1. 1 Review of the Evidence: Risk for Wheezing after Live, Attenuated Influenza Vaccine (LAIV: FluMist ® ) in Children Aged 2–4 Years Karen R. Broder, MD Commander, USPHS Immunization Safety Office Centers for Disease Control and Prevention National Immunization Conference, Atlanta, GA March 18, 2008

2. 2 LAIV Safety Contributors  Mathew Daily 1  Kathryn Edwards 2  Tony Fiore 3  Paul Gargiullo 3  John Iskander 4  Elaine Miller 4  Grace Lee 5  Penina Haber 4  Wei Hua 6  Hector Izurieta 6  Dixie Snider 7  Eric Weintraub 4 1. University of Colorado and Kaiser Permanente, CO; 2. Vanderbilt University, TN; 3. Influenza Division, CDC, GA; 4. Immunization Safety Office, CDC, GA; 5. Harvard Pilgrim Health Care, MA; 6. Center for Biologics Evaluation and Research, FDA, MD; 7. Office of the Chief Science Officer, CDC.

3. 3 Live, Attenuated Influenza Vaccine (LAIV: FluMist ® ): United States  Only US-licensed intranasal vaccine  Licensed in 2003 for use in healthy, non- pregnant persons aged 5–49 years  Contains identical seasonal influenza strains as inactivated trivalent influenza vaccine (TIV)  Label revised in 2007 to include healthy children aged 2–4 years  Post-vaccination wheezing identified as potential safety concern in young children Source: photo at http://www.sph.umich.edu/news_events/flumist/ and http://www.washingtonpost.com/wp- dyn/content/article/2007/09/19/AR2007091902187.htmlhttp://www.sph.umich.edu/news_events/flumist/

4. 4 Presentation Outline: LAIV and wheezing  Pediatric safety studies in children aged <5 years  Advisory Committee on Immunization Practices (ACIP) recommendations in children aged 2–4 years  Post-licensure safety monitoring for wheezing Vaccine Adverse Event Reporting System (VAERS) Other surveillance and studies

5. 5 Clinical Pediatric LAIV Studies 2004–2006 Source: 1. Bergen, PIDJ 2004. 2. Piedra, Pediatrics 2005. 3. Ashkenazi, PIDJ 2006 No. of subjectsAgesHistory of asthma/ wheezing Risk for asthma/ wheeze after LAIV LAIV: 3769 vs. (Placebo: 1862) 1–8 yrExcludedAbout 4X increased risk during the 42 days post- vaccination aged 18–35 months 1 LAIV: 11,096 (compared to self) 18 mo– 18 yr Included wheeze and mild asthma About 3X risk during 1 of 4 study years during 15– 42 days aged 18 mo–4 yrs 2 LAIV: 1101 vs. TIV: 1086 6–72 moIncluded recurrent respiratory infections, including bronchiolitis Similar wheezing rates in both groups during 42 days after vaccination LAIV: 12.5% vs. TIV 13.2% 3

6. 6 Belshe et al Study 2007: Supported License Change to include Children Aged 2–4 Years  Population Children aged 6 –59 months (49% US) LAIV group N=4243, TIV group N=4232 Excluded if history of severe asthma or medically diagnosed or treated wheezing within 42 days before enrollment  Design Multi-center, randomized clinical trial Assessed pre-specified wheezing outcomes after dose 1 through 42 days after the last vaccine dose * Sources: FDA and MedImmune briefing documents, FDA VRPBAC meeting, May 16, 2007; Belshe NEJM 2007.

7. 7 Belshe et al Study 2007: “Medically Significant Wheezing” (MSW)*  Wheezing on physical exam and one or more of the following: Sign of respiratory distress (tachypnea, retractions, or dyspnea) Hypoxemia (O2 sat <95%), or New prescription for daily bronchodilator therapy (not on an “as needed” basis) Sources: FDA and MedImmune briefing documents, FDA VRPBAC meeting, May 16, 2007; Belshe NEJM 2007. * Occurring from receipt of dose 1 through 42 days after the last dose

8. 8 Belshe et al Study 2007: Results for “Medically Significant Wheezing” (MSW) after Dose 1  Age 6–23 months: Increased risk for MSW after LAIV  Age 24–59 months: No increased risk after LAIV Age Mo.LAIV No./ total no. subjects (%)* TIV No./ total no. subjects (%)* Adjusted Rate Difference † (95% CI) 6-2355/1725 (3.2)34/1706 (2.0)1.18 (0.13, 2.29) 24-5919/1521 (1.2)14/1520 (0.9) 0.30 (-0.46, 1.09) *Not previously vaccinated against influenza Source: Belshe NEJM 2007. † Adjusted for subject’s age and presence or absence of recurrent wheezing

9. 9 LAIV: FluMist ® Package Insert for 2007-2008 Formulation “ Indicated for individuals 2-49 years of age”  Warnings and Precautions –“FluMist should not be administered to any individual with asthma and children <5 years of age with recurrent wheezing because of potential increased risk of wheezing post vaccination” Source: Package insert at: http://www.flumist.com/pdf/FluMist-prescribing-information.pdfhttp://www.flumist.com/pdf/FluMist-prescribing-information.pdf

10. 10  Either LAIV or inactivated trivalent influenza vaccine (TIV ) can be used to vaccinate healthy non-pregnant persons aged 2--49 years.  Clinicians and immunization programs should screen for possible reactive airways diseases when considering use of FluMist for children aged 2--4 years, and should avoid use of this vaccine in children with asthma or a recent wheezing episode.

