1. Review of VAERS reports involving seizures following 7-valent pneumococcal conjugate vaccine (PCV7) Scott Campbell, RN, MSPH* John Iskander, MD, MPH* Robert Wise, MD, MPH** and the VAERS Working Group*** *Immunization Safety Branch, National Immunization Program, CDC *Immunization Safety Branch, National Immunization Program, CDC **Epidemiology Branch, Center for Biologics and Evaluation, FDA

2. National passive surveillance system; 10,000 to 12,000 reports annually Adverse events (AE) reported to VAERS follow vaccination but may not be causally related Variable underreporting of AE also occurs (AJPH) Accepts reports from manufacturers, health care providers, vaccinees/family members, and state immunization programs Purpose potential safety problems (especially with new vaccines) which pre-licensure trials may miss, monitor numbers of reports for recognized risks Vaccine Adverse Event Reporting System (VAERS)

3. The leading cause of bacterial meningitis in the United States. Invasive pneumococcal disease kills about 200 young children (under age 5 years) annually in the U.S. Severe disease in children under five years old, especially those under 2 years old: –over 700 cases of meningitis –13,000 blood infections –pneumonia –brain damage Spread person to person through close contact. Increasing resistance to commonly used antibiotics Background: Streptococcus pneumoniae

4. 7 serotype conjugate vaccine licensed in the United States in February 2000 Phase III trial showed febrile seizures slightly more common with PCV7 than with similar meningococcal vaccine, but most associated with concomitant whole-cell pertussis vaccine The seizure rate within 3 days of PCV7 vaccine given concurrently with other vaccines was approximately 1 per 7,000 doses. This is less than historic rates of seizures after whole-cell pertussis vaccines Background: PCV7 licensure and preliminary data on seizures

5. Most common cause for referral to pediatric neurologist Children diagnosed with epilepsy often have history of their first seizure having occurred with a URI or other febrile illness Frequency and age range of occurrence: –Febrile seizures are most common seizure disorder during childhood –Overall incidence is 3% to 4% in young children –Peak incidence is 14-18 months; typical range is 9 months to 5 years Background: seizures in children* *Textbook of Pediatrics, 15 th edition, Nelson et al editors

6. Assess consecutive series of PCV7 VAERS reports with seizures Study Objective

7. Case Series: The first 100 VAERS-PVC7 reports involving seizures Dates of Study: February 2000 to April 2001 Evaluate: –frequency of fever –possible febrile seizure –evidence of prior seizure history Follow-up by telephone to reporters to gather additional details of history, vaccinations, and subsequent clinical course Methods

8. 100 VAERS reports No fever/no seizure hx History of seizure/fever Additional follow-up to determine possible causes of seizure

9. 98 unduplicated reports Age distribution of vacinees: –0 to 7 months: 29% –7 to 12 months: 14% –12 to 18 months: 38% –18 to 24 months: 9% –Over 24 months: 10% concomitant vaccines in 78% of reports seizure within 72 hours after vaccination in 71% Half of vaccinees were ill at time of vaccination (usually URI, otitis media, roseola) Results

10. PRIOR HISTORY OF SEIZURE Yes No TOTAL Yes 3 69 72 FEVER No 7 19 26 TOTAL 10 88 98 Results 79 with fever or prior seizures 19 apparently afebrile and without prior seizure

11. 19 patients without evident fever or seizure history which might account for post vaccinal-convulsions: 15 of the 19 patients received other vaccinations concomitant with PCV7 At least 2 months after the initial post-vaccinal convulsion, 12 of the 19 patients had no further seizures and were not receiving anticonvulsant therapy; 7 patients had additional seizures and/or seizure medication: –3 received anticonvulsants; 2 for epilepsy and 1 for atypical Acardi Syndrome –2 were seizure-free after a period of anticonvulsant therapy –1 with only subsequent febrile seizure –1 with subsequent diagnosis of epilepsy, untreated Results

12. VAERS data alone does not allow for determinations of actual incidence rates of various adverse events after vaccination due to: –lack of denominator information –multiple vaccines on many VAERS reports –inability to determine causality of most reported adverse events –no comparison /control group Study Limitations

13. The VSD Working Group (NEJM 2001; 345(9):656-661): DTP associated with increased risk of febrile seizures only on day of vaccination (adjusted RR 5.70; 95% CI 1.98 to 16.42). MMR was associated with an increased risk of febrile seizures 8 to 14 days after vaccination (adjusted RR 2.83; 95% CI 1.44 to 5.55). Neither vaccine was associated with an increased risk of non-febrile seizures. The children with febrile seizures after vaccination were not found to be at higher risk for subsequent seizures or neurodevelopmental disabilities when compared to children with other febrile seizures. Discussion Other Data on Seizures from U.S. Vaccine Safety Studies The VAERS Working Group (Pediatrics 2000; 106(4):e51): The total number of evaluable reports involving convulsions was 82; after exclusion of convulsions 1 week or more after vaccination, febrile seizures, convulsions with reported likely non-vaccine cause, and possible (rule-out) convulsions, 34 reports remained, and none of the 34 children were reported to have developed a seizure disorder or epilepsy. The number of febrile seizures reported for any pertussis containing vaccine was 39 in 1995, 30 in 1996, 21 in 1997, and 20 for the first half of 1998.

14. similar dosing schedules; both vaccines given to young infants pre-licensure clinical trials for each vaccine revealed a potential signal similar number of VAERS reports which contained this potential signal in the first year after licensure However: –no pattern emerged which suggested independent causality by PCV7 –pre-licensure “signal” for PVC7 was confounded by DTP co-administration –no serious long-term adverse consequences associated with seizure reports Discussion Similarities/Differences to RotaShield pre/post Licensure

15. VAERS seizure reports may not always be classified as “serious” reports; thus special follow-up activity was needed to complete the study Follow-up calls may reveal critical missing information Acquiring additional information requires additional resources Children with seizures (esp febrile) have a good prognosis overall, despite: –Frightening nature of event –Potentially high consumption of medical resources after event Discussion

16. A majority of the 98 vaccinees in the case series received other vaccines such as DTaP which might have contributed to the incidence of fever and subsequent febrile seizure, similar to pre-licensure data Most of the seizures reported with PCV7 vaccine (81%) may be explained by the possibility of a febrile seizure or prior history of seizure in the vaccinee Of the remaining 19%, most did not experience another seizure. Of those who did, most were diagnosed with a condition which likely existed prior to vaccination. In this group, fever appears to be a major mediator of seizure activity No pattern emerged suggesting PCV7 association with recurrent seizures Conclusions

17. CDC personnel: –Roseanne English, B.A –Rob Pless, MD, MSc –Anne Huang, MPH –Elaine Miller, RN, MPH Analytical Sciences, Inc State immunization coordinators, physicians, patients, parents, and others who take the time to file VAERS reports Acknowledgements