1. CDC Influenza Vaccine Safety Monitoring Immunization Safety Office (ISO) Penina Haber John Iskander Authors have no financial and other conflict of interest

3. Outline Influenza vaccine usage in the US Vaccine Adverse Event reporting system (VAERS) Influenza season CDC annual seasonal influenza vaccine monitoring: collaborative project with FDA Challenges:  vaccine schedules, multiple products, new cohort of vaccinee Summary CDC-FDA influenza vaccine scientific publications

4. Trivalent Inactivated Influenza Vaccine (TIV) The most widely used vaccine in adults in the US The only vaccine annually administered to adults and children Monitoring seasonal use of influenza vaccine remains the cornerstone of public health strategies to reduce morbidity and mortality of influenza virus infections * >18 years

5. Vaccine Adverse Event Reporting System (VAERS) National passive surveillance ~receives 25,000 reports per year Operated jointly by CDC and FDA Reports are received from Health care providers, manufacturers, immunization programs, patients and parents VAERS accepts all reports of any adverse event occurring after any U.S. licensed vaccines

6. Influenza Season Influenza season: is defined as for all reports with vaccination date from July first of year one to June 30 th of the following year Serious reports: Reports involving hospitalizations, prolongation of hospitalization, death, life-threatening illness or permanent disability (according to CFR) Non-serious reports: all other reports

7. Case Definition Brighton Collaboration is a global effort to promote comparability of vaccine safety data through primarily developing case definitions and guidelines for adverse events following immunization [AEFI]. e.g. GBS, anaphylaxis's, local reactions, seizures http://www.brightoncollaboration.org/internet/ en/index.html http://www.brightoncollaboration.org/internet/ en/index.html

8. Influenza Vaccine Monitoring Monitoring of adverse events reports following influenza vaccine, a joint effort with FDA include:  Daily e-mail alerts and review of new serious adverse event reports (AE’s)  Weekly electronic summary tables and line lists:  reports by severity level, most frequently reported AE’s by age-group and products  Safety profiles - comparing the different influenza products by age and most frequently reported outcomes  Comparing death, non-fatal and GBS reports the current seasons vs. previous seasons (at a specific date each season)

9. Influenza Vaccine Monitoring (continued) Weekly conference calls with FDA to review most recent reports of interest, reporting trends and potential concerns (signals) Since 1994, verification (questionnaire) of all suspected GBS reports to VAERS following all influenza vaccine (all ages)

10. Influenza Vaccine Monitoring: Challenges Influenza vaccine composition changes each season Denominator data (doses administered)  Not available by age and/or vaccine combination Increased complexity  Vaccination in age groups who previously were not widely vaccinated  Increase number of vaccine manufacturers and number of AE’s  Timely safety evaluation of new products and potential new/rare AE’s

11. Annual Influenza Vaccination Recommendations Since 2000 2000: All adults 50 and older 2004:  All children aged 6 - 23 months  All contacts of children aged 0 - 23 months  All women who will be pregnant during influenza season 2005: All persons with any condition that can compromise respiratory function or the handling of respiratory secretions 2006: All children aged 24 - 59 months and their household contacts and out-of-home caregivers 2008: All children aged 6 months through 18 years

12. Approved Influenza Vaccines, United States, 2008-09 Season Vaccine Trade Name ManufacturerPresentationAge GroupThimerosal Preservative TIVFluzoneSanofi Pasteur.25 mL prefilled syringe6 - 35 moNone 0.5 mL prefilled syringe> 36 moNone 0.5 mL vial;> 36 moNone 5.0 mL multi-dose vial > 6 moYes TIVAfluriaCSL 0.5 mL prefilled syringe > 18 years None 5.0 multi-dose vialYes TIVFluvirinNovartis Vaccine 0.5 mL prefilled syringe > 4 years Preservative free (<1 mcg mercury/dose) 5.0 mL multi-dose vial Yes TIVFluarixGSK 0.5 mL prefilled syringe > 18 years Preservative free (<1 mcg mercury/dose) TIVFluLavalGSK/IDB 5.0 mL multi-dose vial > 18 yearsYes LAIVFluMistMedImmuneSingle-dose sprayer 2 - 49 years, healthy None

