1. Guillain-Barré Syndrome (GBS) among Recipients of Menactra® Meningococcal Conjugate Vaccine (MCV4)
Fatma A. Soud RN/M PhD
Epidemic Intelligence Service Officer
Immunization Safety Office
Office of the Chief Science Officer
Good morning, thank you for being here.

2. Background: Vaccine Licensure
MCV4 licensed by the Food and Drug Administration (FDA) in January 2005
MCV4 a polysaccharide diptheria toxoid conjugate vaccine (Sanofi -Aventis-Pasteur) for meningococcal serogroups A,C,Y, and W-135
Menactra, is a sterile, 0.5ml. intramuscularly administered vaccine

3. ACIP Recommendations: MCV4
Young adolescents – year olds before high school entry
College freshman living in dormitories
Routine vaccination:
- military recruits,
- travelers to endemic areas,
- microbiologists who are routinely
exposed to Neisseria Meningitidis
Persons who have - complement component deficiencies, asplenia
MCV4 is contraindicated in non-high risk groups, such as patients with previous history of GBS, or allergies to diptheria toxoid.

4. Rates of Meningococcal Disease (A/C/Y/W135) by Age, 11-30yo, United States, 1991-2002
, Rate among 11-19yo, 0.9/100,000
2004, Rate among 11-19yo, 0.5/100,000
Neisseria meningitidis, is a bacteria that causes both sporadic disease and outbreaks. The age-specific incidence of meningococcal disease continues to be highest among infants younger than one year old, however, since 1991 there have been increased outbreaks among adolescents and young adults. In the United States, overall rates of the disease during the period have varied with yearly counts from , a rate of /100,000 of the population.

5. Background: Guillain-Barré Syndrome
Serious neurological disorder involving demyelination of peripheral nerves
Subacute onset of flaccid weakness/paralysis, in limbs and/or cranial nerve-innervated muscles
Bilateral onset of weakness/paralysis
Decreased or absent deep tendon reflexes in affected limbs
Case fatality GBS ~ 8%;
20% prolonged disability
GBS can occur spontaneously or after certain antecedent events such as infections or vaccines. Symptoms progress for days to 4 weeks.
There was evidence of an association between GBS in adults to the 1976 swine influenza vaccine.

6. Background on GBS
Preceding symptoms of infection associated to GBS is Campylobactor jejuni
C. jejuni, a leading cause of gastroenteritis globally, most frequent antecedent pathogen of GBS
None of the involved states reported outbreaks of C. jejuni during this time period.
There was no evidence of C. jejuni in reported cases, however many C. jejuni infections are asymptomatic.

7. Methods: Investigation of Reported Cases
Case definition created by CDC, FDA, Boston University Medical Center and Sanofi-Aventis
Key elements:
Clinical case definitions stratified by levels of diagnostic certainty, moving from the definition with the most supportive evidence, but clinically consistent with a diagnosis of GBS (Level 1), to the definition with less supportive evidence, but clinically consistent with a diagnosis of GBS (Level 3)
The surveillance case definition was designed to assist in active case-finding; and was intended to be more sensitive, but less specific.

8. Methods: Investigation of Reported Cases: Vaccine Dose Distribution
To determine if the reporting rate following MCV4 was greater than the expected background incidence rate of GBS
The reporting rate was calculated by dividing the 8 confirmed GBS cases by the number of vaccine dose distributed by the manufacturer
Background incidence rate of GBS 1-2/100,000 with slightly more males affected than females.

9. Results: Occurrence of GBS in Recipients of Menactra
As of February , eight confirmed cases were reported to Vaccine Adverse Events Reporting System (VAERS) after Menactra
All reported patients are years old, and from PA (2), OH(2), NY(1), NJ (1), CA (1) and AZ (1)
No GBS cases observed in prelicensure studies encompassing 7000 participants
The VAERS system receives approximately 10,000 to 12,000 of adverse event reports annually. If any of these events are detected, then VAERS serves as a trigger to further clinical, epidemiological or lab studies. The extent of underreporting to VAERS is unknown.

