# Presentation: 823973

## ADACELTM

**Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed**

**Vaccine and Related Biological Products Advisory Committee**
**March 15, 2005**

**sanofi pasteur**

## Adacel - Agenda

**Introduction****	****Luc Kuykens, MD, MPH****	****VP Regulatory Affairs**
**Pertussis Epidemiology****	****David Johnson, MD, MPH****	****Director Scientific and Medical Affairs**** **
**Immunogenicity ****	****Michael Decker, MD, ****	****MPH ****	****VP Scientific and Medical Affairs**
**Safety and Conclusion ****	****Luc Kuykens, MD, MPH**
**	****VP Regulatory Affairs**

## Public Health Need for Adolescent and Adult Pertussis Vaccination

**Reduce morbidity associated with pertussis ****in all age groups**
**Reduce pertussis disease in adolescents and adults**
**Prevent transmission of pertussis from adolescents and adults to infants**

## Vaccine Formulation

|  | Adacel | Daptacel | Td
Adsorbed |
| --- | --- | --- | --- |
| Tetanus Toxoid | 5 Lf | 5 Lf | 5 Lf |
| Diphtheria Toxoid | 2 Lf | 15 Lf | 2 Lf |
|               5 Component Pertussis Vaccines |  |  |  |
| Pertussis Toxoid | 2.5 g | 10 g | - |
| Filamentous Hemagglutinin | 5 g | 5 g | - |
| Pertactin  | 3 g | 3 g | - |
| Fimbriae Types 2 and 3 | 5 g | 5 g | - |

**Adjuvant: 0.33 mg aluminum ****0.6% v/v ****2-phenoxyethanol**

## Vaccine Formulation

|  | Adacel | Daptacel | Td
Adsorbed |
| --- | --- | --- | --- |
| Tetanus Toxoid | 5 Lf | 5 Lf | 5 Lf |
| Diphtheria Toxoid | 2 Lf | 15 Lf | 2 Lf |
|               5 Component Pertussis Vaccines |  |  |  |
| Pertussis Toxoid | 2.5 g | 10 g | - |
| Filamentous Hemagglutinin | 5 g | 5 g | - |
| Pertactin  | 3 g | 3 g | - |
| Fimbriae Types 2 and 3 | 5 g | 5 g | - |

**Adjuvant: 0.33 mg aluminum ****0.6% v/v ****2-phenoxyethanol**

## Vaccine Formulation

|  | Adacel | Daptacel | Td
Adsorbed |
| --- | --- | --- | --- |
| Tetanus Toxoid | 5 Lf | 5 Lf | 5 Lf |
| Diphtheria Toxoid | 2 Lf | 15 Lf | 2 Lf |
|               5 Component Pertussis Vaccines |  |  |  |
| Pertussis Toxoid | 2.5 g | 10 g | - |
| Filamentous Hemagglutinin | 5 g | 5 g | - |
| Pertactin  | 3 g | 3 g | - |
| Fimbriae Types 2 and 3 | 5 g | 5 g | - |

**Adjuvant: 0.33 mg aluminum ****0.6% v/v ****2-phenoxyethanol**

## Importance of FIM in the 5-Component Acellular Pertussis Vaccines

**The importance of PRN and FIM in protection against typical pertussis was established in the household contact study nested in Sweden I Efficacy Trial****1**
**Efficacy correlated with having high titers of ****anti-PRN (75%), high anti-FIM (72%), or both (85%)**
**Two other household contact studies also support an important role for FIM****2,3**

**1****Storsaeter J, Hallander HO, Gustafsson L, et al. *****Vaccine.***** 1998;16:1907-1916;**
**2****Cherry JD, Gornbein J, Heininger U, et al. *****Vaccine.***** 1998;16:1901-1906;**
**3****Deen JL, Mink CM, Cherry JD, Christenson PD, Pineda EF, Lewis K, Blumberg DA, Ross LA. *****Clin Infect Dis*****. 1995;21(5):1211-9.**

## Adacel Components

**All components of Adacel are licensed immunogens in ****Daptacel ****or Td adsorbed**
**The manufacturing and testing methods for components of Adacel are the same as those used for Daptacel and Td adsorbed**
**Manufactured in Daptacel production facility**

## Adacel Clinical Development Program

**Demonstration of non-inferiority for:**
**Safety**
**Comparison to standard of care (Td adsorbed vaccine) **
**Immunogenicity  **
**Comparison to standard of care (Td adsorbed vaccine) ****for diphtheria and tetanus**
**Comparison to efficacious 5 component DTaP vaccine****for pertussis**
**Concomitant administration with hepatitis B (HB) or influenza vaccine**

## Adacel Clinical Experience 

| 

Population | US Licensure Trials | Supportive Canadian Trials | Total |
| --- | --- | --- | --- |
| Adults | 2448 | 638 | 3086 |
| Adolescents | 3393  | 324  | 3717 |
| TOTAL |  5841 | 962  | 6803 |

**Post-marketing experience: > 6 million doses of  Adacel-containing vaccines distributed.**

## Adacel Key Findings

**Safe and well tolerated among adolescents ****and adults**
**Similar safety profile as licensed Td vaccine **
**Achieved all pre-specified non-inferiority criteria ****for immunogenicity vs. Td**
**One dose in adolescents and adults produces pertussis antibody levels exceeding 3 doses ****of Daptacel**
**Can be given concomitantly with HB vaccine or influenza vaccine**

## Adacel - Agenda

**Introduction****	****Luc Kuykens, MD, MPH****	****VP Regulatory Affairs**
**Pertussis Epidemiology****	****David Johnson, MD, MPH****	****Director Scientific and Medical Affairs**** **
**Immunogenicity ****	****Michael Decker, MD, MPH**
**	****	****VP Scientific and Medical Affairs**
**Safety and Conclusion****	****Luc Kuykens, MD, MPH**
**	****	****VP Regulatory Affairs**

## Reports of PertussisUnited States, 1980 – 2004 

*** Preliminary Data**
**CDC. MMWR 1997;46(54):71-80.  Murphy T. Data on file, personal communication, 2001.  MMWR 2000;50:1175.  ****MMWR 2001;50(33):725.  MMWR 2002;51:723.  MMWR 2003;52:747.  Bacterial Vaccine Preventable Disease Branch, National Immunization Program, 2004.**

**Year**

**Cases (Thousands)**

**7796**

**6586**

**4570**

**11,647**

**9771**

**18,957***

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**14**

**16**

**18**

**20**

**1980**

**1982**

**1984**

**1986**

**1988**

**1990**

**1992**

**1994**

**1996**

**1998**

**2000**

**2002**

**2004**

## Reports of Pertussis in the U.S.

**Centers for Disease Control and Prevention. *****MMWR*****. 2002;51:73-76; ****G****ü****ri****ş**** et al. *****Clin Infect Dis*****. 1999;28:1230-1237.**
**National Immunization Program, Bacterial Vaccine Preventable Diseases Branch. ****Pertussis Surveillance Report, August 6, 2004**

