1. 1 Diphtheria Toxoid-containing Vaccines: Safety Evidence for ACIP* Recommendations on Intervals and Administration Sequence Karen R. Broder, MD, FAAP Lieutenant Commander, USPHS National Center for Immunization and Respiratory Diseases (proposed) Centers for Disease Control and Prevention National Immunization Conference March 6, 2007 Kansas City, MO *Advisory Committee on Immunization Practices

2. 2 Acknowledgments Group Health Center for Health Statistics, Seattle Washington Lisa Jackson* Dartmouth College, Lebanon, New Hampshire Elizabeth Talbot* CDC NCIRD Kristin Brown* Katrina Kretsinger* Barbara Slade* Tej Tiwari Trudy Murphy Nancy Messonnier CDC Immunization Safety Office Robert Davis* John Iskander* Eric Weintraub Laura Leidel Claudia Vellozzi 16 Dalhousie University, Halifax, Nova Scotia, Canada Scott Halperin National Vaccine Program Office Ben Schwartz ACIP Pertussis Working Group † GlaxoSmithKline Leonard Friedland sanofi pasteur Michael Decker Thomas Papa Al Reinhardt *NIC abstract co-author † See list of names in CDC. MMWR. 2006:55(RR03:1-34.

3. 3 Background: Diphtheria Toxoid Containing Vaccines (DTCV) Diphtheria toxoid used –To immunize effectively against diphtheria –As a conjugate protein in other bacterial vaccines 1964-2004: Td only routinely recommended DTCV for U.S. adolescents/adults –Adolescent booster then every 10 years –Acceptably safe and immunogenic against diphtheria 2005-2006: Two new DTCV introduced into U.S. adolescent and adult schedules: Tdap and MCV4* –Acceptable safety of each vaccine demonstrated *Tdap: Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (BOOSTRIX ® and ADACEL ® ) MCV4: tetravalent meningococcal conjugate vaccine (Menactra ® )

4. 4 DTCV Used among Adolescents and Adults in the United States, 2007 *Limit of flocculation unit; 1 Lf ~ 4 mcg VaccineReason for Diphtheria Toxoid Quantity Diphtheria Toxoid TdImmunization against diphtheria 2 Lf (~8 mcg) TdapImmunization against diphtheria 2.5 Lf (BOOSTRIX ® ) 2 Lf (ADACEL ® ) MCV4Carrier protein to enhance immunologic response to meningococcal antigens 48 mcg (similar quantity as big “D” in DTaP) † † U.S.-licensed pediatric DTaP contain 6.7 to 25 Lf diphtheria toxoid (~30-100 mcg) sanofi pasteur briefing document at http://www.fda.gov/ohrms/dockets/ac/04/briefing/4072B1_1.pdf

5. 5 Recommended Adolescent Immunization Schedule ─ United States, January 2005 Td only DTCV

6. 6 Recommended Adolescent Immunization Schedule ─ United States, January 2007 Two new DTCVs added: Tdap and MCV4

7. 7 Key Post-licensure Safety Questions for Use of Diphtheria Toxoid-containing Vaccines in Adolescents and Adults How soon can Tdap safely be administered after Td? –Adolescents? –Adults? What is the optimally safe administration sequence for Tdap and MVC4 when both vaccines are indicated? –Applies mainly to adolescents

8. 8 Presentation Outline: Diphtheria Toxoid-containing Vaccine (DTCV) Use in Adolescents and Adults Safety evidence informing ACIP recommendations ACIP recommendations on intervals and administration sequence Ongoing post-licensure safety evaluations and studies

9. 9 Safety Evidence Informing ACIP Recommendations 16

10. 10 DTCV Safety for Adult Boosters: Historical Observation “At an early stage it was noticed that adults often suffer from severe reactions during diphtheria immunization... it was not uncommon to have pyrexia, severe malaise and confinement to bed after innoculation” Scheibel Acta Pathol Microbiol Scand 1948