10. Results: Clinical and Epidemiological Features
Symptom onset days post vaccination
One patient had two prior episodes of GBS post vaccination in childhood
One patient had an acute illness prior to neurological symptom onset

11. Results: Clinical and Epidemiological Features (cont.)
Remaining patients had no episodes of respiratory or gastrointestinal illness
All 8 patients received immunoglobulin and plasma therapy
One patient required intubation; all recovered or are recovering
In addition to these eight cases, three more reports of GBS following vaccination were made to VAERS. These cases were confirmed as GBS at 15, 16 and 18 weeks post MCV4 respectively. Since the time of onset was longer than 6 weeks, they were not included in calculation of GBS rates in this investigation.

12. Results: Vaccine Dose Distribution (cont.)
3.47 million doses of MCV4 distributed between March 2005 and January 2006
OBSERVED incidence rate (OIR) 1.35 (95% CI )
OIR was compared to data from a multi-state hospital discharge database (Health Care Utilization Project [HCUP])
For the years the incidence rate of GBS among year olds was estimated to be 1.4/100,000 per year or 0.17 during a six week time period

13. Summary
Eight confirmed reported cases of GBS among recipients of MCV4 to VAERS
There is insufficient evidence that MCV4 causes GBS
Onset of first symptoms of GBS within six weeks post vaccine administration is concerning
Enhanced surveillance should continue and significant events after MCV4 should be reported to VAERS

14. Conclusion: MCV4 and GBS
Present evidence neither proves nor disapproves that MCV4 causes GBS
Timing of onset of neurological symptoms (i.e.) within 2-6 weeks of vaccination is still of concern
Persons not at high risk of meningococcal disease should not be vaccinated

15. Public Health Actions
CDC and FDA alerted health care providers via MMWR (10/06/05) and an update of additional cases is in progress
Vaccine manufacturer and FDA updated the vaccine package insert to list GBS as a contraindication
Vaccine Information Statement (VIS) and fact sheet noting the information on the reported GBS cases is available at

16. CDC Recommendations: MCV4 and GBS
Adolescents and caregivers should be informed of this ongoing investigation
Adverse events after MCV4 administration should be reported to VAERS
Enhanced surveillance for GBS continues in accordance with state/local disease-reporting guidelines
In addition, ACIP and the Global Advisory Committee on Vaccine Safety (GAVCS) in December 2005 recommended no change in MCV4 vaccination policies.

17. Vaccine Adverse Event Reporting System (VAERS) 1-800-822-7967 vaers
Vaccine Adverse Event Reporting System (VAERS) vaers.hhs.gov

18. Acknowledgements CDC-ISO CDC-NCID - Nancy Rosenstein - Thomas Clark
John Iskander
Katrin Kohl
Frank Destefano
Eric Weintraub
Elaine Miller
Christine Casey
Laura Leidel
Penina Haber
CDC-NIP
Gina Mootrey
Karen Broder
CDC-NCID
- Nancy Rosenstein
- Thomas Clark
- Martha Iwamoto
- Jim Sejvar
CDC-OD
- Tanja Popovic
CISA Network
- Colin Marchant
FDA-CBER
- Rober Ball
- Jane Woo
- Jesse Goodman

19. Thank you

20. Establishing Causal Link: Adverse Event and Vaccine
Illness or Syndrome
Yes No
Rate in vaccinated a/a+b a
Yes b
Vaccination
Rate in unvaccinated c/c+d
For comprehensive assessment of vaccine safety, what is ultimately needed is capture of all 4 cells of the two by two table.
These weaknesses of VAERS are best demonstrated by this basic 2 by 2 table, the type of table commonly used to calculate relative risks and which are helpful in determining statistical associations.
To determine relative risk values to link vaccination and subsequent illness, one needs data for each of the four boxes appearing on this slide
But VAERS only provides data for square A, and even the data for square A provided by VAERS is not complete.
Therefore, methods besides VAERS surveillance are required to provide the data for the other squares which can demonstrate whether a link between a vaccine and an adverse event is causal or coincidental.
This is currently obtained through the 3% of the population covered by the vaccine safety datalink, but data may not be available in a timely manner and lacks statistical power to assess rare events or rarely given vaccine combination.
Capturing and analyzing this information for a greater proportion of the population will increase CDC’s ability to assure vaccine safety in an increasingly complex vaccination landscape. No c d