**0**

**500**

**1000**

**1500**

**2000**

**2500**

**3000**

**3500**

**<1 yr**

**1-4 yrs**

**5-9 yrs**

**10-19 yrs**

**20+ yrs**

**Average Number****of Cases / Year**

**1990-1993     **

**1994-1996     **

**1997-2000     **

**2001-2003**

## Prolonged Cough Illness in Adolescents and Adults Due to Bordetella pertussis

| 
Source | 
Locale | 
Year(s) | % of cough illness  |
| --- | --- | --- | --- |
| Nennig et al | San Francisco | 1994-95 | 12 |
| Strebel et al | Minn-St Paul | 1995-96 | 13 |
| Jackson et al | Seattle | 1983-87 | 15 |
| Jansen et al | San Diego | 1993-94 | 17 |
| Birbeback et al | Denmark | 1995-97 | 17 |
| Wright et al | Nashville | 1992-94 | 21 |
| Robertson et al | New S Wales | 1985-86 | 26 |
| Mink et al | Los Angeles | 1986-89 | 26 |
| Rosenthal et al | Chicago | 1993-94 | 26 |
| Wirsing v Köenig et al | Germany | 1992-94 | 31 |
| Schmitt-Grohé et al | Germany | 1992-94 | 32 |
| Vicent et al | Korea | 1997-98 | 50 |
| Gilberg et al | Paris | 1999 | 52 |

## Common Clinical Manifestations of Adolescent-Adult Pertussis

**Cough 97% ******** 3 weeks, 52% ******** 9 weeks**
**Paroxysms ******** 3 weeks in 73%**
**Whoop in 69%**
**Post-tussive emesis in 65%**
**Teens missed average 5 days of school; ****Adults missed average 7 days of work**
**Average 14 days of disrupted sleep**

**De Serres et al. *****J Infect Dis*****. 2000;182:174–9.**

## Complications of Adolescent – Adult Pertussis

**Complications common in adolescents (16%) and adults (28%)**
**Cyanosis found in 6% of adolescents ****and 9% of adults**
**Pneumonia occurs in 2% of patients <30 years old and 5% to 9% of older patients**
**Hospitalization of adolescents and adults ****at 1.4% and 3.5%, respectively**

**De Serres et al. *****J Infect Dis*****. 2000;182:174–9.**

## Infant Pertussis Deaths by Decade1980-1989 vs. 1990-1999

**Vitek et al. *****PIDJ.***** 2003;22:628-634.**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**0-1**
**Mos**

**2-3**
**Mos**

**4-5**
**Mos**

**6-11**
**Mos**

**Deaths**

**1980-1989**

**1990-1999**

**0-1**
**Mos**

**2-3**
**Mos**

**4-5**
**Mos**

**6-11**
**Mos**

## CDC Study –Infant Pertussis: Who Was the Source?

**774 infant cases from 4 states**
**264 cases had source identified**
**75% family members**
**43% mother**
**20% father**
**26% sibling**
**11% grandparent**
**25% neighbor, friend, day care, and other**

**Bisgard, K. *****PIDJ.***** 2004;23:985-9.**

## Age of Pertussis Source* for Infants

***219 source-persons with known age**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**0-4**

**5-9**

**10-19**

**20+**

**Age of Source (Years)**

**% of Infant Cases**

**Bisgard, K. *****PIDJ.***** 2004;23:985-9.**

## Healthcare Professionals Involvedin Transmission of Pertussis

**Physicians****	****1912  Schwenkenbecher**
**Nurses****	****1972  Kurt et al**
**Physicians****	****1992  Etkind et al****	**
**Nurses****	****1995  Christie et al****	**
**Nurses****	****1997  Matlow et al****	**
**Nurses and Physicians****	****2004  CDC**

**Schwenkenbecher, 1912;****Kurt et al. *****JAMA.***** 1972;221(3):264-7;****Etkind et al. *****Am J Dis Child.***** 1992;146:173-6; ****Christie et al. *****Infect Control Hosp Epidemiol.***** 1995;16:556-63; ****Matlow et al.***** Infect Control Hosp Epidemiol.***** 1997;18:715-16;**
**CDC. *****MMWR*****. 2004;54(03):67-71.**

## Adacel Experience in Canada

**Adacel licensed in Canada – May 1999**
**NACI issued a supportive statement, ****but at that time did not give a recommendation for universal routine use**
**3 provinces or territories launched Adacel vaccination programs **

**Health Canada. CCDR. 2000;26(ACS-1):1-8.**

## Pertussis Incidence and Vaccine Use, 1993 – 2004Canada’s Northwest Territories

**Kandola, K.  Abstract in *****Can J Infect Dis Med Microbiol.***** 2004;15:351.  Manuscript in preparation.**

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**1993-1996**

**1997-2000**

**2001-2002**

**2003-2004**

**Time Periods**

**Average Yearly****Cases / 10,000**

## The Adacel Program in Newfoundland

**Replaced Td in 1999 school year**
**Adacel delivered in a Grade 9 (14 year olds) school-based program**
**Approximately 25,000 doses given by June 2004**

## Incidence of Pertussis, 1986 – 2003Canada vs. Newfoundland

- Incidence of Pertussis, 1986 – 2003Canada vs. Newfoundland

**Source: Data derived from CCDR Notifiable Disease Annual Summaries**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**1986**

**87**

**88**

**89**

**90**

**91**

**92**

**93**

**94**

**95**

**96**

**97**

**98**

**99**

**00**

**01**

**02**

**03**

**Year**

**Incidence****per 100,000**

**Canada**

**Newfoundland**

## Adacel Experience in Canada (cont’d)

**NACI Adacel Recommendation – September 2003**
**	****A single booster dose should be administered to adolescents and adults in place of Td to protect against pertussis**
**All remaining provinces and territories launched Adacel adolescent programs in 2003 - 2004**
**Prince Edward Island conducted broad-based ****catch-up program – Fall 2004**
**Quebec launched adolescent, adult, and “cocoon” program – September 2004**

**Health Canada. CCDR. 2000;26(ACS-1):1-8; 2003;29(ACS-5):1-9.**** **

## Pertussis Epidemiology Summary

**Reports of pertussis continue to increase dramatically**
**Pertussis is common in adolescents and adults, ****causing significant morbidity and complications**
**Adolescents and adults are important sources of pertussis transmission to vulnerable infants, in whom mortality is increasing**
**Ongoing epidemiological surveillance data from Canada demonstrate potential of Adacel to control pertussis **

## Adacel - Agenda

**Introduction****	****Luc Kuykens, MD, MPH****	****VP Regulatory Affairs**
**Pertussis Epidemiology****	****David Johnson, MD, MPH****	****Director Scientific and Medical Affairs**** **
**Immunogenicity ****	****Michael Decker, MD, MPH**
**	****	****VP Scientific and Medical Affairs**
**Safety and Conclusion****	****Luc Kuykens, MD, MPH**
**	****	****VP Regulatory Affairs**

