Autoimmune diseases and vaccinations

ARTICLE

Auteur(s) : Thierry VIAL, Jacques DESCOTES

Centre Antipoison et Centre Régional de Pharmacovigilance, 162, avenue Lacassagne, 69424 Lyon Cedex 03, France

Article accepted on 20/01/2004

Although vaccines are generally considered safe, any question regarding potentially severe adverse effects becomes a source of considerable debate. This was recently exemplified by the French media coverage of the questionable link between hepatitis B vaccination and increased risk of multiple sclerosis. More generally, many investigators have extensively explored a possible relationship between immunization and the occurrence of autoimmune diseases in the past, but no conclusive evidence has emerged from the available data [1]. The observed increase in the incidence of several autoimmune diseases, the poor understanding of the underlying mechanisms and the growing use of vaccines have all served as an impetus for more research in this area.
This review will illustrate current issues from selected examples. The medical literature is full of isolated case reports that detailed the appearance of autoimmune diseases temporally associated with immunization. Interestingly, most of the reported autoimmune diseases are organ-specific diseases, such as Guillain-Barré syndrome, multiple sclerosis and insulin-dependent diabetes mellitus, whereas systemic autoimmune diseases, such as rheumatoid arthritis or systemic lupus erythematous are less frequently described.
As indicated in a comprehensive review of the epidemiology of autoimmune reactions associated with vaccines [2], the three following questions should be addressed when suspecting a link between vaccines and autoimmunity: Is a specific vaccine associated with the development of a new unique autoimmune disease? Does a particular vaccine increase the risk of any autoimmune disease in some predisposed individuals? Can a vaccine be safely administered to a patient who is suffering from a known autoimmune disease?

Guillain Barré syndrome and influenza vaccination

Guillain-Barré syndrome is an acute inflammatory demyelinating polyradiculoneuritis that results in progressive paralysis. Although the exact origin of the syndrome is not fully understood, an immunological mechanism leading to the activation of humoral and cellular immunity is generally accepted. A pre-existing viral infection (camphylobacter jejuni, Epstein-Barr virus, hepatitis B virus, cytomegalovirus), which is thought to produce cross-immunization against myelinic antigens, has sometimes been identified in affected patients. Several vaccines have been claimed to be associated with the onset of Guillain-Barré syndrome, but influenza vaccine was the most frequently cited.

The causal role of the A/New Jersey influenza vaccine was clearly suggested following a vaccination campaign against swine influenza performed in the United States in 1976-1977 [3]. An increased number of reported cases of Guillain-Barré syndrome that occurred within weeks following vaccination led to the temporary suspension of the vaccination program. Further investigations found that the incidence rate of the syndrome was 4 to 8-fold higher in the vaccinated population as compared to that expected in the general population. The excess number of cases was therefore about one additional case per 100,000 vaccinations. More importantly, the increased risk of developing Guillain-Barré syndrome was concentrated during the first 5 weeks after vaccination with no increase noted beyond 6 weeks post-vaccination. Epidemiological studies that surveyed the risk of Guillain-Barré syndrome were unable to reproduce these findings after subsequent influenza vaccination campaigns. However, a retrospective analysis of the campaigns performed in 1992-1993 and 1993-1994 were able to identify a low, but significant association for the 6-week period after vaccination, but the estimated excess risk was only one additional case per one million vaccinations [4]. As compared to tetanus-diphtheria vaccination, a significantly increased risk of acute and severe Guillain-Barré syndrome after influenza vaccination was also found recently, using an analysis of data from the US Vaccine Adverse Events Reporting System (VAERS) [5]. This study identified a significant variation in the incidence of Guillain-Barré syndrome among different manufacturers of influenza vaccine and suggested that different concentrations of endotoxin in these vaccines may be of relevance in the occurrence of the disease.

The risk of relapse of Guillain-Barré syndrome after subsequent vaccination has been rarely, if at all, explored. One isolated report described a relapse of Guillain-Barré syndrome in 2 patients revaccinated with the strain implicated in the 1976 epidemic [6], but another report did not find any relapse in a patient who received different strains of influenza virus within the 15 years that followed the episode of Guillain-Barré syndrome [7]. More recently, a postal survey of patients who had a previous history of Guillain-Barré syndrome or chronic inflammatory polyradiculoneuritis suggested that the risk of recurrence of the neurological symptoms after vaccination was minimal, with only minor symptoms, including in patients for whom a temporal relationship between the initial episode and a previous vaccination had been suggested [8].

