1. ACIP
Feb , 2007
Guillain-Barré Syndrome (GBS) Among Recipients of Meningococcal Conjugate Vaccine (MCV4,Menactra®) Update Oct Jan. 2007
Robert L. Davis, MD, MPH
Director
Immunization Safety Office
Office of the Chief Science Officer
Centers for Disease Control and Prevention

2. Outline Update on surveillance for GBS following MCV4
Vaccine Adverse Event Reporting System (VAERS)
Vaccine Safety Datalink (VSD)
Observed compared to expected rate calculations
Age and season stratified analyses
Discussion and limitations
Today we will provide updated information on surveillance for Guillan Barre syndrome following meningococcal conjugate vaccine, using data obtained from both VAERS and VSD.

3. GBS after MCV4 Vaccination: Background
GBS is a rapidly evolving polyradiculoneuropathy generally manifest as a symmetric motor paralysis
MMWR reports reviewed GBS cases following receipt of Menactra®
October 2005: 5 cases reported to VAERS
April 2006: 3 additional cases reported to VAERS
October 2006: 9 additional GBS cases reported to VAERS
GBS is a serious neurologic conditions which typically presents as subacute ascending paralysis. ISO has been following reports of GBS following Menactra since late Since the last update was provided in the MMWR in October 2006, 2 new GBS reports have been received by VAERS.

4. GBS after MCV4 Vaccination: Background
Two new cases since last MMWR through January 2007: total of 19 GBS cases <6 wks after MCV4 vaccination reported to VAERS
There were also 4 confirmed reports of GBS in year olds with onset intervals > 6 weeks; these are not included in further analyses
GBS is a serious neurologic conditions which typically presents as subacute ascending paralysis. ISO has been following reports of GBS following Menactra since late Since the last update was provided in the MMWR in October 2006, 2 new GBS reports have been received by VAERS.

5. GBS after MCV4 Vaccination: July 2005 – Jan 2007
A total of 19 cases of GBS after Menactra vaccine with:
Onset interval of 2-33 days.
Of these, 17 were years old
Information from MCOs within the VSD indicated that ~94% of MCV4 recipients were
11–19 year olds
Through the end of January, there have been a total of 19 GBS reports involving year olds within six weeks following Menactra administration. According to data from within the VSD, this age group accounts for the vast majority of vaccine usage.
The key question is whether the new reports alter the risk assessment for GBS following MCV4.

6. Number of GBS Reports to VAERS within 6 weeks of MCV4 Administration, by Age
This slide indicates the age distribution of GBS cases reported to VAERS following Menactra.

7. GBS after MCV4 Vaccination: Data from VSD
VSD Rapid Cycle Project from April 2006 through January 2007:
156,542 doses administered
Zero cases GBS observed among vaccine recipients 11–19 years old within 6 weeks of vaccination
0-1 cases were expected
Data from VSD continues to show no cases of GBS within six weeks of MCV4 administration. The number of doses under surveillance is more than 150,000.
This data must be considered in light of the rarity of GBS, which has an approximate average incidence of 1/100,000 person years.

8. GBS after MCV4 Vaccination: Observed vs. Expected
Was the observed reporting rate (RR) for GBS after MCV4 vaccination in VAERS higher than expected?
VAERS Observed = 1.78 cases per million person-months
Calculation:
6.93 million vaccine doses distributed to 11–19 year olds = 9.57 million person-months (6.93* 6 weeks follow-up per dose)
17 observed cases /9.57 million person-months
Using dose distribution data and an assumed six week follow up period, the observed reporting rate in VAERS for GBS is calculated to be slightly less than 2 cases per million person months.

9. Observed (VAERS)/ expected
Expected (using HCUP ) =
1.13 per million person-months (11-19 y/o)
Observed/expected = 1.78/1.13 = 1.57
(95% CI = .94 – 2.45)
Expected (using VSD ) =
1.11 per million person-months (11-19 y/o)
Observed/expected = 1.78/1.11 = 1.59
(95% CI = .90 – 2.67)
Using data from HCUP and VSD, background rates for GBS among year olds were calculated. Both estimates were approximately 1.1 per million person months. The observed/expected ratio was ~ 1.6 but the increase was not statistically significant.