## Adacel Clinical Studies for US LicensureStudies, Age Groups, and Vaccinees

**Total number of Adacel recipients:     6884**

| Study | Purpose | Age Group | N | Adacel |
| --- | --- | --- | --- | --- |
| Td506 | Large scale safety and immunogenicity, vs. Td | 11-64 yr | 4461 | 	 3017 |
| Td505 | Lot Consistency | 11-17 yr | 1806 |  	1806 |
| Td501 | Interaction with HB | 11-14 yr | 403 |  	403 |
| Td502 | Interaction with Influenza | 19-64 yr | 696 |  	696 |
| TC9704 | Lot Consistency | 12-54 yr | 600 |  	449 |
| Td9707 | Adacel vs Td, aP | 19-60 yr | 370 |  	244 |
| Td9805 | Interaction with HB | 11-13 yr | 269 |  	269 |

## Overall Summary: Safety and Immunogenicity Populations 

| Study | Planned Subjects     | Enrolled | Safety | Immuno |
| --- | --- | --- | --- | --- |
| Td506 | 4400 | 4480 | 4301 | 2296 |
| Td505 | 1800 | 1811 | 1806 | 1056 |
| Td501 |  410 |   410 |   403 |   312 |
| Td502 |  690 |   720 |   696 |   678 |
| Total | 7300 | 7421 | 7206 | 4342 |

**Of the safety population, 5841 received Adacel and 1365 received Td.**

## Overall Summary: Safety and Immunogenicity Populations 

| Study | Planned Subjects     | Enrolled | Safety | Immuno |
| --- | --- | --- | --- | --- |
| Td506 | 4400 | 4480 | 4301 | 2296 |
| Td505 | 1800 | 1811 | 1806 | 1056 |
| Td501 |  410 |   410 |   403 |   312 |
| Td502 |  690 |   720 |   696 |   678 |
| Total | 7300 | 7421 | 7206 | 4342 |

**Of the immunogenicity population, 3316 received Adacel and ****1026 received Td.**

## Td505 and Td506 Distribution of ITT Populations By Gender and Race/Ethnicity

|  | Adolescents (N = 3782)% | Adults(N = 2325)
% | Total(N = 6107)
% |
| --- | --- | --- | --- |
| Gender |  |  |  |
|    Female	 | 49.3 | 64.0 | 54.9 |
|    Male | 50.7 | 36.0 | 45.1 |
| Race/Ethnicity    |  |  |  |
|    Caucasian | 86.1 | 84.9 | 85.7 |
|    Black |   9.1 |   9.6 |   9.3 |
|    Hispanic |   2.0 |   3.1 |   2.4 |
|    Asian |   1.2 |   1.3 |   1.2 |
|    Other |   1.6 |   1.0 |   1.4 |

## Measuring Immunogenicity

**Immunological Endpoints**
**Seroprotection Rates**
**% of participants who develop a benchmark ****(eg, protective) diphtheria or tetanus titer**
**Primary outcome measure in all of the core****clinical trials **
**Booster Rates**
**% of participants who develop a defined increase in titer, stratified by pre-titer**
**Primary outcome measure in one core clinical trial**

## Measuring Immunogenicity (2)

**Immunological Endpoints**
**Geometric Mean Titers**
**Normalized average of the post-immunization titers**
**Primary pertussis outcome measure; descriptive for diphtheria and tetanus **
**Reverse Cumulative Distribution Curves**
**Graphical presentation of the antibody distribution of the entire studied population**
**Descriptive only **

## Measuring Immunogenicity

|    Endpoint  |    Non-inferiority or equivalency
   criteria using 90% or 95% CI |
| --- | --- |
|    Seroprotection and    Booster Rates  |    Difference in rates between groups 
   at 10% margin |
|    GMTs |    GMTs ratio between groups 
   at 1.5 margin |

## Adacel Link to Efficacy

**Adacel link to efficacy: Td506 vs. Sweden I efficacy trial**
**Sweden I was an NIH-sponsored, prospective, randomized, double-blinded, placebo-controlled and whole-cell-pertussis-controlled efficacy trial in Sweden 1992-1995**
**Infants received 3 doses of Daptacel at 2, 4, 6 months of age**
**85% efficacy vs. WHO-defined classic pertussis; 78% efficacy vs. any pertussis (lab-confirmed, ******** 1 day of cough)**
**Pertussis immunogenicity results following 1 dose of Adacel in US pivotal trial Td506 were compared to those following 3 doses of Daptacel in Sweden I Efficacy Trial**
**Sera from Adacel recipients and stored sera from infants in the Sweden I Efficacy Trial were tested contemporaneously in same laboratory, under same conditions, using the same validated assay**

## Rationale for Serologic Bridge to Sweden I Efficacy Trial Data

**Adacel and Daptacel are the same vaccine, except that PT and D toxoids have been reduced in Adacel to levels appropriate for adolescent-adult use**
**Household contacts (representing all ages, from infants to older adults) who developed clinical pertussis had PRN and agglutinin titers below the same cut-off level**
**Immunologic correlates of protection from one population have been used routinely to license booster vaccines in a different age group**

## Rationale for Serologic Bridge to Sweden I Efficacy Trial Data

**The VRBPAC meeting of June 5, 1997 was devoted to the question of licensing criteria for adolescent-adult aP vaccines. The committee endorsed licensure based on a serologic bridge to infant efficacy data:**
**Question 1: Can demonstration of efficacy of a given acellular pertussis vaccine administered as a primary series to infants serve as a basis for efficacy of that vaccine when administered as a booster dose to adolescents and adults? ****YES**
**Question 2: Is demonstration of comparable antibody responses in adults/adolescents and infants an appropriate indicator that the different age groups respond to the vaccine in equivalent manners?  ...In other words, can we use antibodies to bridge between the two age groups, as we have done between the primary series and the booster series? ****YES**

## Measuring Immunogenicity 

**Results to be Presented**
**Td506: Comparative trial in adolescents and adults**
**Td505: Lot consistency trial in adolescents**
**Td501: Concomitant Adacel and hepatitis B trial in ****	****adolescents**
**Td502: Concomitant Adacel and influenza trial in adults**

## Td506: Comparative Clinical Trial vs. Td in Adolescents and Adults

**Multicenter, large scale immunogenicity and safety study, 39 US sites, 4461 vaccinees**
**Randomized, modified double blind study; ****age stratified: **
**11-13**
**14-17**
**18-28**
**29-48**
**49-64 years**** **

## Td506: Diphtheria Seroprotection  0.1 IU/mL and Booster Rates

**Adacel Adolescents**

**Td Adolescents**

**Percent **

**20**

**40**

**60**

**80**

**100**

**0**

**Seroprotection ******** 0.1 IU/mL**

**Booster Response Rates**

**Diphtheria - Pre**

**Diphtheria - Post**

**Diphtheria Booster**

| Adacel Adol | 382 of 527, 72.5% | 526 of 527, 99.8% | 501 of 527, 95.1% |
| --- | --- | --- | --- |
| Td Adolescents | 364 of 515, 70.7% | 515 of 516, 99.8% | 489 of 515, 95.0% |

| Adacel Adults | 464 of 741, 62.6% | 697 of 741, 94.1% | 646 of 739, 87.4% |
| --- | --- | --- | --- |
| Td Adults | 321 of 507, 63.3% | 482 of 507, 95.1% | 422 of 506, 83.4% |

