelines published by the Advisory Committee on Immunization Practices (ACIP) and detailed guidelines that have been proposed by the American College of Rheumatology and the European League Against Rheumatism (to be discussed next).

CERTAINTY ABOUT VACCINES, UNCERTAINTY ABOUT COMPATIBILITY OF ADMINISTRATION IN CERTAIN SETTINGS For those physicians that are aware of the vaccines currently available and recommended for their patients, questions are sometimes raised regarding what to do when patients are being treated with immunomodulators or the efficacy of vaccines in patients that are immunosuppressed. These concerns are based on the observation that immunosuppression resulting from primary or secondarily altered immunocompetence creates the greatest risk for infections in patients. Most patients being managed by rheumatologists are immunosuppressed by drugs prescribed to control their autoimmune disease and, thus, the immunodeficiency is a function of dose and type of therapy. A publication from the American College of Rheumatology Drug Safety Committee succinctly addresses this challenge and is the source of the recommendations highlighted in the following sections (Dao and Cush, 2012). Distinguishing those vaccines that are live from those that are inactivated is critical when considering immunization of patients with autoimmune diseases on immunomodulatory treatments. Examples of live vaccines include the following: smallpox, adenovirus type 4 and 7, Bacille Calmette Gue´rin, typhoid (oral), rotavirus, cholera, yellow fever, herpes zoster, influenza (live attenuated), varicella zoster, and measles mumps rubella. In the case of live vaccines, therapy with low doses of methotrexate and azathioprine are not considered sufficiently immunosuppressive, and corticosteroid therapy is not usually a contraindication in the following cases: duration of

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22. AUTOIMMUNE DISEASES: THE ROLE FOR VACCINES

treatment is less than 2 weeks, use of a dose less than 20 mg/day, duration of $ 2 weeks but with alternate-day treatment of short-acting formulations, doses that are physiologic, or the route of administration is topical or injected within joints, tendons, or bursae. However, the ACIP identifies patients receiving tumor necrosis factor (TNF) inhibitors or doses of prednisone greater than 20 mg/day (for longer than 2 weeks) to be sufficiently immunosuppressed that the use of live-attenuated vaccines is not recommended due to the concern for uncontrolled replication of the viral/bacterial microorganism in the host. If higher doses of steroids are used ( . 20 mg/day for more than 2 weeks), it is recommended to wait a month after immunosuppression before a live vaccine is given as severe complications have been reported following vaccinations with live vaccines. Such concerns do not apply to inactivated vaccines (whether killed whole-organism, subunit, recombinant, polysaccharide, or toxoid vaccines). However, one should keep in mind that methotrexate 1 TNF inhibitors, anti-CD20 antibody, abatacept, and possibly azathioprine can reduce the immune response to these vaccines. Especially in the case of B-cell depleting biologic therapy, vaccines should be administered before the start of therapy. Examples of inactivated vaccines include the following: typhoid (polysaccharide), tetanus-diphtheria/acellular pertussis, hepatitis A, hepatitis B, human papilloma, influenza (A/B/H1N1), pneumococcal, polio, rabies, and meningococcal. The reader should be aware that some vaccines licensed for immunization and distribution in the United States (e.g., influenza and typhoid) have been developed by different manufacturers as distinct live or inactivated products. A complete list may be found at the following website: http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM093833.

SEARCH AND YOU WILL FIND Guidance has been published for the use of vaccination in patients with autoimmune diseases. This has been in part due to the increasing awareness of the importance of vaccines in healthy populations and, ironically, also due to the perceived risk with newer vaccines containing adjuvants. Furthermore, more studies are being conducted and published on the value of vaccinations in patients with autoimmune diseases. A recent review paper has succinctly summarized the epidemiology of vaccine-preventable infectious diseases and the efficacy and safety of vaccination to prevent these diseases in patients with autoimmune diseases (Westra et al., 2015). Influenza, pneumococcal disease, herpes zoster, and HPV infection are all more common (or cause complications more frequently) in these patients. Most vaccines are effective in preventing disease in patients with autoimmune disease despite their chronic use of immunomodulatory treatments with the exception of rituximab and abatacept that probably can suppress immune responses after vaccination (Westra et al., 2015). A summary of the 2010 EULAR recommendations for vaccination of adults with autoimmune disease is included in that review paper, and a more detailed publication outlining timing and specific notes for available vaccines was published in 2016 (Tanrio¨ver et al, 2016). The reader is also referred to the Centers for Disease Control and Prevention web-based article (“What vaccines are recommended for you,” 2017) at the following website: https://www.cdc. gov/vaccines/adults/rec-vac/index.html for additional details.