11. 11 ACIP Recommendations for LAIV: Screening for Reactive Airways Disease  Consult the medical record, when available, to identify children aged 2--4 years with asthma or recurrent wheezing that might indicate asthma.  Parents or caregivers of children aged 2--4 years should be asked: "In the past 12 months, has a health-care provider ever told you that your child had wheezing or asthma?"  Children whose parents or caregivers answer "yes" and children who have asthma or who had a wheezing episode noted in the medical record within the past 12 months, should not receive FluMist.  TIV is available for use in children with asthma or possible reactive airways diseases. Source: CDC, MMWR, 2007.

12. 12 Vaccine Adverse Event Reporting System (VAERS) Post-Marketing Surveillance for LAIV *Code of Federal Regulations 21CFR600.80 Serious adverse event defined as involving hospitalization or prolongation of hospitalization, death, life-threatening illness or permanent disability  National passive surveillance system for reporting vaccine adverse events  Limitations Risk of underreporting or reporting bias Potential for incomplete, unreliable data  CDC / FDA scientists review daily alerts of serious adverse event (SAE) reports* and other medically important conditions, including wheezing after LAIV

13. 13 Vaccine Adverse Event Reporting System http://vaers.hhs.gov /  Vaccinee Age Sex Medical history Medication  Vaccine(s) administered  Adverse event Onset interval Description  Reporter

14. 14 VAERS LAIV reports received per 100,000 doses distributed by influenza season *Through December 31, 2007 Non-serious reports: Serious reports: Source: Data provided by Chris Ambrose, MedImmune

15. 15 VAERS LAIV Reports by Pediatric Age Group: 7/2003 – 1/2008 Aged 2–4 YrsAged 5–18 Yr Total Reports38327 Serious Reports (% total) 2 (5%)20 (6%) Hospitalizations1 (3%)18 (6%) Deaths00 LAIV only35 (92%)283 (87%) Median onset interval for adverse event 1 day Median age3.5 yrs9 yrs Source: unpublished VAERS data, 3/2008; known vaccination date

16. 16 VAERS LAIV total reports by pediatric age group 7/2003 – 1/2008 Source: unpublished VAERS data, 3/17/008; reports with known vaccination date Age Group Before label change 7/03–9/07 After label change 10/07–1/08 AllSeriousAllSerious 0-120160 2-4110272 (7%) 5-101857 (4%)404 (10%) 11-18829 (11%)200 Total28016 (6%)1036 (6%)

17. 17 VAERS Pediatric LAIV Reports of Wheezing and Asthma After LAIV July 1, 2007– January 31, 2008 Age GroupAsthma/ wheezing reports (% of total) Total reports to VAERS 0–11 (6%)17 2–42 (7%)27 5–106 (15%)40 11–181 (5%)20 All pediatric ages10 (10%)104 Medical Dictionary for Regulatory Activities (MedDRA) terms: wheezing, asthma, or bronchospasm Source: unpublished VAERS data, 3/2008; known vaccination date

18. 18 VAERS Pediatric LAIV Reports of Wheezing and Asthma After LAIV July 1, 2007– January 31, 2008 Clinical Review  Onset of adverse event after vaccination: 0 – 4 days  Only LAIV: 9  History of asthma wheeze No: 7 children Yes: 2 children Unsure: 1 child  Serious: 2 (both hospitalized)

19. 19 Vaccine Safety Datalink Sites Group Health Cooperative Northwest Kaiser Permanente No. CA Kaiser Permanente So. CA Kaiser Permanente Kaiser Permanente Colorado Health Partners Marshfield Clinic Harvard CDC = Infants, children, adolescents under 18 = All ages Collaboration between CDC and 8 MCOs;* provides medical and immunization histories for >5.5 million people annually * MCOs: managed care organizations

20. 20 Vaccine Safety Datalink (VSD) and LAIV  To date, limited use of LAIV in VSD sites, except as part of ongoing Phase 4 study  VSD will examine rates of clinically important outcomes in young children, including wheezing Near real-time surveillance (rapid cycle analysis) Traditional epidemiological studies

21. 21 Uptake LAIV for 7 VSD sites during 7/2006-2/2008 Source: Weintraub, unpublished VSD data, 2008. *