**All non-inferiority criteria met**

## Td506: Tetanus Seroprotection  0.1 IU/mL and Booster Rates

| Adacel Adol | 525 of 527, 99.6% | 527 of 527, 100% | 483 of 527, 91.7% |
| --- | --- | --- | --- |
| Td Adolescents | 512 of 516, 99.2% | 516 of 516, 100% | 471 of 516, 91.3% |
| Adacel Adults | 723 of 743, 97.3% | 742 of 742, 100% | 468 of 742, 63.1% |
| Td Adults | 488 of 509, 95.9% | 508 of 509, 99.8% | 340 of 509, 66.8% |

**Adacel Adolescents**

**Td Adolescents**

**Adacel Adults**

**Td Adults**

**Percent **

**20**

**40**

**60**

**80**

**100**

**0**

**Seroprotection ******** 0.1 IU/mL**

**Booster Response Rates**

**Tetanus - Pre**

**Tetanus - Post**

**Tetanus Booster**

**All non-inferiority criteria met**

## Td506: Pertussis Post-Vaccination GMTs, Adolescents, vs. Sweden I

| Adacel | 309.3 | 214.8 | 344.5 | 1792.4 |
| --- | --- | --- | --- | --- |
| Td | 15.6 | 20.9 | 11.7 | 28.8 |

**Adacel Group**

**Td Group**

**0**

**100**

**200**

**300**

**400**

**500**

**600**

**GMT (EU/mL)**

**PT**

**FHA**

**PRN**

**0**

**200**

**400**

**600**

**800**

**1000**

**1200**

**1400**

**1600**

**1800**

**2000**

**FIM**

**GMT (EU/mL)**

| Sweden I | 86.6 | 40.0 | 108.1 | 341.1 |
| --- | --- | --- | --- | --- |

## Td506: Pertussis Post-Vaccination GMTs, Adults, vs. Sweden I

**Adacel Group**

**Td Group**

**Sweden I**

**All non-inferiority criteria met**

**0**

**200**

**400**

**600**

**800**

**1000**

**1200**

**PT**

**FHA**

**PRN**

**FIM**

**0**

**100**

**200**

**300**

**400**

**500**

**600**

**GMT (EU/mL)**

**GMT (EU/mL)**

| Adacel | 178.8 | 192.9 | 341.9 | 852.7 |
| --- | --- | --- | --- | --- |
| Td | 13.2 | 19.3 | 11.7 | 31.7 |
| Sweden I | 86.6 | 40.0 | 108.1 | 341.1 |

## Td506: Immunogenicity Conclusions

**Adacel vaccine is**
**Non-inferior to Td vaccine for diphtheria and tetanus immune responses**
**Highly immunogenic with respect to pertussis responses**
**Non-inferior to Sweden I for pertussis responses**

## Measuring Immunogenicity 

**Results to be Presented**
**Td506: Comparative trial in adolescents and adults**
**Td505: Lot consistency trial in adolescents**
**Td501: Concomitant Adacel and hepatitis B trial in ****	****adolescents**
**Td502: Concomitant Adacel and influenza trial in adults**

## Td505: Lot-Consistency Trial

**Multicenter study, 18 US sites, in 1806 adolescents 11-17 years**
**Age-stratified, randomized, modified double blind study**

## Td505: Diphtheria and Tetanus Seroprotection at  0.1 IU/mL 

| Lot 1 | 269 of 351, 76.6% | 351 of 351, 100% | 345 of 350, 98.6% | 351 of 351, 100% |
| --- | --- | --- | --- | --- |
| Lot 2 | 269 of 350, 76.9% | 347 of 349, 99.4% | 342 of 349, 98% | 350 of 350, 100% |
| Lot 3 | 262 of 355, 73.8% | 352 of 353, 99.7% | 352 of 355, 99.2% | 353 of 353, 100% |

**Percent**

**0**

**20**

**40**

**60**

**80**

**100**

**Diphtheria****Pre **

**Diphtheria****Post**

**Tetanus****Pre**

**Tetanus****Post**

**All equivalency criteria met**

## Td505: Pertussis GMTs Post-Vaccination 

**0**

**500**

**1000**

**1500**

**2000**

**2500**

- Td505: Pertussis GMTs Post-Vaccination

**GMT (EU/mL) **

**0**

**100**

**200**

**300**

**400**

**500**

**PT**

**FHA**

**PRN**

**FIM**

**GMT (EU/mL) **

| Lot 1 | 343.7 | 285.1 | 366.1 | 1901.6 |
| --- | --- | --- | --- | --- |
| Lot 2 | 347.4 | 265 | 394.7 | 2025.4 |
| Lot 3 | 323.9 | 247.8 | 343.2 | 1528.8 |

**Lot 1**

**Lot 2**

**Lot 3**

## Td505: Equivalence of Pertussis GMTs90% CI of Ratios of Lots 

- Td505: Equivalence of Pertussis GMTs90% CI of Ratios of Lots

**0**

**0.5**

**1**

**2**

**1.5**

**0.67**

**Within Limit**

**Outside Limit**

**Outside Limit**

**0.99**

**1.06**

**1.07**

**1.15**

**1.07**

**0.94**

**1.24**

**1.55**

**1.32**

**0.93**

**1.07**

**1.15**

**PT**

**FHA**

**PRN **

**FIM **

## Td505: Pre- and Post-Immunization FIM Titers for 3 Lots of Adacel Vaccine 

- Td505: Pre- and Post-Immunization FIM Titers for 3 Lots of Adacel Vaccine

**Fimbriae (EU/mL)**

**10**

**50**

**60**

**70**

**80**

**90**

**0**

**100**

**20**

**30**

**40**

**1**

**10**

**100**

**1000**

**10,000**

**100,000**

**Percentage of Subjects**

**Adacel 1 (Pre)**

**Adacel 1 (Post)**

**Adacel 2 (Pre)**

**Adacel 3 (Pre)**

**Adacel 2 (Post)**

**Adacel 3 (Post)**

## Td505: Lot Consistency Study Conclusions

**Equivalency demonstrated for: **
**Diphtheria Seroprotection and Booster Rates and GMTs**
**Tetanus Seroprotection and Booster Rates ****and GMTs**
**Pertussis GMTs **
**PT**
**FHA**
**PRN**
**2 of 3 FIM comparisons (third was borderline)**

## Measuring Immunogenicity 

**Results to be Presented**
**Td506: Comparative trial in adolescents and adults**
**Td505: Lot consistency trial in adolescents**
**Td501: Concomitant Adacel and hepatitis B trial in ****	****adolescents**
**Td502: Concomitant Adacel and influenza trial in adults**

