Elsevier

The Lancet

Volume 362, Issue 9396, 15 November 2003, Pages 1659-1666
The Lancet

Review
Vaccination and autoimmune disease: what is the evidence?

https://doi.org/10.1016/S0140-6736(03)14802-7Get rights and content

Summary

As many as one in 20 people in Europe and North America have some form of autoimmune disease. These diseases arise in genetically predisposed individuals but require an environmental trigger. Of the many potential environmental factors, infections are the most likely cause. Microbial antigens can induce cross-reactive immune responses against self-antigens, whereas infections can non-specifically enhance their presentation to the immune system. The immune system uses fail-safe mechanisms to suppress infection-associated tissue damage and thus limits autoimmune responses. The association between infection and autoimmune disease has, however, stimulated a debate as to whether such diseases might also be triggered by vaccines. Indeed there are numerous claims and counter claims relating to such a risk. Here we review the mechanisms involved in the induction of autoimmunity and assess the implications for vaccination in human beings.

Published online June 3, 2003 http://image.thelancet.com/extras/02art9340web.pdf

Section snippets

Autoimmune disease and infection

Human beings have a highly complex immune system that evolved from the fairly simple system found in invertebrates. The so-called innate invertebrate immune system responds non-specifically to infection, does not involve lymphocytes, and hence does not display memory. The adaptive immune system, shared by vertebrates, displays both specificity and memory, and is designed to provide protection against almost all infections. Furthermore, polymorphisms in genes that control the immune system

Molecular mimicry

A popular explanation for how infectious agents stimulate autoimmunity in an antigen-specific way is via molecular mimicry.9 Antigenic determinants of microorganisms can thus be recognised by the host immune system as being similar to antigenic determinants of the host itself (figure 1). Molecular mimicry among sugar structures is common and leads to numerous manifestations of infection-associated and antibody-mediated neuropathies.10, 11 For example, about a third of all cases of

Vaccination and autoimmune disease

The medical literature is full of claims and counter claims with respect to the risk of autoimmune disease as a consequence of vaccination. Only in a few rare cases, however, has autoimmune pathology been firmly associated with particular vaccines. For example, a form of Guillain-Barre syndrome (polyradiculoneuritis) was associated with the 1976–77 vaccination campaign against swine influenza, using the A/New Jersey/8/76 swine-flu vaccine.48 The estimated attributable risk of vaccine- related

Hepatitis B and multiple sclerosis

The possibility of an association between the hepatitis B vaccination and development of multiple sclerosis was first raised in France, after a report of 35 cases of primary demyelinating events occurring at a hospital in Paris between 1991 and 1997, within 8 weeks of recombinant hepatitis B vaccine injection.57, 58 The neurological manifestations were similar to those observed in multiple sclerosis. There were inflammatory changes in the cerebrospinal fluid and lesions were noted in the

Diabetes

Over the past few decades, there has been a regular increase in the incidence of type 1 diabetes in most countries of the world. That childhood vaccines have been identified as a potential trigger event for this disease is, therefore, not surprising.

This possibility has been assessed in a few epidemiological studies. Results of a case-control study done in Sweden in the mid-1980s did not indicate any great effect of vaccination against tuberculosis, smallpox, tetanus, pertussis, or rubella on

How can a doctor assess a potential link

There exist no general criteria for diagnosing vaccine-related autoimmune disease, which has to be assessed on a case-by-case basis. Appropriate epidemiological studies should be done before a particular autoimmune clinical condition is associated with a given vaccination. Such investigation can then be followed by the identification of known biological markers of the identified autoimmune disease in other vaccinees. However, the degree of vaccine-related risk should always be compared with

Consistency and strength

The association of a purported autoimmune event with the administration of a vaccine should be consistent. Therefore, the findings should be the same if the vaccine is given to a different group of people, by different investigators not unduly influencing one another, and irrespective of the method of investigation. The association should be strong in an epidemiological sense.

Specificity

The association should be distinctive and the adverse event linked uniquely or specifically to the vaccine concerned. The association should, for instance, not arise frequently, spontaneously, or commonly in association with other external stimuli or conditions. An adverse event could be caused by a vaccine adjuvant or additive, rather than by its active component, hence spuriously affecting the specificity of the association between vaccine and adverse event.

Temporal relation

There should be a clear temporal relation between the vaccine and the adverse event, in that receipt of the vaccine should precede the earliest manifestation of the event or should occur a few weeks before a clear exacerbation of a continuing condition. Therefore, an association between vaccine administration and an autoimmune adverse event is most likely to be considered strong when the evidence is based on:

  • •

    the results of carefully undertaken clinical trials for which a study design was

New-generation vaccines

Although available epidemiological data are reassuring we must remain vigilant, particularly with respect to some of the new-generation vaccines. Special attention should be paid to new vaccine adjuvants, especially when they produce strong, innate responses.67 Additionally, cancer vaccines based on dendritic cells pulsed with tumour antigens carry a substantial risk of autoimmunity.68

During the course of vaccine development, only a comprehensive and multidisciplinary strategy can help to

Concluding remarks

A clear distinction should be made between autoimmunity and autoimmune disease. Autoimmunity is a feature of the normal healthy immune system. There is little doubt that laboratory measurable signs of autoimmunity can associate with infection and might occasionally appear after vaccination. It is comforting to appreciate that the immune system has evolved sufficient fail-safe mechanisms to ensure that these signs rarely develop into clinical disease.

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