11. 11 Historical Literature Summary Diphtheria and Tetanus Toxoid: Adverse Events (AEs) after Adult Booster Dose(s) Diphtheria and Tetanus Toxoid Rate of local AEs after vaccination Up to 80% Historical risk factors for severe local AEs Higher doses toxoid High serum antitoxin level before vaccination (e.g., due to frequent boosters) Impurities in diphtheria toxoid Td vs. TTAE rate after Td higher than after TT; Td safety acceptable IOM, Adverse Events Associated with Childhood Vaccines 1994 Galazka AM et al. Vaccine 1994;14:845 Lloyd et al. Vaccine 2003;21:3746-3750

12. 12 Arthus Reaction Local Type III Hypersensitivity Rarely occurs after vaccination –Observed after tetanus and diphtheria toxoid-containing vaccines Characterized by –Pain, swelling, induration, edema, some with local hemorrhage and necrosis –Fever –Onset 4-12 hr after dose Immune complex deposition initiates local vasculitis and inflammation IOM, Adverse Events Associated with Childhood Vaccines, 1994. Abbas AK. Cellular & Molecular Immunology, 1991

13. 13 Pre-licensure Tdap and MCV4 Studies 16

14. 14 Tdap (BOOSTRIX ® ) Adolescent Safety* Rates of Selected Solicited Adverse Events within 15 Days after a Single Dose of Tdap or Td Product label available at http://us.gsk.com/products/assets/us_boostrix.pdfhttp://us.gsk.com/products/assets/us_boostrix.pdf † Rate of any injection-site pain after Tdap higher than after Td (p <0.05) *Adolescents aged 10 to 18 years †

15. 15 Tdap (ADACEL ® ) Adolescent Safety* Rates of Selected Solicited Adverse Events within 15 Days after a Single Dose of Tdap or Td † Tdap did not meet the non-inferiority criteria for the rate of “any” injection-site pain compared with the Td rate Product label available at http://www.vaccineplace.com/products/http://www.vaccineplace.com/products/ † *Adolescents aged 11 to 17 years ‡ Fever rate was statistically higher after Tdap than Td but non-inferiority criterion was met ‡

16. 16 Tdap (ADACEL ® ) Adult Safety* Rates of Selected Solicited Adverse Events within 15 Days after a Single Dose of Tdap or Td Product label available at http://www.vaccineplace.com/products/http://www.vaccineplace.com/products/ *Adults aged 18 to 64 years

17. 17 MCV4 (Menactra ® ) Adolescent Safety* Rates of Selected Solicited Adverse Events within 8 Days after a Single Dose of MCV4 or MPS4 Product label available at http://www.vaccineplace.com/products/http://www.vaccineplace.com/products/ † † Rates of injection-site reactions and fever after MCV4 higher than after MPS4 (p <0.05) *Adolescents aged 11-18 years; Meningococcal Polysaccharide Vaccine (MPS4) does not contain diphtheria toxoid †† †

18. 18 Both schedules induced immune response to diphtheria toxoid Diphtheria antitoxin geometric mean titer (GMT) 14 times higher after Td and MCV4 than Td alone FDA briefing documents at http://www.fda.gov/ohrms/dockets/ac/cber04.html MCV4 Adolescent Safety* MCV4 and Td Co-administration *Adolescents aged 11 to 17 years

19. 19 MCV4 Adolescent Safety* Rates of Selected Solicited Adverse Events within 8 Days after a Simultaneous or Sequential Administration of Td and MCV4 FDA briefing documents at http://www.fda.gov/ohrms/dockets/ac/cber04.html *Adolescents aged 11 to 17 years † Rate after Td and placebo † †

20. 20 Limitations of Tdap and MCV4 U.S. Pre-licensure Safety Trials Tdap trials included no subjects who received –Diphtheria or tetanus toxoid-containing vaccine within 5 years* –MCV4 before or during trial MCV4 trials included no subjects who received Tdap before or during the trial Not enough subjects to detect rare adverse events Product labels available at http://us.gsk.com/products/assets/us_boostrix.pdf and http://www.vaccineplace.com/products/http://us.gsk.com/products/assets/us_boostrix.pdf http://www.vaccineplace.com/products/ *Excluded from ADACEL® studies if Td dose within 5 years; BOOSTRIX® if within 10 years