## Td501: Co-Administration with HB Vaccine

**Multicenter, randomized, controlled, open-label study in 403 adolescents aged 11-14 years**
**Concomitant Adacel+HB vaccine (n = 202) vs. Adacel, then HB vaccine 1 month later (n = 201)**
**Objective: Demonstrate non-inferiority of simultaneous vs. sequential administration of Adacel and HB vaccine**

## Td501: Adacel and HB, Diphtheria Seroprotection  0.1 IU/mL and Booster Rates 

**Simultaneous**

**Sequential**

| Simultaneous | 126 of 161, 78.3% | 161 of 161, 100% | 157 of 161, 97.5% |
| --- | --- | --- | --- |
| Sequential | 117 of 151, 77.5% | 150 of 151, 99.3% | 145 of 151, 96% |

**Percent **

**0**

**20**

**40**

**60**

**80**

**100**

**Seroprotection ******** 0.1 IU/mL**

**Response Rates**

**Diphtheria - Pre**

**Diphtheria - Post**

**Diphtheria Booster**

**All non-inferiority criteria met**

## Td501: Adacel and HB, Tetanus Seroprotection  0.1 IU/mL and Booster Rates 

- Td501: Adacel and HB, Tetanus Seroprotection  0.1 IU/mL and Booster Rates

**Simultaneous**

**Sequential**

**Tetanus - Pre**

**Tetanus - Post**

**Tetanus Booster**

**All non-inferiority criteria met**

**Seroprotection ******** 0.1 IU/mL**

**Response Rates**

**Percent **

**0**

**20**

**40**

**60**

**80**

**100**

| Simultaneous | 144 of 161, 89.4% | 161 of 161, 100% | 159 of 161, 98.8% |
| --- | --- | --- | --- |
| Sequential | 145 of 151, 96% | 151 of 151, 100% | 148 of 151, 98% |

## Td501: Adacel and HB HB Seroprotection  10 mIU/mL

| Simultaneous | 1 of 161, 0.6% | 155 of 161, 96.3% |
| --- | --- | --- |
| Sequential | 1 of 151, 0.7% | 146 of 150, 97.3% |

**Seroprotection % ******** 10 mIU/mL**

**Simultaneous**

**Sequential**

**Hep B Pre**

**Hep B Post**

**0**

**20**

**40**

**60**

**80**

**100**

**Percent **

**All non-inferiority criteria met**

## Td501: Adacel and HB, Pertussis GMTs

**0**

**50**

**100**

**150**

**200**

**250**

**300**

**350**

**PT**

**FHA**

**PRN**

**FIM**

**GMT (EU/mL)**

**0**

**500**

**1000**

**1500**

**2000**

**GMT (EU/mL)**

| Simultaneous | 303.5 | 301.5 | 292.9 | 1906.4 |
| --- | --- | --- | --- | --- |
| Sequential | 321.6 | 305.4 | 284.6 | 1926.7 |

**Simultaneous**

**Sequential**

**All non-inferiority criteria met**

## Td501: Co-Administration with HBImmunogenicity Conclusions

**Adacel may be administered concomitantly with hepatitis B vaccine**
**Simultaneous and sequential vaccination resulted in comparable immune responses for:**
**Diphtheria and Tetanus**
**Pertussis**
**Hepatitis B**

## Measuring Immunogenicity 

**Results to be Presented**
**Td506: Comparative trial in adolescents and adults**
**Td505: Lot consistency trial in adolescents**
**Td501: Concomitant Adacel and hepatitis B trial in ****	****adolescents**
**Td502: Concomitant Adacel and influenza trial in adults**

## Td502: Co-Administration with Flu Vaccine

**Multicenter, randomized, controlled, open label study in 696 adults aged 19-64 years**
**Concomitant Adacel+Fluzone (n = 356) vs. Fluzone, then Adacel 1 month later (n = 340)**
**Objective: Demonstrate non-inferiority of simultaneous vs. sequential administration of Adacel and Fluzone**

## Td502: Adacel and Fluzone, Diphtheria Seroprotection  0.1 IU/mL and Booster Rates

| Simultaneous | 129 of 354, 36.4% | 305 of 354, 86.2% | 308 of 354, 87.0% |
| --- | --- | --- | --- |
| Sequential | 105 of 323, 32.5% | 282 of 324, 87.0% | 281 of 323, 87.0% |

**Simultaneous**

**Sequential**

**Diphtheria - Pre**

**Diphtheria - Post**

**Diphtheria**
**Booster**

**Percent **

**0**

**20**

**40**

**60**

**80**

**100**

**All non-inferiority criteria met**

**Seroprotection ******** 0.1 IU/mL**

**Response Rates**

## Td502: Adacel and Fluzone, Tetanus Seroprotection  0.1 IU/mL and Booster Rates

**Simultaneous**

**Sequential**

**Tetanus - Pre**

**Tetanus - Post**

**Tetanus**
**Booster**

**Percent **

**Seroprotection ******** 0.1 IU/mL**

**Response Rates**

| Simultaneous | 316 of 353, 89.5% | 353 of 354, 99.7% | 278 of 353, 78.8% |
| --- | --- | --- | --- |
| Sequential | 278 of 323, 86.1% | 318 of 324, 98.1% | 269 of 323, 83.3% |

**0**

**20**

**40**

**60**

**80**

**100**

## Td502: Adacel and Fluzone, HAI Titers %  1:40

**Simultaneous**

**Sequential**

**A/Panama H3N2**

**A/New Caledonia H1N1**

**B/Yamanashi**

**Pre**

**Post**

**Pre**

**Post**

**Pre**

**Post**

**Percent **

**0**

**20**

**40**

**60**

**80**

**100**

| Simultaneous | 90 of 341, 26.4% | 295 of 341, 86.5% | 12 of 341, 3.5% | 184 of 341, 54.0% | 71 of 341, 20.8% | 275 of 341, 80.6% |
| --- | --- | --- | --- | --- | --- | --- |
| Sequential | 61 of 294, 20.7% | 261 of 294, 88.8% | 10 of 294, 3.4% | 138 of 294, 46.9% | 58 of 297, 19.5% | 273 of 295, 80.3% |

**All non-inferiority criteria met**

## Td502: Adacel and Fluzone, Pertussis GMTs

- Td502: Adacel and Fluzone, Pertussis GMTs

**0**

**50**

**100**

**150**

**200**

**250**

**300**

**PT**

**FHA**

**PRN**

**FIM**

**GMT (EU/mL)**

**0**

**200**

**400**

**600**

**800**

**1000**

**1200**

**GMT (EU/mL)**

| Simultaneous | 186.4 | 200.6 | 191.7 |   925.8 |
| --- | --- | --- | --- | --- |
| Sequential | 234.5 | 242.2 | 260.3 | 1136.3 |

| Sweden I |  86.6 |   40.0 | 108.1 |   341.1 |
| --- | --- | --- | --- | --- |

## Td502: Simultaneous vs. SequentialAdacel and Influenza Vaccine Conclusions 

**Simultaneous and sequential vaccination resulted in comparable immune responses for:**
**Diphtheria and tetanus**
**Influenza (all 3 strains)**
**Pertussis responses were somewhat reduced with concomitant influenza vaccine, but pertussis GMTs markedly exceeded those from Sweden I**
**Adacel can be administered concomitantly with influenza vaccine**

