1. 1 Syncope and Related Injuries after Vaccination Wan-Ting Huang, MD Immunization Safety Office Office of the Chief Science Officer The 42 nd National Immunization Conference Atlanta, GA March 17, 2008

2. 2 Vasovagal Syncope Transient loss of consciousness as a consequence of decreased brain perfusion Bradycardia, vasodilatation or hypotension resulting from abnormal sympathetic reflex Elicited by a variety of stimuli in settings of fear or emotional distress Occurs after medical procedures, including vaccinations

3. 3 General Recommendations on Immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP) * “… vaccine providers should strongly consider observing patients for 15 minutes after they are vaccinated. If syncope develops, patients should be observed until symptoms resolve.” * MMWR 2006; 55 (No. RR-15)

4. 4 Learning Objectives Describe trends in syncope events reported to Vaccine Adverse Event Reporting System (VAERS) Identify potential risk factors for postvaccination syncope Understand recommended strategies to prevent postvaccination syncope and related injury

5. 5 Vaccine Adverse Event Reporting System (VAERS) National passive surveillance system Jointly operated by CDC and FDA since November 1990 Covering all U.S. licensed vaccines Receives >20,000 reports per year Subject to well-described limitations including underreporting and reporting bias

6. 6 Published VAERS Data on Syncope Serious injuries with at least one fatality have occurred * 89% occurred within 15 minutes † ; 24% with convulsive movements mimicking seizures VAERS data, 1990 – 2004 ¶ (n=3,168) 35% were among persons aged 10–18 years 14% resulted in hospitalization for injury or medical evaluation * Woo EJ et al. Arch Pediatr Adolesc Med 2005; † Braun MM et al. Arch Pediatr Adolesc Med 1997; ¶ MMWR 2006; 55 (No. RR-15)

7. 7 Methods Population: VAERS reports received Jan 1, 2005–Jul 31, 2007 Case definition: MedDRA ® coding terms * — “syncope” or “syncope, vasovagal” Case-patients aged ≥5 years Syncope onset <1 calendar day after vaccination Available records reviewed for selected reports * Medical Dictionary for Regulatory Activities (MedDRA ® )

8. 8 Adverse Events * Reported to VAERS, January 1, 2002–July 31, 2007 Year2002–20042005–2007 n=23,934n=25,861 Adverse eventsn(%)n Syncope203(1)463(2) Serious † syncope 20(10) ¶ 33(7) ¶ * Case-patients aged ≥ 5 years † Defined by FDA as resulting in death, life-threatening illness, hospitalization, prolong hospitalization or disability; according to information provided by the reporter of the adverse event ¶ Proportion of serious reports among all syncope reports

9. 9 MCV4 † February 10, 2005 ¶ Tdap † June 29, 2005 ¶ HPV † June 29, 2006 ¶ 200420062007 *Case-patients aged ≥5 years † MCV4: meningococcal conjugate vaccine; Tdap: tetanus toxoid, reduced diphtheria toxoid and acellular pertusis vaccine; HPV: quadrivalent human papillomavirus vaccine ¶ Date of ACIP Vaccines For Children (VFC) Program vote 2005

10. 10 *Age or sex unknown (n=5) are not included 229 (49%) 49 (24%)

11. 11 Vaccines Associated with Adverse Events in VAERS, January 1, 2005–July 31, 2007 SyncopeAll adverse events n(%)n HPV229(19)1,184(100) MCV490(13)697(100) Tdap64(8)816(100) HPV, MCV4, and/or Tdap291(12)2,355(100) Other vaccine(s)172(<1)23,506(100) Total463(2)25,861(100) *Categories of types of vaccines were not mutually exclusive

12. 12 Number of Vaccines * Administered and Syncope, January 1, 2005–July 31, 2007 Number of vaccines * SyncopeAll adverse events given concurrentlyn(%)n 1182(11)1,655(100) ≥2≥2109(16)700(100) 266(15)441(100) 330(17)181(100) ≥4≥413(17)78(100) Total291(12)2,355(100) *Including vaccine types of HPV, MCV4, and/or Tdap

13. 13 Syncope Associated with Injuries in VAERS Reports, January 1, 2005–July 31, 2007 (n=41 * ) Adolescent (11–18 years), n=31 Females, n=22 (71%) Males, n=9 (29%) Syncope onset after vaccination: 20 (49%) within 5 minutes 33 (80%) within 15 minutes Serious † cases, n=10 (24%) * Excludes cases with unknown onset intervals (n=14) † Defined as adverse events provided by the reporter which result in death, life- threatening illness, hospitalization, prolong hospitalization or disability

