Update: Guillain-Barré Syndrome Among Recipients of Menactra^® Meningococcal Conjugate Vaccine --- United States, October 2005--February 2006

In October 2005, a possible association between Guillain-Barré Syndrome (GBS) and receipt of meningococcal conjugate vaccine (i.e., meningococcal polysaccharide diphtheria toxoid conjugate vaccine [Menactra^®])* (MCV4) was reported (1). GBS is a serious neurologic disorder involving inflammatory demyelination of the peripheral nerves. At the time of the first report, five confirmed cases of GBS after receipt of MCV4 had been reported to the Vaccine Adverse Events Reporting System (VAERS). During the 4 months since, three additional confirmed cases of GBS have been reported. This report describes two of these recent cases and provides additional data collected through February 2006. Because available evidence neither proves nor disproves a causal relation between MCV4 and GBS, further monitoring and studies are ongoing within VAERS and the Vaccine Safety Datalink (VSD). CDC continues to recommend use of MCV4 for persons for whom vaccination is indicated (1); the additional reported cases have not resulted in any change to that recommendation.

Case Reports

Brief clinical and epidemiologic descriptions of two of the newly reported cases follow. The third case is undergoing detailed clinical investigation but meets the provisional case definition for GBS.^†

Case 1. On August 8, 2005, a male aged 19 years from Arizona was vaccinated with MCV4. Approximately 25 days later, he experienced numbness and tingling in his hands and feet, followed by weakness in his legs, difficulty running, and decreased dexterity in his hands. In the month before neurologic symptom onset, he had no defined episode of respiratory or gastrointestinal illness. He had traveled to Mexico twice during the preceding 3 months. Electrophysiology studies revealed a diffuse neuropathic process with both demyelinating and axonal features, consistent with GBS. Testing for Epstein-Barr virus capsid IgG and IgM antibodies was negative. Testing for cytomegalovirus IgG and IgM antibodies also was negative, as were serologic studies for hepatitis A, B, and C to rule out other probable causes of GBS. The patient was treated with intravenous immunoglobulin. At follow-up examination 8 weeks after onset, he had fully recovered.

Case 2. On November 4, 2005, a male aged 17 years from Ohio received MCV4. Eleven days later, he experienced numbness and tingling in his right foot, followed by the same symptoms in the left foot, which progressed proximally during the next 5 days. He also described a neck hyperextension injury sustained while playing sports 2 days before the start of sensory symptoms and sore throat and congestion 1 day before sensory symptoms. He had no gastrointestinal illness during the 6 weeks before hospital admission, which occurred 6 days after symptom onset. Cervical spine radiographs revealed no fractures; magnetic resonance imaging (MRI) of the spine revealed mild enhancement along the surface of distal cord and lumbar nerve roots, consistent with GBS. Nerve conduction studies also were consistent with GBS. Polymerase chain reaction (PCR) assays for enterovirus were negative, as were tests for Mycoplasma pneumoniae IgG and IgM. The patient was treated with intravenous immunoglobulin. At follow-up examination 2 weeks after admission, he had completely recovered.

In the two cases described in this report, the period from MCV4 vaccination to symptom onset was less than 6 weeks. This is the time window of elevated risk noted for GBS after administration of certain other vaccines (2).

To determine whether the reporting rate of GBS after MCV4 vaccination was higher than the expected incidence rate of GBS for the appropriate age group population, the reporting rate was calculated by dividing the eight confirmed GBS cases with onset within 6 weeks of vaccination by the number of vaccine doses distributed as provided by the manufacturer (approximately 3.77 million doses of MCV4 were distributed during March 2005--February 2006). The eight cases were divided by the 3.77 million distributed doses to provide the reporting rate for GBS after MCV4. The expected incidence rate of GBS was estimated from a multistate hospital discharge database (Health Care Utilization Project).^§ For the years 2000--2003, the incidence rate of GBS among persons aged 11--19 years was estimated to be 1.4 per 100,000 population per year or 0.17 per 100,000 population during a 6-week period. Therefore, the ratio of the reporting rate of GBS after MCV4 vaccination to the expected incidence rate was 1.4 (95% confidence interval = 0.7--2.8), suggesting that the occurrence of eight cases of GBS within 6 weeks of MCV4 administration is similar to what might be expected to occur by chance alone.

As part of the investigation, other possible causes of GBS, such as Campylobacter jejuni, were assessed. C. jejuni is a leading cause of gastroenteritis globally and the most frequent antecedent pathogen in GBS (3). No evidence of C. jejuni was observed in any of the eight cases reported; however, many C. jejuni infections are asymptomatic. No serum samples from GBS cases reported after MCV4 vaccination were available for testing. To further assess the possibility that C. jejuni was a precipitating cause, unpublished data were collected and analyzed from all five state health departments involved in initial GBS case reports to VAERS (Arizona, New Jersey, New York, Ohio, and Pennsylvania). Despite an expected seasonal peak of GBS cases from June to October 2005 (CDC, unpublished data, 2005), none of the involved states reported outbreaks of C. jejuni during this period.