Multiple sclerosis and hepatitis B vaccination

Multiple sclerosis is an inflammatory autoimmune disorder of the central nervous system with destruction of the myelin sheath surrounding neurons. Although the disease probably results from a complex interplay between environmental and genetic factors, the sequence of events that initiates the disease is unknown. The possibility that several vaccines may cause or exacerbate multiple sclerosis usually originates from case reports describing the onset or recurrence of demyelinating symptoms shortly after vaccination [2]. Obviously, such isolated reports do not allow any inference on the causal relationship and they might represent a mere coincidental temporal association with vaccination. The claims related to a possible role of hepatitis B vaccination in the risk of multiple sclerosis may serve as an illustration.

The first report that associated hepatitis B vaccination temporally with evidence of central nervous system demyelination in two patients was published in the Lancet in 1991 [9]. French neurologists later described 35 cases of primary demyelinating diseases that occurred within 8 weeks of hepatitis B vaccination, and definite multiple sclerosis was later confirmed in half of the patients [10]. In 1998, the accumulation of spontaneous reports of multiple sclerosis to the French pharmacovigilance system led the French Ministry of health to temporarily suspend the school-based program of hepatitis B vaccination initiated in 1995. Although there was no direct evidence to support the biological plausibility of an association between hepatitis B vaccines and multiple sclerosis, this resulted in a vivid debate in the scientific community and the media, and the lack of epidemiological data exacerbated the confusion.

Since 1994, more than 1000 reports of central or peripheral demyelinating disorders, of which 80 % were multiple sclerosis, have been reported to the French pharmacovigilance system (AFSSAPS, press release, November 2002). The analysis of these spontaneous reports does not evidence any striking clinical characteristics in these patients, and most of the cases are in keeping with the known epidemiology of multiple sclerosis. In particular, no cases of multiple sclerosis were identified in children less than 3 years of age. There was also no relationship between the occurrence of symptoms and the rank of vaccination.

Approximately 30 million people have now received hepatitis B vaccination in France and the data from spontaneous notification do not allow correct assessment of the problem. Several epidemiological studies have therefore been conducted in France and other countries to explore any causal association between hepatitis B vaccination and demyelinating diseases. Using different designs (pre- and post-exposure studies, case control studies, retrospective comparative cohort), seven studies were unable to detect a statistically significant increase in the risk of multiple sclerosis after hepatitis B vaccination in previously healthy people, neither in the adult nor in the adolescent population [11-16]. Based on these negative findings, the US Institute of Medicine and other review panels therefore concluded that the evidence favours the rejection of a causal association between hepatitis B vaccine and multiple sclerosis [17]. A risk-benefit analysis using different scenarios for pre-adolescent vaccination in France also concluded that the benefits of hepatitis B vaccination largely exceed the maximum hypothetical increased risk of a first episode of central demyelinating disease [18]. Only one very recent nested case-control study within the General Practice Research Database suggested that recombinant hepatitis B vaccine administered within 3 years before the date of the first symptoms of multiple sclerosis may be associated with a significant increased risk of the disease, but the results of the study are only available in abstract form [19]. It should be emphasized that most of the negative studies lacked sufficient statistical power to detect a slight increase in the incidence of the disease. The existence of a susceptible sub-population at a higher risk of developing the disease may not cause an overall increase in disease incidence and thus cannot be excluded.

In addition, despite individual case reports, current epidemiological evidence does not support a causal association with several other vaccines, such as influenza, tetanus, measles, mumps or rubella and the onset or exacerbation of central nervous demyelinating diseases, regardless of the timing of vaccination [12].