## PT Antibody Responses in Adolescents:Sweden I vs. Td501, Td505, and Td506

- PT Antibody Responses in Adolescents:Sweden I vs. Td501, Td505, and Td506

**Percentage of Subjects**

**PT (EU/mL)**

**100**

**1**

**10**

**100**

**1000**

**10,000**

**100,000**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**0**

## FHA Antibody Responses in Adolescents:Sweden I vs. Td501, Td505, and Td506

- FHA Antibody Responses in Adolescents:Sweden I vs. Td501, Td505, and Td506

**FHA (EU/mL)**

**100**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**0**

**1**

**10**

**100**

**1000**

**10,000**

**100,000**

**Percentage of Subjects**

**FHA**

**Sweden I**

**Adacel Td501**** **

**Adacel Td505**

**Adacel Td506**

## PRN Antibody Responses in Adolescents:Sweden I vs. Td501, Td505, and Td506

- PRN Antibody Responses in Adolescents:Sweden I vs. Td501, Td505, and Td506

**PRN (EU/mL)**

**100**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**0**

**1**

**10**

**100**

**1000**

**10,000**

**100,000**

**Percentage of Subjects**

## FIM Antibody Responses in Adolescents:Sweden I vs. Td501, Td505, and Td506

- FIM Antibody Responses in Adolescents:Sweden I vs. Td501, Td505, and Td506

**FIM (EU/mL)**

**100**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**0**

**1**

**10**

**100**

**1000**

**10,000**

**100,000**

**Percentage of Subjects**

**FIM**

**Sweden I**

**Adacel Td501**** **

**Adacel Td505**

**Adacel Td506**

## PT Antibody Responses in Adults:Sweden I vs. Td502 and Td506

- PT Antibody Responses in Adults:Sweden I vs. Td502 and Td506

**Percentage of Subjects**

**PT (EU/mL)**

**100**

**1**

**10**

**100**

**1000**

**10,000**

**100,000**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**0**

## FHA Antibody Responses in Adults:Sweden I vs. Td502 and Td506

- FHA Antibody Responses in Adults:Sweden I vs. Td502 and Td506

**FHA (EU/mL)**

**Percentage of Subjects**

**100**

**1**

**10**

**100**

**1000**

**10,000**

**100,000**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**0**

## PRN Antibody Responses in Adults:Sweden I vs. Td502 and Td506

- PRN Antibody Responses in Adults:Sweden I vs. Td502 and Td506

**Percentage of Subjects**

**100**

**1**

**10**

**100**

**1000**

**10,000**

**100,000**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**0**

**PRN (EU/mL)**

## FIM Antibody Responses in Adults:Sweden I vs. Td502 and Td506

- FIM Antibody Responses in Adults:Sweden I vs. Td502 and Td506

**Percentage of Subjects**

**100**

**1**

**10**

**100**

**1000**

**10,000**

**100,000**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**0**

**FIM (EU/mL)**

## Canadian Licensure Trials of Adacel

**Subset populations from the 3 preceeding studies were evaluated for immunogenicity at 1, 3, and 5 years following receipt of Adacel**
**Safety data were submitted in support of ****US licensure**

**TC9704: Evaluation in adolescents and adults of Adacel vs. Td; evaluation of lot consistency**
**Td9707: Evaluation in adults of Adacel vs. Td**
**Td9805: Evaluation in young adolescents of concomitant Adacel and hepatitis B**

## Adacel: Key Immunogenicity Findings

**Adacel stimulated robust antibody responses to all included antigens**
**Adacel achieved all pre-specified non-inferiority criteria for immunogenicity vs. Td**
**Pertussis antibody levels in adolescents and adults following one dose of Adacel exceeded levels seen in infants following three doses of Daptacel ****(which were associated with 85% efficacy against WHO-defined pertussis)**
**Adacel can be given concomitantly with HB vaccine or influenza vaccine**

## Adacel - Agenda

**Introduction****	****Luc Kuykens, MD, MPH****	****VP Regulatory Affairs**
**Pertussis Epidemiology****	****David Johnson, MD, MPH****	****Director Scientific and Medical Affairs**** **
**Immunogenicity ****	****Michael Decker, MD, MPH**
**	****	****VP Scientific and Medical Affairs**
**Safety and Conclusion****	****Luc Kuykens, MD, MPH**
**	****	****VP Regulatory Affairs**

## Safety Objectives

**To compare safety profile of Adacel to ****safety profile of Td**
**Demonstrate that rates of selected solicited local ****and systemic reactions reported by Adacel and Td recipients are comparable **
**To characterize overall safety profile of Adacel given separately or simultaneously with HB or influenza vaccine**

## Presentation Outline and Safety Data Collection

**Immediate Reactions **
**30 minutes post vaccination**
**Solicited Local and Systemic Reactions**
**Unsolicited Adverse Events**
**Events of Special Interest**
**Serious Adverse Events**

## Immediate Reactions: Adolescents and Adults

|  | Adacel
N = 5841 |  | Td Vaccine
N = 1365 |  |
| --- | --- | --- | --- | --- |
|  | n | % | n | % |
| Total participants with at least one reaction | 32 | 0.55 | 6 | 0.44 |
| Most frequently reported events: |  |  |  |  |
| 	Dizziness | 6 | 0.10 | 1 | 0.07 |
| 	Hypoaesthesia  | 3 | 0.05 | 1 | 0.07 |
| 	Paraesthesia | 2 | 0.03 | 1 | 0.07 |
| 	Vasovagal attack | 2 | 0.03 | 2 | 0.15 |
| 	Pain in limb | 2 | 0.03 | 0 | 0.0 |
| 	Injection site bruising | 2 | 0.03 | 0 | 0.0 |
| 	Injection site erythema | 3 | 0.05 | 0 | 0.0 |
| 	Syncope | 3 | 0.05 | 2 | 0.15 |
| 	Injection site pain | 1 | 0.02 | 0 | 0.0 |
| 	Dyspepsia, Nausea, Vomiting | 3 | 0.05 | 0 | 0.0 |
| 	Other | 13 | 0.22 | 1 | 0.07 |

## Presentation Outline and Safety Data Collection

**Immediate Reactions **
**Solicited Local ****and Systemic**** Reactions**
**Erythema, swelling, pain, underarm lymph node swelling, ****and limb circumference, collected on diary card day 0 - 14, ****severity documented**
**Unsolicited Adverse Events**
**Events of Special Interest**
**Serious Adverse Events**

