1. TM Immunization Adults Inactivated Influenza Vaccine Vaccine Adverse Event Reporting System (VAERS) – 14 Years Experience Penina Haber 39 th National Immunization Conference (NIC)

2. Outline:  Overview: – influenza adverse event reports to VAERS, 1990-2004 –Epidemiology of Guillain-Barré Syndrome (GBS) –GBS and the swine influenza vaccine (1976-77)  VAERS influenza studies: – GBS reporting trends (1990-2003) – GBS Follow-up study (1994-2003) – Bell’s palsy study (1990-2001)

4. Vaccine Adverse Event Reporting System (VAERS)  National passive surveillance  ~receives 12,000 reports/year  Operated jointly by CDC and FDA  Reports from Health care providers, manufacturers, immunization programs, and the public  Potential for rapid detection of rare/new adverse events

5. Safety Profile of Trivalent Influenza Vaccine in Adults*, VAERS 1990-2004  From 1990-2004 VAERS received 17,660 reports following flu vaccinations; 690 millions adults were vaccinated –Reporting rate of 25.5 per million vaccinations –79% of all adult reports to VAERS were after a single influenza  27% of all reports in adults are following influenza vaccine  Most frequently reported AE: –S erious AE* : GBS (20%) –All other (non-serious) AE : injection site reactions (23%) * Non-fatal serious if one of the following occurred : Hospitalization, life-threatening illness, extended hospital stay, disability or death

6. Safety Profile of Trivalent Influenza Vaccine in Adults*, VAERS 1990-2004 (cont.) Severity level Flu vaccine % All other vaccines % Fatal2.00.4 Non-fatal Serious*128.0 Mean (median) age (years) 52 (52)40 (38) >18 years;

7. Epidemiology of GBS  GBS is an acute, immune-mediated paralytic disorder of the peripheral nervous system.  annual incidence of GBS range from 0.4 to 4.0 per 100,000 populations, with most studies pointing to a level of 1-2 cases per 100,000  About 2/3 of GBS cases occurs several days or weeks after an infectious event, commonly a diarrheal illness or a virus- like-upper-respiratory infection

8. GBS and the Association with the Swine Influenza vaccine (1976-1977)  Concerns about the risk of developing GBS after influenza vaccination have been present since the association was first noticed during 1976-77 (swine influenza) vaccination campaign – GBS rate exceeded the background rate by slightly less than 10 cases per million vaccinee –Relative risks ranged from 4.0-7.6 for 6- or 8 weeks periods after vaccinations.  Subsequent studies of GBS and influenza vaccines found low relative risks that were not statistically significant

9. 1992-1993 and 1993-94 Flu/GBS VAERS Study  An apparent increase of the number of GBS reports in 1993-94 –Resulted in a case-control study for that season and for 1992-93 season –The study found a combined RR GBS among vaccinee of 1.7 ( 95% CI 1.0-2.8;p =.04) clustering 6 weeks following vaccination –The attributable risk was estimated to 1 additional case of GBS per million vaccinee

10. GBS Analysis  Selected all GBS reports following flu vaccine in persons aged >18 years, vaccinated between 1/1990-6/2003  Influenza season: is defined as for all reports with vaccination date from July 1 st of year one to June 30 th of the following year  Denominator data: estimated population census by 3 age-groups (18-49, 50-64 and >65 years ) multiplied by the proportion of persons receiving influenza vaccine as determined from the National Health Interview Survey (NHIS) data  Poisson regression and z-test were applied to evaluate GBS reporting trends by season and age-group

11. GBS and Non-GBS Reporting Rates Following Influenza Vaccination, VAERS 1990-2003 Influenza Season* *total of 501 reports; reporting rate in 1993-4 RR was 0.17 (P<.001) and declined to low of 0.04 in 2002-3 (p <.001)

12. GBS Reporting Rates by Age* and Influenza Season, VAERS 1990-2003 *

13. Reporting Rates of GBS and Non-GBS following Influenza Vaccine, VAERS 1990-2003 Age-group GBS Non-GBS CoefficientP-valueCoefficientP-value 18-49-.0734.004+.0168<.0001 50-64-.1565<.0001+.0072.21 65+-.0812<.0001-.0114.0046 All ages-.0977<.0001+.0142<.0001 Reporting rate of GBS declined for all age-groups but varied for non-GBS reports

14. Figure : Onset-Interval of GBS and Non-GBS Following influenza Vaccine in VAERS 1990-2003 * Median onset interval for GBS reports 13 days and for non-GBS 1 day

15. Figure a: Onset-Interval of GBS and Other Neurological Non-GBS Reports Following influenza Vaccine in VAERS 1990-2003