21. 21 Post-licensure Canadian Study of Intervals between Td and Tdap: Methods Tdap (ADACEL ® ) vaccination campaign among 7001 children/adolescents (aged ≥7 to 19 years) residing on Prince Edward Island –Adverse event diaries completed for 5931 (85%) subjects Rates of selected AEs compared in subjects vaccinated at year-intervals of 2 – 9 years (8 cohorts) vs. ≥10 years after tetanus and diphtheria toxoid-containing vaccines –Subjects in “2-year” interval received Td >18 to ≤30 months earlier 13 Halperin et al. Pediatr Infect Dis J. 2006;25(3):195-200.

22. 22 Adolescent Tdap Safety after Td* Rates of Selected Solicited Adverse Events within 15 Days after a single dose of Tdap after Td Halperin et al. Pediatr Infect Dis J. 2006;25(3):195-200. *Typical age 14 to 17 years

23. 23 Summary: Safety Evidence before ACIP before Tdap Votes* Historical data suggested a potential safety concern for administering more diphtheria toxoid at shorter intervals to adults/adolescents Not clear if all lessons from historical studies apply to current U.S. situation –Less impurities in modern DTCV –Diphtheria not endemic –Practice of administering multiple tetanus toxoid boosters no longer common * ACIP voted to recommended Tdap for adolescents in June 2005 and for adults in October 2005 and February 2006.

24. 24 Summary: Safety Evidence before ACIP Tdap Votes (continued) Td-to-Tdap intervals acceptably safe –≥5 years in U.S. adolescents and adults –as short as ~2 years in Canadian adolescents (who did not receive MCV4) Two Td and MCV4 administration sequences studied in adolescents and appear to be safe –Td and MCV4 together on same day –Td first followed by MCV4 1 month later

25. 25 Summary: Gaps in Safety Evidence before ACIP Tdap Votes* Td-to-Tdap intervals –<5 years in adults –<2 years in adolescents and adults –In populations receiving MCV4 Administration sequences –MCV4 first, Td later –Any MCV4 and Tdap schedule * ACIP voted to recommended Tdap for adolescents in June 2005 and for adults in October 2005 and February 2006.

26. 26 ACIP Recommendations on DTCV Interval and Administration Sequence 16

27. 27 ACIP Adolescent Recommendations for Td-to-Tdap Interval* Tdap is “encouraged” for adolescents who already received Td ≥ 5 year interval is “encouraged to reduce the risk for local and systemic reactions” May administer Tdap to adolescents at a shorter interval –“particularly when the benefit of providing protection against pertussis is likely to be increased” CDC. Adolescent Tdap Recommendations. MMWR. 2006:55(RR03):1-34. *Adolescents aged 11 to 18 years

28. 28 ACIP Adult Recommendations for Td-to-Tdap Interval* Tdap is recommended for healthcare personnel with direct patient contact –An interval as short as 2 years “recommended” –Shorter intervals may be used Tdap recommended for persons with close contact with infants –An interval as short as 2 years from the last Td “suggested” –Shorter intervals may be used CDC. Adult Tdap Recommendations. MMWR. 2006:55(RR17):1-33. *Adult aged 19 to 64 years

29. 29 ACIP Recommendation for Administration Sequence of Tdap and MCV4 Vaccine providers should administer Tdap (Td) and MCV4 during the same visit if both vaccines are indicated and available MCV4 and Tdap (Td) may be administered using any sequence. –“persons who recently received one DTCV might have increased rates of adverse reactions after a subsequent DTCV…” 16 CDC. MCV4 Recommendations. MMWR. 2005:54(RR07:1-21). CDC. Adolescent Tdap Recommendations. MMWR. 2006:55(RR03):1-34. CDC. Adult Tdap Recommendations. MMWR. 2006:55(RR17):1-33.