## Td506: Solicited Local ReactionsSafety Hypothesis

**any erythema, swelling or pain, and with**
**moderate and severe erythema, swelling or pain reported during Day 0 through Day 14.**

_**Non-inferiority criteria:**_**Upper limit of the two-sided ****95% Cl of the difference *****p******Adacel***** – *****p******Td***** < 10%**

**Adacel is non-inferior to Td in the proportion of adolescents and adults with:**

## Td506: Solicited Local Reactions, Days 0-14 Adolescents

**Adacel**

**Td**

**Adacel**

**Td**

**Adacel**

**Td**

**Erythema**

**Swelling**

**Pain**

**Percent**

**0**

**20**

**40**

**60**

**80**

**100**

## Td506: Non-Inferiority of Solicited Local Reactions, Days 0-14 Adolescents, 95% CI of Difference (Adacel minus Td)

- Td506: Non-Inferiority of Solicited Local Reactions, Days 0-14 Adolescents, 95% CI of Difference (Adacel minus Td)

**-15**

**-10**

**-5**

**0**

**5**

**10**

**15**

**Erythema**

**Pain**

**Swelling**

**Within Limit**

**Outside****Limit**

## Td506: Solicited Local Reactions, Days 0-14 Adults

**Adacel**

**Td**

**Adacel**

**Td**

**Adacel**

**Td**

**Erythema**

**Swelling**

**Pain**

**Percent**

**0**

**20**

**40**

**60**

**80**

**100**

## Td506: Non-Inferiority of Solicited Local Reactions, Days 0-14 Adults, 95% CI of Difference (Adacel minus Td)

- Td506: Non-Inferiority of Solicited Local Reactions, Days 0-14 Adults, 95% CI of Difference (Adacel minus Td)

**-15**

**-10**

**-5**

**0**

**5**

**10**

**15**

**Within Limit**

**Outside****Limit**

**Erythema**

**Pain**

**Swelling**

## Erythema Rates, Days 0-14Adolescents

**Percent**

**Td506**

**Td505**

**Td501**

**Adacel**

**Td**

**Adacel**

**Adacel +****HB**

**Adacel,****HB**

**0**

**20**

**40**

**60**

**80**

**100**

## Swelling Rates, Days 0-14Adolescents

**Percent**

**Adacel**

**Td**

**Adacel**

**Adacel +****HB**

**Adacel,****HB**

**Td506**

**Td505**

**Td501**

**0**

**20**

**40**

**60**

**80**

**100**

## Pain Rates, Days 0-14Adolescents

**Percent**

**Adacel**

**Td**

**Adacel +****HB**

**Adacel,****HB**

**Td506**

**Td501**

**0**

**20**

**40**

**60**

**80**

**100**

**Adacel**

**Td505**

## Erythema Rates, Days 0-14Adults

**Td506**

**Td502**

**Percent**

**Adacel**

**Td**

**Flu, Adacel**

**Adacel + Flu**

**0**

**20**

**40**

**60**

**80**

**100**

## Swelling Rates, Days 0-14Adults

**Percent**

**Adacel**

**Td**

**Td506**

**Td502**

**Flu, Adacel**

**Adacel + Flu**

**0**

**20**

**40**

**60**

**80**

**100**

## Pain Rates, Days 0-14Adults

**Percent**

**Adacel**

**Td**

**Adacel + Flu**

**Td506**

**Td502**

**Flu, Adacel**

**0**

**20**

**40**

**60**

**80**

**100**

## Other Solicited Local Reactions

**Limb circumference**
**Mean baseline limb circumference in Td506**
**Adolescents: 26.4 cm**
**Adults: 31.7 cm**
**No difference in mean change observed in Td506 between Adacel and Td recipients**
**Adolescents 1.25 cm vs. 1.35 cm**
**Adults 1.51 cm vs. 1.29 cm**

## Td506: Increase in Limb Circumference After Vaccination With Adacel vs. Td, Days 0-14, in Adolescents

**% With Indicated Maximum Increase**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**Adacel**

**Td**

## Td506: Increase in Limb Circumference After Vaccination With Adacel vs. Td, Days 0-14, in Adults

**% With Indicated Maximum Increase**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**Adacel**

**Td**

## Other Solicited Local Reactions

**Underarm Lymph Node swelling**
**No difference observed in Td506 between ****Adacel and Td recipients **
**Adolescents 6.64% vs. 5.34%**
**Adults 6.48% vs. 4.10%**
**Similar rates reported across three other studies  **
**Adolescents 6.64% - 8.96%**
**Adults 3.83% - 6.48%**

## Presentation Outline and Safety Data Collection

**Immediate Reactions **
**Solicited ****Local and**** Systemic Reactions**
**Fever, headache, tiredness, generalized body ache, chills, nausea, vomiting, diarrhea, sore and/or swollen joints, and rash, collected on diary card day 0 - 14, severity documented **
**Unsolicited Adverse Events**
**Events of Special Interest**
**Serious Adverse Events**

## Td506: Fever, Days 0-14Adolescents and Adults

- Td506: Fever, Days 0-14Adolescents and Adults

**Percent**

**Adacel**

**Td**

**Adacel**

**Td**

**Adolescents**

**Adults**

**0**

**20**

**15**

**10**

**5**

## Td506: Fever, Non-Inferiority of Rates, Days 0-14 95% CI of Difference (Adacel minus Td)

- Td506: Fever, Non-Inferiority of Rates, Days 0-14 95% CI of Difference (Adacel minus Td)

**Adults**

**-15**

**-10**

**-5**

**0**

**5**

**10**

**15**

**Within Limit**

**Outside****Limit**

## Fever Rates, Days 0-14Adolescents

- Fever Rates, Days 0-14Adolescents

**Percent**

**Adacel**

**Td**

**Adacel**

**Adacel +****HB**

**Adacel,****HB**

**0**

**20**

**15**

**10**

**5**

**Td506**

**Td505**

**Td501**

## Fever Rates, Days 0-14Adults

- Fever Rates, Days 0-14Adults

**Percent**

**Adacel**

**Td**

**Adacel + Flu**

**Flu, Adacel**

**Mild          **

**Moderate          **

**Severe**

**Td506**

**Td502**

**0**

**20**

**15**

**10**

**5**

## Td506: ‘Any’ Systemic Reaction Profile Adolescents 

|  | AdacelN = 1184% | Td VaccineN = 792% |
| --- | --- | --- |
| Total participants with any systemic reaction | 65.5 | 61.0 |
| Headache | 43.7 | 40.4 |
| Tiredness | 30.2 | 27.3 |
| Bodyache | 30.4 | 29.9 |
| Chills | 15.1 | 12.6 |
| Nausea | 13.3 | 12.3 |
| Diarrhea | 10.3 | 10.2 |
| Sore/Swollen Joints | 11.3 | 11.7 |
| Vomiting |   4.6 |   2.8 |
| Rash |   2.7 |   2.0 |