16. Primary Diagnosis of GBS Rates* from Nationwide Inpatient Sample (NIS), 1989-2001 Per 100,000 population; GBS as primary diagnosis; from 1989-1997 unchanged s around 3.2 per 100,000 pop. From 1997-2001 decline from 3.1 to 2.5 per 100,000 pop. (p=.009)

17. * 28% decrease in Campylobacter infections in humans due to enhanced food safety interventions

18. GBS follow-up Study  Since 1994, CDC conducted active follow-up on all possible GBS reports to VAERS following influenza vaccination.  The neurologist was contacted to verify: –Final diagnosis GBS –Other illness 4 weeks prior onset of GBS –Previous occurrence of GBS –Previous influenza vaccines

19. Table 2: Flu GBS Follow-up Study, VAERS 1994 - 2003 Results N % All reports 323 100 GBS diagnosis – verified 264 82 Non-GBS - verified 26 8 Lost to Follow-up 33 10 Prior influenza vaccination 105 33 Prior illness within 4 weeks # 76 24 # Schonberger et al. reported prior illness in 62% unvaccinated vs. 33% in vaccinated

20. Conclusions  Both, the distribution of GBS onset intervals and the low prevalence of antecedent illness, support a potential vaccine association –During the swine flu investigations, markedly lower proportion of vaccinated compared with unvaccianted cases with history of a recent illness (33% vs. 62%) provided strong evidence for causal relationship between influenza vaccinations and GBS, suggesting that vaccine replaced acute illness as a trigger of GBS

21.  The reported decline of Campylobacter in the FoodNet and the similarity in the distribution of onset intervals support most recent evidence of the role of Campylobacter infection for GBS  Currently we are evaluating available samples of the 1976-77 swine flu vaccine for evidence of a component which could explain the link with GBS, including Campylobacter and other antigens Conclusions (cont.)

22. Background: Bell ’ s Palsy Idiopathic peripheral facial paresis Clinical diagnosis Unclear etiology complete recovery within 4-8 weeks

23. Epidemiology of Bell ’ s Palsy  Lifetime Prevalence: 6.4 / 1000  Incidence: increases with age –Overall: 15-50/100,000 population per year  Gender: overall equal  Seasonality: –More common in the winter

24. Intranasal Influenza Vaccine and Bell’s Palsy in Switzerland  A new intranasal influenza vaccine introduced to Swiss market 10/2000  46 cases of Bell’s palsy among vaccinees reported 10/2000 - 4/2001  Distribution discontinued  A case-control study initiated in 5/2001 confirmed the association with vaccine

25. Onset Interval of Bell’s Palsy after Influenza Vaccines

26. Onset month of Bell’s Palsy after Influenza Vaccines

27. Proportional Reporting Ratio (PRR) VaccineAE-XOther AEsTotal Vaccine Aaba+b Other Vaccines cdc+d Totala+cb+da+b+c+d PRR for Bell’s Palsy: FLU: 4.1 (potential signal?) HBV: 1.7 PRR= [ a /(a +b)] / [ c /(c +d)]

28. Conclusions  Total of 154 reports  A potential signal of possible association between influenza vaccines and an increased risk of Bell’s palsy: –Onset interval of Bell’s palsy differed from the overall onset pattern in VAERS: clustered in the first month after vaccination Cluster during –the winter which is consistent with the flu vaccination  Currently the VSD is conducting a population- based study of Bell’s Palsy and trivalent inactivated Influenza vaccines at 3 HMO’s

29. Acknowledgement  I would like to acknowledge; –Co-authors –VAERS team –Stephen Gordon & Marla Sidey-Vener –Lu Peng-Jun, James Singleton and Barry Sirotkin

30. Inactivated Influenza Vaccine Inactivated Influenza Vaccine VAERS Publications  The Guillain-Barré Syndrome and the 1992-93 and 1993-94 influenza vaccines. Lasky T, Terracciano GJ, Magder L, et al.. N Engl J Med. 1998; 339:1797-802  A potential signal of Bell’s palsy after parenteral inactivated influenza vaccines: reports to the Vaccine Adverse Event reporting system (VAERS) –United States, 1991-2001. Zhou W, Pool V., Destefano F., Iskander J., Haber P., Chen R. and the VAERS team. Phamacoepi Drug Safety 2004; 13:1-6  Guillain-Barre- Syndrome (GBS) following influenza vaccine. Penina Haber, Frank Destefano, Fredric Angulo, John Iskander, Sean Shadomy, Robert. T. Chen. JAMA. 2004; 292 : 2478-2481