CONCLUSION The primary focus of this chapter is to update clinicians treating patients with autoimmune disease with a concise overview of the challenges facing vaccine development and the best application of this health intervention for their patient population. Those familiar with autoimmune diseases and those involved with vaccine development may already be aware of the common thread to both fields—that is, the triggering of the immune response. However, for those not familiar with these specialties, this common thread has also led, sometimes, to unjustified speculations regarding the relationship between this disease state and this disease intervention. While it is critical to have a high level of scrutiny for the benefit/risk ratio of any prophylactic or therapeutic intervention in human subjects, one needs to keep in mind that vaccines have been responsible for preventing more deaths than virtually any other medicinal product. The value and impact of vaccinations for human health are undeniable—this is the most cost-effective intervention in preventive medicine. Those clinicians not utilizing vaccines routinely in their practices are requested to familiarize themselves in detail regarding vaccines (those with and without adjuvants, live vs inactivated), the patient populations likely to benefit from such interventions (e.g., young girls and HPV vaccination), and their correct use in patients undergoing immunosuppressive treatments. It is hoped that this review has provided a concise overview that will serve as the basis for more detailed study and prepare the clinicians for the questions posed by their patients about the safety of vaccines.

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FURTHER READING

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References Ahmed, S.S., Volkmuth, W., Duca, J., Corti, L., Pallaoro, M., Pezzicoli, A., et al., 2015. Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2. Sci. Transl. Med. 7 (294), ra105. Arbuckle, M.R., McClain, M.T., Rubertone, M.V., Scofield, R.H., Dennis, G.J., James, J.A., et al., 2003. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N. Engl. J. Med. 349, 1526 1533. Beeler, J., Varricchio, F., Wise, R., 1996. Thrombocytopenia after immunization with measles vaccines: review of the vaccine adverse events reporting system (1990 to 1994). Pediatr. Infect. Dis. J. 15, 88 90. Chen, R.T., Pless, R., Destefano, F., 2001. Epidemiology of autoimmune reactions induced by vaccination. J. Autoimmun. 16, 309 318. Cooper, G.S., Stroehla, B.C., 2003. The epidemiology of autoimmune diseases. Autoimmun. Rev. 2, 119 125. Dao, K., Cush, J.J., 2012. A vaccination primer for rheumatologists. DSQ (Drug Saf. Q.) 4 (1), 1 4. De Keyser, J., Zwanikken, C., Boon, M., 1998. Effects of influenza vaccination and influenza illness on exacerbations in multiple sclerosis. J. Neurol. Sci. 159 (1), 51 53. Han, F., Lin, L., Warby, S.C., Faraco, J., Li, J., Dong, S.X., et al., 2011. Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in China. Ann. Neurol. 70 (3), 410 417. Hemauer, A., Beckenlehner, K., Wolf, H., Lang, B., Modrow, S., 1999. Acute parvovirus B19 infection in connection with a flare of systemic lupus erythematodes in a female patient. J. Clin. Virol. 14, 73 77. Jacobson, D.L., Gange, S.J., Rose, N.R., Graham, N.M., 1997. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin. Immunol. Immunopathol. 