Type 1 diabetes and vaccination

Genetic and environmental factors are thought to be involved in type 1 diabetes mellitus, a disease that results from the autoimmune destruction of pancreatic β-cells. In addition, there is some evidence to suggest a role for natural infections in the pathogenesis of type 1 diabetes mellitus in susceptible individuals, although the mechanisms by which viral infections cause autoimmune diabetes have not been fully clarified [20].
Several experimental data have suggested that vaccination might exert a protecting or aggravating effect on the occurrence of diabetes, depending on the timing of vaccination [21]. Accordingly, Classen and Classen [22] hypothesized that several vaccines administered at birth can decrease the risk of developing diabetes mellitus whereas primary vaccination after 2 months of age increased the risk of diabetes mellitus. Their theory was based on the findings of an increased risk of autoimmune diabetes in diabetes-prone non-obese diabetic (NOD) mice after administration of pediatric vaccines [23]. However, others using the same animal model were unable to reproduce these findings after similar vaccination schemes performed at 10, 12 and 14 weeks of age, and even suggested a slight reduction in the incidence of autoimmune diabetes or a moderate decrease in blood glucose levels [24].
The accumulating human data from various epidemiological studies do not support a causal association between vaccination and an increased risk of type 1 diabetes [20]. Case control or ecological studies indicate that neither pertussis nor BCG vaccinations have a significant effect on the incidence of type 1 diabetes [25, 26]. In a Canadian case control study, BCG vaccination rates were similar in patients with type 1 diabetes and controls, although the authors suggested a possible delayed occurrence in the onset of diabetes in birth-vaccinated compared to non-vaccinated cases [27]. A Swedish case control study did not find any evidence for an increase in the risk of diabetes after BCG, smallpox, tetanus, pertussis, rubella and mumps vaccinations, and even indicated a possible decreased risk after measles vaccination [28]. A large, population-based, case control study used data from 4 health maintenance organizations (HMO) in the United States to examine the effects of different vaccines [29]. Children with type 1 diabetes mellitus born were matched on HMO, sex, date of birth and length of health plan enrolment to 3 controls. Based on the analysis of 252 cases of type 1 diabetes mellitus and 768 controls, there was no increased risk of type 1 diabetes with any of the routinely administered childhood vaccines. The risk of diabetes was not different between children vaccinated at birth with the hepatitis B vaccine and those who received their first dose at 2 months of age or later, suggesting that the timing of vaccination did not influence the likelihood of developing diabetes. Finally, a case control study of 317 children who had a first-degree family member with type 1 diabetes found no significant association between the development of β-cell autoimmunity and exposure to a number of vaccines, and no effect of the timing of exposure [30].
Most of the debate focused on a possibly increased risk in the incidence of type 1 diabetes mellitus that was temporally associated with the nationwide introduction of haemophilus influenzae type b (Hib) vaccine in Finland. However, a large 10-year follow-up study of over 110,000 Finnish children who participated in a clinical trial of Hib vaccine did not evidence any increased risk of diabetes in children first vaccinated at the age of 24 months as compared to a cohort of children born in the preceding 24 months before the vaccination period [31]. Classen and Classen [32] subsequently questioned the way the data had been analyzed. Their own analysis suggested an increase in the cumulative incidence of diabetes in children first vaccinated at 3 months of age who received four doses of the vaccine as compared to unvaccinated children. They also found that cases clustered between 36 and 48 months after immunization. Another 10-year follow-up study performed in children from the United States failed to identify an increased risk of diabetes after Hib vaccination [33]. A recent study still suggests that Hib vaccine might be a risk factor in the induction of islet cell and glutamic acid decarboxylase autoantibodies measured at one year of age [34]. The authors proposed that this vaccine produced an unspecific stimulatory polyclonal effect, which might be of clinical importance in the presence of other factors stimulating β-cell autoimmunity.
Although additional data regarding the effects of Hib vaccine are required to clarify this issue, there is no clear evidence that vaccines are associated with an increased risk of diabetes, whatever the timing of vaccination and including children with a familial history of diabetes.

Rheumatoid arthritis and lupus

The only available evidence is based on isolated case reports or small series of patients describing the appearance or flare-up of rheumatoid arthritis or systemic lupus erythematous lupus within days or weeks after the vaccination [2, 35]. The presence of HLA B27 antigen in the majority of patients who developed rheumatoid arthritis suggests a possible role of vaccination in susceptible individuals.

As most of the reports involved hepatitis B vaccination [36, 37], two case control studies using data from the General Practice Research Database in UK were carried out to examine a possible link between hepatitis B vaccination and the risk of rheumatoid arthritis or lupus [38, 39]. The results that are available only in abstract form did not evidence an increased risk of either disease after hepatitis B vaccination and the suggestion of a significant increase in the risk of lupus among the subpopulation of patients older than 40 years of age needs to be more extensively analyzed.

Vaccination in patients with autoimmune disease

The question of the safety of vaccination in patients with previously diagnosed autoimmune disease is of particular relevance. Several studies have carefully examined the risk of flare-up of a progressive autoimmune disease after various types of vaccination.