Reported by: Center for Biologics Evaluation and Research, Food and Drug Admin. Arizona State Health Dept. New Jersey Dept of Health and Senior Svcs. New York State Dept of Health. Columbus City Health Dept, Columbus, Ohio. Pennsylvania Dept Health. Immunization Safety Office, National Immunization Program; National Center for Infectious Diseases; F Soud, PhD, EIS Officer, CDC.

Editorial Note:

In October 2005, CDC and the Food and Drug Administration (FDA) alerted health-care providers about a possible association between GBS and MCV4 and encouraged reporting of adverse events to VAERS (1). Since that time, three additional confirmed cases of GBS with onset within 6 weeks of MCV4 vaccination have been reported. However, even with these reported cases, the reported incidence remains similar to the expected incidence. In addition, three other cases of GBS have been reported, with symptom onsets at >6 weeks (107 days, 116 days, and 125 days) after vaccination with MCV4; these three cases were not included in calculation of GBS rates. Because VAERS is a voluntary reporting system, the completeness of reporting of GBS remains unknown. Only three cases were reported since October 2005, suggesting that MCV4 might not be causally related to GBS. The background incidence rate of GBS is one to two cases per 100,000 population. However, the timing of onset of neurologic symptoms within 2--5 weeks of vaccination is still a concern.

Additional preliminary data from VSD,^¶ a collaborative project between CDC and eight managed care organizations in the United States, have not identified GBS cases in MCV4 recipients. However, VSD has a limited ability to detect rare health events such as GBS. To further evaluate any potential risk, additional controlled studies of GBS after MCV4 are being planned.

The case definition developed for the initial investigation has been refined by an extended working group of the Brighton Collaboration,** an international voluntary collaboration of scientists. The Clinical Immunization Safety Assessment Network,^†† in collaboration with CDC, continues to research and conduct standardized clinical evaluation of affected vaccinees to better understand the pathophysiology of select adverse events after vaccination, such as GBS. In response to the evaluation of the reported cases to VAERS, Sanofi Pasteur and FDA updated the Menactra vaccine package insert to list previous GBS as a contraindication and provide a warning of the temporal relation between GBS and MCV4 (4).

In October 2005, CDC recommended continuing use of MCV4 for persons for whom vaccination is recommended; the additional cases reported in this update do not affect that recommendation (1). In December 2005, the Global Advisory Committee on Vaccine Safety also recommended no change in MCV4 vaccination policies (5).

The Advisory Committee on Immunization Practices has recommended that persons with a history of GBS should not be vaccinated with MCV4 unless they are at elevated risk for meningococcal disease (6). Persons at elevated risk for meningococcal disease include first-year college students living in dormitories, military recruits, travelers to areas in which meningococcal disease is hyperendemic or epidemic, microbiologists who are routinely exposed to isolates of Neisseria meningitidis, patients with anatomic or functional asplenia, and patients with terminal complement deficiency. Information regarding the current investigation should be shared with adolescents and caregivers before MCV4 vaccination. A Vaccine Information Statement and fact sheet noting the information on the reported GBS cases is available at http://www.cdc.gov/nip/publications/vis/default.htm. An updated fact sheet for health-care workers is available at http://www.cdc.gov/nip/vacsafe/concerns/gbs/menactra.htm. CDC continues to recommend that health-care workers and any other persons aware of adverse events associated with MCV4 or any other vaccination report to VAERS cases of GBS or any other clinically significant adverse events. Reports may be submitted securely online at http://www.vaers.hhs.gov or by fax at 877-721-0366. Reporting forms and additional information is available at telephone, 800-822-7967.

References

1. CDC. Guillain-Barré syndrome among recipients of Menactra^® meningococcal conjugate vaccine---United States, June--July 2005. MMWR 2005;54:1023--5.
2. Schonberger LB, Bergman DJ, Sullivan-Bolyai JZ, et al. Guillain-Barré syndrome following vaccination in the National Influenza Immunization Program, United States, 1976--1977. Am J Epidemiol 1979;110: 105--23.
3. Takawashi M, Koga M, Yokoyama K, Yuki N. Epidemiology of Campylobactor jejuni isolated from patients with Guillain-Barré and Fisher syndrome in Japan. J Clin Microbiol 2005;43:335--9.
4. Food and Drug Administration. Meningococcal (sero groups A,C,Y, and W 135) polysaccharide toxoid conjugate vaccine, Menactra^®. Available at http://www.fda.gov/cber/label/mpdtave102105LB.pdf.
5. World Health Organization. Conjugate meningococcal vaccine and Guillain-Barré Syndrome. Wkly Epidemiol Rec 2006;2:13--20.
6. CDC. Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2005;54(No. RR-7):1--21.

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Date last reviewed: 4/6/2006