84, 223 243. Kroger, A.T., Sumaya, C.V., Pickering, L.K., Atkinson, W.L., 2011. Recommendations of the Advisory Committee on Immunization Practices (ACIP). Morb. Mortal. Wkly. Rep. 60, 1 60. National Narcolepsy Task Force Interim Report, 2011. National Institute for Health and Welfare, Helsinki. Oikonen, M., Laaksonen, M., Aalto, V., Ilonen, J., Salonen, R., Era¨linna, J.P., et al., 2011. Temporal relationship between environmental influenza A and Epstein-Barr viral infections and high multiple sclerosis relapse occurrence. Mult. Scler. 17 (6), 672 680. Rivers, D.T., Sprunt, D.H., Berry, G.P., 1933. Observations on attempts to produce acute disseminated encephalomyelitis in monkeys. J. Exp. Med. 58 (1), 39 53. Schonberger, L.B., Bregman, D.J., Sullivan-Bolyai, J.Z., Keenlyside, R.A., Ziegler, D.W., Retailliau, H.F., et al., 1979. Guillain-Barre syndrome following vaccination in the National Influenza Immunization Program, United States, 1976 1977. Am. J. Epidemiol. 110, 105 123. Siegrist, C.A., Lewis, E.M., Eskola, J., Evans, S.J., Black, S.B., 2007. Human papilloma virus immunization in adolescent and young adults: a cohort study to illustrate what events might be mistaken for adverse reactions. Pediatr. Infect. Dis. J. 26, 979 984. Statement on Narcolepsy and Vaccination, 2011. Global Advisory Committee on Vaccine Safety, World Health Organization, Geneva. Steinman, L., 2003. Optic neuritis, a new variant of experimental encephalomyelitis, a durable model for all seasons, now in its seventieth year. J. Exp. Med. 197, 1065 1071. Steinman, L., Zamvil, S.S., 2006. How to successfully apply animal studies in experimental allergic encephalomyelitis to research on multiple sclerosis. Ann. Neurol. 60, 12 21. Stojanovich, L., 2006. Influenza vaccination of patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Clin. Dev. Immunol. 13, 373 375. Swaddiwuthipong, W., Weniger, B.G., Wattanasri, S., Warrell, M.J., 1998. A high rate of neurological complications following Semple antirabies vaccine. Trans. R. Soc. Trop. Med. Hyg. 82 (3), 472 475. ¨ ., Ertenli, I., Kiraz, S., 2016. Vaccination recommendations for adult patients with rheu˘ O Tanrio¨ver, M.D., Akar, S., Tu¨rkc¸apar, N., Karadag, matic diseases. Eur. J. Rheumatol. 3 (1), 29 35. US Census Bureau, 2011. Statistical Abstract of the United States, Table 7. Resident Population by Sex and Age: 1980 to 2009. US Government Printing Office, Washington, DC, ,http://www.census.gov/compendia/statab/2011/tables/11s0007.pdf.. van Assen, S., Elkayam, O., Agmon-Levin, N., Cervera, R., Doran, M.F., Dougados, M., et al., 2011. Vaccination in adult patients with autoimmune inflammatory rheumatic diseases: a systematic literature review for the European League Against Rheumatism evidence-based recommendations for vaccination in adult patients with auto-immune inflammatory rheumatic diseases. Autoimmun. Rev. 10, 341 352. Westra, J., Rondaan, C., van Assen, S., Bijl, M., 2015. Vaccination of patients with autoimmune inflammatory rheumatic diseases. Nat. Rev. Rheumatol. 11 (3), 134 145. Wraith, D.C., Goldman, M., Lambert, P.H., 2003. Vaccination and autoimmune disease: what is the evidence? Lancet 362, 1659 1666.

Further Reading Krieg, A.M., Efler, S.M., Wittpoth, M., Al Adhami, M.J., Davis, H.L., 2004. Induction of systemic TH1-like innate immunity in normal volunteers following subcutaneous but not intravenous administration of CPG 7909, a synthetic B-class CpG oligodeoxynucleotide TLR9 agonist. J. Immunother. 27, 460 471.

IV. INITIATORS OF AUTOIMMUNE DISEASE