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

The Norwegian Experience With a Meningococcal B Outer-Membrane Vesicle Vaccine With Aluminum Hydroxide Adjuvant

From 1975 to 1995, Norway experienced an epidemic of meningococcal group B disease, with a maximal incidence rate of eight cases per 100,000. Since no vaccine was commercially available at the time, the Norwegian Institute of Public Health (NIPH) developed an outer-membrane vesicle vaccine based on the prevalent epidemic strain, B:15:P1.7,16. The vaccine was prepared by fermenter growth and extraction of the bacteria with the detergent deoxycholate.[37] Each vaccine dose contained 25 μg antigen and 1.65 mg aluminum hydroxide. The vaccine has been evaluated in 28 clinical trials including three large Phase III trials. One of these was a double-blind, school-randomized, placebo-controlled trial that comprised 172,800 teenagers aged 13-16 years and was conducted from 1988 to 1991. In the trial, the vaccine provided 57% protection over a period of 29 months, with an indication of 87% protection during the first 10 months.[38] According to the protocol, the placebo candidates were offered an active vaccine after the code was broken in 1991. The second Phase III study consisted of the follow-up of the total cohort after vaccination of the placebo candidates with active vaccine.

During these two trials, four cases of serious inflammatory or demyelinating neurological diseases were reported within 56 days of vaccination among the participants receiving the active vaccine. Three of the cases occurred during the first placebo-controlled Phase III trial. A previously healthy 12-year-old girl experienced myelopathy with weakness in both legs, dysesthesia in her foot and calf and lack of sensation in bladder and bowel 10 days after the first dose was administered. A previously healthy 13-year-old boy with heredity for MS experienced a demyelinating disease with transient hemiparesis 3 weeks after the first dose. A previously healthy 13-year-old girl experienced transverse myelitits with paresis and sensory disturbance in the lower extremities 6 weeks after receiving the first dose. After vaccination of the placebo candidates, an 18-year-old boy had the first symptoms of GBS 21 days after the first vaccine dose was administered.

In the search for possible risk factors and plausibility of a causal relationship to the vaccine, we focused on the following: the vaccine did not contain meningococcal DNA. The possibility that antibodies to meningococcal group B polysaccharide could cross-react to fetal brain tissue was raised in 1983,[39] but the vaccine only contained trace amounts of the group B polysaccharide. The vaccine did, however, contain lipopolysaccharide (LPS) L3,7,9 (lacto-N-neotetraose) and antibodies towards this epitope might possibly cause autoimmune disease. However, there were no reports of increased risk of such diseases after systemic meningococcal group B disease, when the amount of LPS is much higher. There were also no reports of similar neurological adverse events after trials with other meningococcal B vaccines with similar LPS types.[40] Furthermore, there were no such cases reported in the third Norwegian Phase III study, where the vaccine had been administered to 27,500 military conscripts. The vaccine also contained aluminum hydroxide as an adjuvant and there were, at that time, suspicions of other aluminum-adjuvanted vaccines causing similar reactions.[41] Therefore, we conducted an epidemiological follow-up to evaluate the risk of serious inflammatory or demyelinating neurological diseases after vaccination.

The epidemiological follow-up was performed on a cohort of 345,000 people born between 1972 and 1977 and living in Norway during the trial years. Of these, 144,000 had received at least one dose of vaccine, 91,000 in 1988-1989 and 53,000 additional individuals when the placebo candidates were offered the vaccine in 1991. The total observation period was 3.5 years. During these years, a total of 57 cases of serious demyelinating and inflammatory neurological diseases were registered. Only four cases, all in vaccinees, appeared during the first 56 days after vaccination. These cases had all been reported through the passive reporting system of the trials, confirming that the system had been able to catch all cases of serious neurological events. Based on these figures and the observation time for the vaccinated and nonvaccinated students, there was no statistically significant increased risk of CNS demyelinating and inflammatory diseases in the first 8 weeks following immunization (incidence rate ratio: 3.2; 95% confidence interval [CI]: 0.62-11; p = 0.16). For GBS syndrome the incidence rate ratio was 2.1 (95% CI: 0.048-14; p = 0.80). There was also no statistically significant increased risk of serious CNS demyelinating and inflammatory diseases or GBS in the 30-day period following vaccination and no specific syndrome or disease pattern was discovered in teenagers vaccinated with the meningococcal B vaccine.[42]

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