## Td506: ‘Any’ Systemic Reaction Profile Adults

|  | AdacelN = 1752% | Td VaccineN = 573% |
| --- | --- | --- |
| Total participants with any systemic reaction | 50.3 | 47.6 |
| Headache | 33.9 | 34.1 |
| Tiredness | 24.3 | 20.7 |
| Bodyache | 21.9 | 18.8 |
| Chills |   8.1 |   6.6 |
| Nausea |   9.2 |   7.9 |
| Diarrhea | 10.3 | 11.3 |
| Sore/Swollen Joints |   9.1 |   7.0 |
| Vomiting |   3.0 |   1.8 |
| Rash |   2.0 |   2.3 |

## Presentation Outline and Safety Data Collection

**Immediate Reactions**
**Solicited Local and Systemic Reactions**
**Unsolicited Adverse Events and Unsolicited ****Adverse Events Requiring Medical Contact**
**Collected from days 0 to 14 and day 15 to end of study, respectively, following Adacel or Td vaccination**
**Events of Special Interest**
**Serious Adverse Events**

## All Studies: Unsolicited Adverse Events Reported by ≥ 1% of Participants/Group During Days 0-28 Post-Vaccination, ITTS Population - Adolescents 

| Adverse Event | Adacel
N = 3393% | Td Vaccine
N = 792% |
| --- | --- | --- |
| Total Participants with any unsolicited AEs | 24.0 | 25.6 |
| Nasopharyngitis | 3.24 | 4.29 |
| Pharyngitis | 3.18 | 3.54 |
| Cough | 2.18 | 2.53 |
| Nasal congestion | 1.68 | 0.88 |
| Upper respiratory tract infection nos | 1.00 | 1.39 |
| Dysmenorrhoea | 0.85 | 1.14 |
| Sinusitis nos | 0.68 | 1.26 |
| Limb injury nos | 0.32 | 1.01 |

## All Studies: Unsolicited Adverse Events Reported by ≥ 1% of Participants/Group During Days 0-28 Post-Vaccination, ITTS Population - Adults

| Adverse Event | Adacel
N = 2448% | Td VaccineN = 573% |
| --- | --- | --- |
| Total Participants with any unsolicited AEs | 24.6 | 20.9 |
| Nasopharyngitis | 3.31 | 1.92 |
| Pharyngitis | 2.37 | 1.22 |
| Cough | 1.43 | 1.05 |
| Back pain | 1.14 | 0.87 |
| Upper respiratory tract infection nos | 1.10 | 0.87 |
| Sinusitis nos | 1.06 | 0.52 |
| Dysmenorrhoea | 0.94 | 1.05 |
| Pain in limb | 0.65 | 1.22 |
| Arthralgia | 0.49 | 1.05 |

## Presentation Outline and Safety Data Collection

**Immediate Reactions**
**Solicited Local and Systemic Reactions**
**Unsolicited Adverse Events and Unsolicited ****Adverse Events Requiring Medical Contact**
**Events of Special Interest**
**Whole Arm Swelling, Diabetes, Seizures and ****Autoimmune Disorders**
**Collected for entire study period (Td506- 6 months, ****Td505- 1 month, Td501- 5 or 6 months, Td502- 1 or 2 months)**
**Serious Adverse Events**

## New Onset Diabetes Mellitus, Seizures and Autoimmune Disorders

**Two reports of new onset DM**
**One adolescent with a family history of IDDM **
**One adult with NIDDM discovered during an hospitalization for a trauma**
**Three reports of seizures **
**Two adolescents, one each after Adacel and Td vaccination, both with a history of seizure disorder **
**One adult with a history of migraines and hypertension**
**All events resolved without sequelae and were considered as not related to vaccination by ****the investigator**
**There were no reports of autoimmune disorders from the US licensure trials**

## Whole Arm Swelling

**There were no reports of whole arm swelling from the US licensure trials**
**There was no other evidence that whole arm swelling occurred**
**15 (0.26%) of 5841 Adacel recipients and 2 (0.15%) ****of 1365 Td recipients had injection site swelling ******** 100mm days 0-14**
**Of the 5 subjects with injection site swelling ******** 150mm days 0-14, none had an increase in ****limb circumference ******** 2cm**

## Presentation Outline and Safety Data Collection

**Immediate Reactions**
**Solicited Local and Systemic Reactions**
**Unsolicited Adverse Events and Unsolicited ****Adverse Events Requiring Medical Contact**
**Events of Special Interest**
**Serious Adverse Events**
**Collected for entire study period (Td506- 6 months, Td505- ****1 month, Td501- 5 or 6 months, Td502- 1 or 2 months)**

## SAEs: All Trials, Day 0 up to 6 Months, Adolescents and Adults

**Total participants reporting SAEs**
**Adacel - 52 of 5841 (0.89%)**
**Td vaccine - 19 of 1365 (1.39%)**
**All except two reported as unrelated ****to study vaccine**
**23 y/o female hospitalized for severe migraine and temporary unilateral palsy one day after vaccination, lasting 3 days, recovered without sequelae**
**49 y/o female developed radicular pain in the left upper arm 12 days post vaccination, recovered without sequelae**

## Deaths

**One death was reported across the 4 studies, ****in Td505**
**15 year old female committed suicide, ****70 days after receiving Adacel**
**Classified by investigator as unrelated ****to study vaccine**

## Adacel - Agenda

**Introduction****	****Luc Kuykens, MD, MPH****	****VP Regulatory Affairs**
**Pertussis Epidemiology****	****David Johnson, MD, MPH****	****Director Scientific and Medical Affairs**** **
**Immunogenicity ****	****Michael Decker, MD, ****	****MPH ****	****VP Scientific and Medical Affairs**
**Safety and Conclusion ****	****Luc Kuykens, MD, MPH**
**	****VP Regulatory Affairs**

## Safety

**Adacel was safe and well tolerated among adolescents and adults**
**Adacel achieved all safety non-inferiority endpoints in the primary comparative trial ****vs. Td, except for any pain in adolescents **
**Adacel can be safely administered either concomitantly or sequentially with hepatitis B vaccine or influenza vaccine**

## Immunogenicity

**Adacel achieved all pre-specified non-inferiority criteria for immunogenicity vs. Td**
**Pertussis antibody levels in adolescents and adults following one dose of Adacel exceeded levels ****seen in infants following three doses of Daptacel ****(which were associated with 85% efficacy against ****WHO-defined pertussis)**
**Adacel can be given concomitantly with hepatitis B vaccine or influenza vaccine**

## Risk / Benefit

**Risks**
**Slight increase in reactogenicity in adolescents compared to Td **
**Benefits**
**Adacel provides tetanus and diphtheria immunogenicity similar to current standard of care, Td**
**Added protection against pertussis in adolescents ****and adults**
**Potential to reduce pertussis disease in general population and prevent transmission of pertussis from adolescents and adults to infants**

## ADACELTM

**Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed**

**sanofi pasteur**

**Vaccine and Related Biological Products Advisory Committee**
**March 15, 2005**