ACIP Feb. 21-22, 2007 Guillain-Barré Syndrome (GBS) Among Recipients of Meningococcal Conjugate Vaccine (MCV4,Menactra®) Update Oct. 2006-Jan. 2007 Robert L. Davis, MD, MPH Director Immunization Safety Office Office of the Chief Science Officer Centers for Disease Control and Prevention

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.

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 2005. Since the last update was provided in the MMWR in October 2006, 2 new GBS reports have been received by VAERS.

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 13-19 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 2005. Since the last update was provided in the MMWR in October 2006, 2 new GBS reports have been received by VAERS.

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 11-19 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 11-19 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.

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.

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.

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.

Observed (VAERS)/ expected Expected (using HCUP 2000-2003) = 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 2000-2004) = 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 11-19 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.

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 = 0.015 – 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 11-19 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)

GBS after MCV4 Vaccination: Rates by Age Among 11-14 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 15-19 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 15-19 year olds. These estimates have been adjusted for the seasonality of GBS.

GBS after MCV4 Vaccination: Discussion For 11-19 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 15-19 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 15-19 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.

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 11-19 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)

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.

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