The effects of vaccines in patients with multiple sclerosis have been particularly examined and several controlled studies have been published. In a randomised double-blind study of 104 patients with multiple sclerosis, the risk of relapse or disease progression over a 6-month period of follow-up was similar in patients exposed to influenza vaccine or placebo [40]. A large case-crossover study using the data of 643 patients included in the European Database for Multiple Sclerosis was also unable to identify an increased risk of relapse in the 2-month period following hepatitis B, tetanus and influenza vaccination compared to control periods without vaccination [41]. However, it should be noted that these results were based on only 89 patients vaccinated in the 12 previous months before the index day of multiple sclerosis relapse.

As compared to no vaccination, influenza vaccination does not seem to exacerbate symptoms of rheumatoid arthritis or disease activity in systemic erythematous lupus [35, 42, 43]. Similar findings were reported in patients with systemic lupus erythematosus immunized with pneumococcal, tetanus toxoid or Hib vaccines [35, 44]. Hepatitis B vaccination was also considered safe compared to no vaccination in 45 patients with rheumatoid arthritis.

Although further experience is needed, these studies indicate that vaccinations should not be discouraged in patients suffering from a progressive auto-immune disease.

Possible mechanisms of vaccine-induced autoimmunity

The pathophysiological mechanisms of most autoimmune diseases are not known. The selection of experimental models designed to evaluate the potential adverse effects of vaccination on autoimmunity is therefore difficult or at best empirical [46]. Moreover, the few existing models were not specifically developed to study this risk. In addition to the vaccine antigens and possible residues from cell cultures (e.g. fibronectin), many substances that are used during the manufacture process must also be taken into consideration, such as adjuvants (e.g. aluminium), stabilizers (e.g. gelatin) or preservatives (e.g. thiomersal), all of which can have their own effect on vaccinated subjects. The possible contributing role of aluminium [47] and thiomersal [48] was indeed recently suspected in animal models.
The induction of autoimmunity by infectious agents was observed in animals [49] and infections are sometimes involved in the precipitation of autoimmune diseases. Based on these assumptions, it was therefore tempting to speculate that immunization might also cause autoimmunity. Several mechanisms have been claimed to account for the development of autoimmune disease after infection or vaccination, at least in susceptible and genetically predisposed individuals [50, 51]. The concept of molecular mimicry holds that the antigenic determinants of vaccines or residues contain a sequence of amino acids sufficiently similar to a self-antigen to produce cross-reactivity with the formation of autoantibodies and/or activation of specific T cells. Although molecular mimicry in itself is probably not sufficient to trigger autoimmunity [52], this possibility is carefully examined for new vaccines by comparing the chemical structure of the vaccine antigen with available protein databanks.
Vaccination could also lead to the formation of immune complexes resulting in vasculitis or the exacerbation of an underlying autoimmune disease. This mechanism was demonstrated during clinical trials with prospective vaccines, but to date no experimental model is available to predict this risk [46]. Several cytokines are potentially released following immunization, and the therapeutic use of interferon-alpha was associated with the occurrence or the worsening of a large number of autoimmune diseases [53]. It is therefore tempting to speculate that the release of sufficient amounts of interferon-alpha following vaccination is able to produce similar phenomena.
Finally, some vaccines may influence the T_H1/T_H2 lymphocyte balance, and this may favour either T_H1 or T_H2 responses. Thus, BCG, which induces a T_H1 response, protects NOD mice from developing autoimmune diabetes, but precipitates a lupus-like disease [54].

Conclusion

Although a temporal relationship between several vaccines and the occurrence of autoimmune diseases has been suggested in many case reports, there is so far no conclusive evidence for a causal link. The lack of experimental and epidemiological evidence for an increased risk of autoimmune disease after vaccination is reassuring, but does not definitively exclude this hypothesis. In epidemiological studies, the criteria used to define autoimmune disease are those commonly accepted for the spontaneous autoimmune disease. However, less typical features may be encountered in association with vaccines and this should be carefully evaluated.
Although the post-vaccination risk of autoimmune diseases in the general population appears to be extremely low, epidemiological studies have not correctly analyzed the role of genetic predisposition. In addition, a complex interplay of genetic, environmental and microbial factors may trigger a disease in subgroups of highly susceptible patients [55]. This hypothesis should be carefully explored during the development of new candidate vaccines and new adjuvants. n

Acknowledgements. We are indebted to Jenny Messenger for translating this article

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