22. 22 LAIV Postmarketing Safety Studies: MedImmune  Safety studies conducted in collaboration with Kaiser Permanente Initiated 2003: Safety in children/adults 5-49 yrs (n=60,000) Initiated 2007: Safety in children 24-59 months (n=25,000)  Study of rates of use and safety of LAIV in populations for whom LAIV is not recommended Will study utilization for 3 seasons: 2007 to 2010 Source: MedImmune, provided by Chris Ambrose. *Sites for aged 5-49 yrs are North California, Colorado, Hawaii; aged 2-4 are North California

23. 23 Summary  During 2007–2008 influenza season, ACIP recommended LAIV as option for vaccinating young children aged 2–4 years.  Initial VAERS reports do not suggest a concern for wheezing after LAIV in young children; however data suggest uptake of LAIV is limited  Continued vaccine safety surveillance for post- vaccination wheezing is needed  Providers should screen young children for recurrent wheezing before administering LAIV

24. 24 Resources  Notice to Readers: Expansion of Use of Live Attenuated Influenza Vaccine (FluMist®) to Children Aged 2--4 Years and Other FluMist Changes for the 2007--08 Influenza Season, MMWR at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5646a4.htm?s_cid=mm5646a4_e http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5646a4.htm?s_cid=mm5646a4_e  Vaccine Information Statement, LAIV http://www.immunize.org/vis/vis_flulive.asp http://www.immunize.org/vis/vis_flulive.asp  Seasonal Flu http://www.cdc.gov/flu/  Vaccine Adverse Event Reporting System http://vaers.hhs.gov/ http://vaers.hhs.gov/  Immunization Safety Office, http://www.cdc.gov/od/science/iso/about_iso.htm http://www.cdc.gov/od/science/iso/about_iso.htm

25. 25 Extra Slides

26. 26 Bergen et al. Study: 2004  Population: children aged 1–17 yrs Total population immunized = 9689 Aged 1–8 yrs N=3769 (LAIV) and N=1862 (placebo) Aged 9–18 yrs N=2704 (LAIV) N=1348 (placebo) Excluded if history of asthma  Design: Randomized clinical trial (LAIV vs. placebo)  Results: Increased risk for asthma events during the 42 days after LAIV vaccination in children aged 18–35 months  Relative risk: 4.06 (90% CI 1.29-17.86) Source: Bergen, PIDJ 2004.

27. 27 Piedra et al Study: 2005  Population: children aged 18 months to 18 years Total number = 11,096 Children with history of wheeze or mild intermittent asthma included  Design: Open-label community-based trial; adverse event rates post-vaccination compared with rates before vaccination  Results: During one of the 4 study years, there was an increased risk for asthma events from 15-42 days after LAIV in children aged 18 mo to 4 yrs. Relative risk 2.85 (95% CI: 1.01-8.03) Source: Piedra et al. Pediatrics 2005.

28. 28 Ashkenazi et al Study: 2006  Population: children 6 – 72 months with recurrent respiratory tract infections (2 or more in past year, including bronchiolitits) LAIV group: N= 1101; TIV group N=1086 Exclusion: “serious chronic disease”  Design: Randomized open label clinical trial: LAIV vs. TIV  Results: Incidence of wheezing similar in both groups during 42 days after vaccination LAIV: 12.5% vs. TIV 13.2% Source: Ashkenazi, PIDJ 2006.

29. 29 VAERS Pediatric LAIV Reports of Wheezing and Asthma After LAIV July 1, 2007– January 31, 2008 2 Serious Cases  Case 1: 7 year old male. History of allergic rhinitis but not asthma. Had wheezing and respiratory distress 1 day after LAIV. Hospitalized for 24 hours; required bronchodilators and steroids.  Case 2: 8 year old female. History of “chronic abdominal pain” and no history of asthma. She had onset of cough and wheezing during the week after vaccination. She received bronchodilators and steroids as an outpatient but worsened. Hospitalized for 5 days. Bronchoscopy showed asthma with right upper lobe collapse.

30. 30 Selected Adverse Events after FluMist ® Reported to VAERS: 2003–2005 Source: Izurieta, Haber et al. JAMA 2005. *Guillain-Barré Syndrome Main ConditionAll Reports (N=460) Serious Reports (N=40) Respiratory217 (47%)15 (38%) Asthma12 (3%)5 (13%) Pneumonia10 (2%)5 (13%) Constitutional67 (15%)4 (10%) Allergic54 (12%)7 (18%) Abdominal33 (7%)1 (3%) Ear-nose-throat18 (4%)0 Neurological10 (2%)7 (18%) GBS*3 (<1%)3 (8%) Bell’s Palsy1 (<1%)1 (3%) Cardiovascular10 (2%)3 (8%) Ocular7 (2%)1 (3%) Other44 (10%)3 (8%)