30. 30 Ongoing Safety Studies and Evaluations for DTCV 16

31. 31 Vaccine Adverse Event Reporting System (VAERS) Top 5 Adverse Event Tdap Reports: Adolescents Aged 11-18 years* *N=626; reports received as of February 27, 2007. Reported adverse events as coded using the Medical Dictionary of Medical Activities (MedDRA) preferred terms. Adverse EventFrequency Pyrexia26% Injection Site Erythema15% Headache15% Pain14% Injection Site Pain11%

32. 32 Vaccine Adverse Event Reporting System (VAERS) Tdap Reports: Adolescents Aged 11-18 years* Vaccine(s)Non-seriousSerious* N=592%N=34% Tdap alone26645%1132% Tdap and MCV412621%7 Tdap and single other vaccine 9115%721% *Serious adverse event defined by Code of Federal Regulations as involving hospitalization, death, disability, life threatening illness, or certain other medically important conditions

33. 33 Vaccine Adverse Event Reporting System (VAERS) Top 5 Adverse Event MCV4 Reports: Adolescents Aged 11-18 years* *N=1000; reports received as of February 27, 2007. Reported adverse events as coded using the Medical Dictionary of Medical Activities (MedDRA) preferred terms. Adverse EventFrequency Pyrexia25% Headache24% Pain16% Dizziness12% Injection Site Erythema11%

34. 34 Vaccine Adverse Event Reporting System (VAERS) MCV4 Reports: Adolescents Aged 11-18 years Vaccine(s)Non-seriousSerious* N=914%N=86% MCV4 alone50956%5362% MCV4 and Tdap12614%78% MCV4 and Td45 5%4 Tdap and single other vaccine 11312%1113% * Serious adverse event defined by Code of Federal Regulations as involving hospitalization, death, disability, life threatening illness, or certain other medically important conditions

35. 35 DTCV Studies and Evaluations Underway StudyMethodsAims CDC Vaccine Safety Datalink* Prospective cohort study (adolescents and young adults) Assess occurrence of medically-attended local reactions in persons with varying patterns of receipt of DTCV Manufacturer Co-administration Trials Randomized Clinical Trials (adolescents) Assess adverse event rates after simultaneous and sequential Tdap and MCV4 administration Safety Evaluation during Tdap Mass Vaccination Campaign Survey of Healthcare Personnel (HCP) (adults) Assess rates of AEs after Tdap in HCP who received the last Td/TT <2 yrs vs. ≥2 years earlier *Principal Investigator is Lisa Jackson, Group Health Center for Health Statistics, Seattle Washington, data collection underway since 8/2006

36. 36 The findings and conclusions in this presentation are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention

37. 37 Back-up Slides 16

38. 38 Antibody Response to Diphtheria Toxoid Galazka AM et al. Vaccine 1994;14:845 Protection ~ > 0.1 IU/ml

39. 39 Arthus Reaction Local Type III Hypersensitivity Immune complex deposition –Vaccine antigen at injection site complexes pre-existing IgG, activates complement, initiates local vasculitis, inflammation IOM, Adverse Events Associated with Childhood Vaccines, 1994; Abbas AK. Cellular & Molecular Immunology, 1991 Ghaffar, Microbiology and Immunology On-line, University of South Carolina School of Medicine, http://pathmicro.med.sc.edu/ghaffar/hyper00.htm

40. 40 U.S. Co-Administration MCV4 and Tdap Trials Underway by Manufacturers* Similar trials underway for GlaxoSmithKline* and sanofi pastuer † Rates of local and systemic adverse events after vaccinations to be assessed for each group Adolescents who received tetanus or diphtheria toxoid-containing vaccine within 5 years excluded * Personal communication with Dr. Friedland on February 4, 2007 † Personal communication with Dr. Papa on February 13, 2007

41. 41 VAERS Background National passive surveillance system for U.S. licensed vaccines; jointly operated with FDA Subject to underreporting, temporal and other reporting biases, general inability to assess causality for individual reports Since January 17 2007, adverse events coded using Medical Dictionary for Regulatory Activities (MedDRA); this is considered the international standard

42. 42 Vaccine Safety Datalink (VSD) Background Automated large linked database involving eight geographically diverse managed care organizations (MCOs) Covers approximately 3% of U.S. population May be underpowered to detect very rare adverse events