10. GBS after MCV4 Vaccination: Public Health Impact
If these data accurately represent the true magnitude of increased risk after MCV4 vaccination, then:
0.89 excess cases/ million doses (CI = – 5.39)
Calculation:
{Number of excess cases of GBS/1 million doses distributed to 11–19 year olds:
(Observed - Expected)/ 6.93 million doses
(17 – 10.8)/ 6.93 million doses}
Based on the preceding calculations, there may be slightly less than one attributable case of GBS following MCV4 administration among year olds. However the wide confidence interval indicates the lack of precision of this estimate.
Prior: 1.25 excess cases/million doses (CI = 0.058–5.99)

11. GBS after MCV4 Vaccination: Rates by Age
Among year olds in VSD
Number doses = 3.0 million (4.2 million person-months)
Expected Background rate GBS = 1.0 case/million
person-months (= 4.2 cases)
Observed in VAERS= 1 case
Observed/expected ratio= 1.0 / 4.2
Rate ratio = 0.25 (.01 – 1.20) – Controlling for Season
Among year olds in VSD
Number doses =3.9 million (5.4 million person-months)
Expected background rate GBS =1.2 case/million
person-months (= 6.5 cases)
Observed in VAERS = 16 cases
Observed/expected ratio = 16/6.5
Rate ratio = 2.48 (1.30 – 4.55) – Controlling for Season
Age-stratified analysis indicates a significantly elevated observed/expected ratio only among year olds. These estimates have been adjusted for the seasonality of GBS.

12. GBS after MCV4 Vaccination: Discussion
For Year Olds, there is no statistically significant evidence of an increased risk of GBS after MCV4 vaccination.
Although there appears to be a small increased risk for GBS after MCV4 vaccination in the year old age category, the inherent limitations of VAERS require that these findings be viewed with caution
Substantial uncertainty exists regarding the risk estimate, using either the HCUP or VSD background incidence rate
Timing of neurologic symptoms within 1–5 weeks of vaccination among reported cases is of concern
Although there appears to be an increased risk for GBS after MCV4 vaccination among year olds, the inherent limitations of VAERS and the uncertainty regarding background incidence rates for GBS require that these findings be viewed with caution.
The magnitude of the increased risk cannot be estimated precisely from this data.

13. GBS after MCV4 Vaccination: Limitations
Completeness of GBS reporting to VAERS is unknown
Under-reporting of GBS after MCV4 vaccination would raise the risk estimates
No surge in GBS reports to VAERS after any MMWR; expected if underreporting were marked
VSD has limited ability to detect rare adverse events
Not finding any GBS after MCV4 vaccination in year olds does not offer substantial reassurance regarding MCV4 safety
These data are almost subject to important system limitations of both VAERS and VSD, namely:
For VAERS, the unknown degree of reporting completeness.
For VSD, the limited ability to detect rare adverse events (those with incidence of less than 1/10,000)

14. GBS after MCV4 Vaccination: Discussion
A larger study is necessary to provide a more definitive assessment
A larger study led by Harvard Pilgrim has begun; data regarding the risk for GBS following MCV4 is expected in approximately 2 years
The study period is necessary to accumulate cases and attain sufficient statistical power
Ongoing evaluation of GBS after MCV4 vaccination is being performed using VSD
A large controlled study seeking to assess whether a causal relationship exists between MCV4 and GBS is being undertaken under the leadership of the Harvard Pilgrim MCO.
Ongoing active surveillance for GBS following MCV4 continues will continue within the wider VSD as well.

15. Acknowledgments Elaine Miller Eric Weintraub Claudia Vellozzi
John Iskander
VSD Principal Investigators
CDC and FDA VAERS Teams