14. 14 Complications in Syncope-related Injuries, January 1, 2005–July 31, 2007 (n=41*) * Excluded cases with unknown onset intervals (n=14) † Each injury may result in multiple complications Categoryn(%) † Facial lacerations717 Concussions37 Skull fractures37 Intracranial hemorrhage25 Tooth injury25 Facial palsy12 Car accidents12 Falls without complication2561

15. 15 Example of Injury Related to Postvaccination Syncope An adolescent girl aged 13 years fainted within 10 minutes of receiving HPV and MCV4. She fell backward, hit her head on the carpeted floor of the clinic and was admitted to the pediatric intensive care unit because of skull fractures and subarachnoid hemorrhage. She had recovered completely within 6 months after the injury.

16. 16 Example of Injury Prevented from Postvaccination Syncope An adolescent girl aged 16 years felt dizzy and was observed to have pallor within 5 minutes of receiving HPV. While being taken back to the examination room, she fainted but the clinic physician prevented her from falling. She was observed for 30 minutes in the clinic and completely recovered.

17. 17 Limitations Cannot calculate syncope incidence rate based on VAERS data Underreporting of adverse events Lack of age or sex specific vaccine doses administered VAERS MedDRA ® coding terms may not reflect diagnosis accurately Cannot determine if syncope related to vaccine, targeted groups or both

18. 18 Conclusions Since 2005, an increase in the number of VAERS syncope reports among: Females aged 11–18 years Nonserious reports Reports associated with vaccines recommended for adolescents Syncope-related injury can be serious but may be preventable by following the waiting period recommendations

19. 19 Areas for Research Address age or sex specific incidence of postvaccination syncope Evaluate adherence and barriers to waiting period Evaluate efficacy of waiting period and other measures to prevent secondary injury Provide interventions for use by clinicians to predict or prevent syncope after vaccination

20. 20 Recommendations and Guidance Advisory Committee on Immunization Practices, 2006 * “vaccine providers should strongly consider observing patients for 15 minutes after they are vaccinated.” American Academy of Pediatrics, 2006 † “personnel should be aware of presyncopal manifestations and take appropriate measures to prevent injuries;” “having vaccine recipients sit or lie down for 15 minutes after immunization could avert many syncope episodes and secondary injuries.” * MMWR 2006; 55 (No. RR-15); † American Academy of Pediatrics. 2006 Red Book: Report of the Committee on Infectious Diseases, 27 th ed.

21. 21 Acknowledgements CDC Karen Broder Julianne Gee John Iskander Andrew Kroger Laura Leidel Lauri Markowitz Elaine R. Miller FDA Robert Ball M. Miles Braun Hector Izurietta Andrea Sutherland * Emily J. Woo * Johns Hopkins University, MD

22. 22 Additional Slides

23. 23 *Case-patients aged ≥5 years † HPV: quadrivalent human papillomavirus vaccine 2005 2006 2007

24. 24 *Case-patients aged ≥5 years † MCV4: meningococcal conjugate vaccine 2005 2006 2007

25. 25 Vaccines Associated with Adverse Events in VAERS, January 1, 2002–December 31, 2004 SyncopeAll adverse events n(%)n HBV † 76(6)1,300(100) TIV † 47(2)2,425(100) Td † 40(5)886(100) Other vaccine(s)58(<1)19,572(100) Total203(1)23,934(100) *Categories of types of vaccines were not mutually exclusive † TIV: trivalent inactivated influenza virus vaccine; HBV: recombinant hepatitis B vaccine; Td: tetanus and diphtheria toxoid adsorbed for adult use

26. 26 Vaccines Associated with Syncope Reports in VAERS, January 1, 2005–July 31, 2007 One vaccine given n=302 Multiple vaccines given concurrently n=161 n(%)n HPV156(52)63(39) * MCV415(5)75(47) * Tdap11(4)53(33) * HPV, MCV4 and/or Tdap182(60)109(68) Other vaccine(s)120(40)52(32) * Not mutually exclusive categories

27. 27 Injection-site Adverse Events *, Days 1–5 After Any Vaccination with HPV HPVAluminum- containing placebo Saline placebo (n=5,088)(n=3,470)(n=320) (%) Pain83.975.448.6 Mild/Moderate81.174.148.0 Severe2.81.30.6 Swelling25.415.87.3 Erythema24.718.412.1 * Female participants aged 9 – 23 years in the detailed safety data † Source: MMWR; 2007; No. 56(RR-2)