Neurological Adverse Events of Immunization: Experience With an Aluminum Adjuvanted Meningococcal B Outer Membrane Vesicle Vaccine

Hanne Nøkleby

Disclosures

Expert Rev Vaccines. 2007;6(5):863-869. 

In This Article

Aluminum-Adjuvanted Vaccines

Serious adverse events may be caused by different constituents in a vaccine: the active antigen, an adjuvant such as potassium aluminium sulfate (alum), a conservative agent such as thimerosal, or remnants from the production process. If there is a suspicion that different vaccines with some common constituents may cause the same kind of adverse events, it is reasonable to look for possible effects of these constituents rather than the active antigen.

Aluminum salts (aluminum hydroxide, aluminum phosphate and alum) have been the main adjuvants used in vaccines for almost 80 years and are the only adjuvants currently licensed for use in humans in the USA. Despite the long experience, the mechanism of action still appears unclear. For many years, the main effect of alum was believed to be keeping the active antigen at the injection site and, therefore, available for initial interaction with the immune system. However, experimental studies have shown that the antigen disappears from the injection site within a few hours.[26] The most important mechanism of alum is probably mediated through activation of antigen-presenting cells. Aluminum adjuvants also strongly influence the type of immune response and are important for stimulation of antibody production but probably do not induce cell-mediated immunity.[26]

The most widely used aluminum-adjuvanted vaccines have been tetanus and diphtheria vaccines, with or without pertussis and other components and, during the last 25 years, hepatitis B and A vaccines. The worldwide impact of these vaccines on health has been enormous,[27] in spite of allegations of serious adverse effects.

Local Adverse Effects. There is a general agreement that vaccines with aluminum adjuvants cause local reactions, such as pain at the injection site, erythema and swelling lasting several days.[28] Sterile abscesses and long-lasting itching nodules have also been described. Some authors have attributed these nodules to a contact allergy to aluminum,[29] but this has not generally been accepted.[30] Persistent nodules may be more common after subcutaneous than intramuscular injection and are possibly more common in females than in males.[31]

General Adverse Effects. It has been claimed that aluminum adjuvants cause systemic adverse effects, although this is highly disputed.[28] The most commonly used infant vaccine with aluminum adjuvant has been the DTP vaccine. The administration of DTP vaccine to infants has been associated with screaming, persistent crying, convulsions, encephalopathy and hypotonic, hyporesponsive episodes, but these signs have generally been linked to the pertussis component and not to the adjuvant.

Hepatitis A and B vaccines also usually contain aluminum adjuvants. Although the hepatitis A vaccine has been administered in millions of doses, there are very few reports of serious adverse events linked to the vaccine.[23] This is different for hepatitis B vaccines, but it would be difficult to explain why the same adjuvant should cause serious neurological diseases when used in one vaccine and no adverse events when used in another. The possible adverse events of hepatitis B vaccine have therefore been linked to the active antigen.[23]

During the last 15 years, a syndrome called macrophagic myofasciitis has been associated with aluminum-adjuvanted vaccines. Most cases have been reported in France and most of the patients have been adults,[32] but there are also descriptions of cases in other countries and in children.[33] The patients have presented with a variety of clinical symptoms, but usually they include myalgias, arthralgias, fatigue and, in some cases, serious neurological diseases, such as MS. Muscular biopsies have, in several cases, been taken from the deltoid region because of the symptoms. The biopsies have shown macrophages surrounding the muscle fibers forming a characteristic histological lesion. Electron microscopy has shown the presence of aluminum hydroxide inclusions in the lesions.[34] The patients have all been vaccinated with different aluminum-containing vaccines from months to years before the biopsy was taken.

It now appears to be well established that vaccines with aluminum adjuvants in some individuals are the cause of the histologic lesion called ‘macrophagic myofasciitis’. It is difficult to say how common such lesions may be for two reasons. The size of the lesions may be very small and are, therefore, not always caught by the biopsy. Also, it would be considered unethical to take biopsies from healthy people, therefore, the true prevalence of these lesions cannot be determined. However, the relationship between these lesions and the clinical symptoms is still considered an unproven hypothesis.[35,36]

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