13. Cumulative Monthly Influenza Vaccine Distribution (*Through 12/28/2007) Doses (Millions) 83.081.2 102.5 * 115.4

14. Most Frequently Reported Adverse Events (VAERS), 1990 - 2008 Serious AEs (N=3199) Guillain-Barré-syndrome (20%) Fever (19%) Asthenia (17%) Paresthesia (14%) Pain (13%) Non-serious AEs (N=21549) Pain (17%) Fever (16%) Injection site pain (14%) Pruritus (12%) Myalgia (10%)

15. Pediatric VAERS Reports Following TIV by Season and Age

16. Summary Seasonal annual monitoring of influenza vaccine AE’s is well coordinated among CDC and FDA CDCFDA collaborative monitoring of influenza AE’s addresses all aspects of vaccine safety activities:  Public/ media response  Daily review  Analytical review (safety profile, reporting rates calculations)  Weekly and monthly calls  Scientific publications (e.g., peer-review, letters to the editor, MMWR)

17. VAERS system enables CDC-FDA to monitor and assess the safety of various influenza products in timely manner (e.g., GBS) Expansion of annual influenza recommendation are challenging and complex Summary - Continued

18. CDC-FDA Influenza Vaccine Safety (Publications) Lasky T, Terracciano GJ, Magder L, et al. The Guillain- Barré syndrome and the 1992-1993 and 1993-1994 influenza vaccines. N Engl J Med 1998 Dec 17; 339 (25): 1797-802 Haber P, DeStefano F, Angulo F, Iskander J, Shadomy S, Chen RT. Guillain-Barré- syndrome (GBS) following influenza vaccine. JAMA. 2004; 292: 2478-2481 Zhou W, Pool V, DeStefano F, Iskander J, Haber P, Chen RT, VAERS team. 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. Phamacoepi Drug Safety. 2004; 13:505-510

19. Izurieta H, Haber P, Wise R, Iskander J, Pratt D, Mink C, Chang S, Braun MM, Ball, R. Early postmarketing surveillance of live, cold- adapted, intranasal influenza vaccine. JAMA. Dec 2005; 294:2720- 2725 McMahon AW, Iskander J, Haber P, Chang S, Woo EJ, Braun MM, Ball R. Adverse events after inactivated influenza vaccination among children less than 2 years of age: analysis of reports from the Vaccine Adverse Event Reporting System, 1990-2003. Pediatrics. 2005;115(2):453-60. Iskander J, Broder K. Monitoring the safety of annual and pandemic influenza vaccines: lessons from the US experience. Expert Review of Vaccines 2008;7(1):75–82. CDC-FDA Influenza Vaccine Safety (Publications) - Continued

20. VAERS influenza team CDC/FDA Lewis Page (ISO) Dale Burwen (FDA) Gary Euler (ISD) Tony Fiore (NCIRD) Greg Wallace (ISD) Acknowledgements

21. Thank You

22. 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  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.

23. Lasky et. al Study Study was initiated du to doubling of GBS reports to VAERS during 1992-93 and 1993-94 seasons Study conducted among patients given DX of GBS in 4 states The relative risk of GBS associated with vaccination adjusted for age, sex and vaccine season was 1.7 for the 2 seasons combined Attributable risk of 1 additional case of GBS per million individuals vaccinated.

24. Reporting Rates Of GBS and Non-GBS* Following Influenza Vaccination, VAERS July 1990 – June 2005 ** Heber et. Al., JAMA. 2004; 292 : 2478-2481 Adults >18 years; Guillain-Barre- Syndrome (GBS) accounted for a quarter of all the serious reports and showed a significant decline over time

25. VAERS Flu GBS Follow-up Study, VAERS 1994 - 2003 # Schonberger et al. reported prior illness in 62% unvaccinated vs. 33% in vaccinated ResultsNPercentage % All Reports323100 GBS Diagnosis – Verified26482 Non-GBS - Verified268 Lost to Follow-up3310 Prior Influenza Vaccination10533 Prior illness within 4 weeks #7624

26. Onset-Interval of GBS and Non-GBS Following influenza Vaccine in VAERS 1990-2003