# Presentation: 823972

## Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed(Tdap, ADACELTM)Aventis Pasteur, Ltd.

**VRBPAC – March 15, 2005**
**ChrisAnna M. Mink, M.D.**
**FDA/OVRR/DVRPA**

## Composition of Study Vaccines

| 
Component | ADACEL
(Tdap) | DAPTACEL1
(DTaP) | Td2 |
| --- | --- | --- | --- |
| Tetanus toxoid | 5Lf | 5 Lf | 5 Lf |
| Diphtheria toxoid | 2 Lf | 15 Lf | 2 Lf |
| PT | 2.5 ug | 10 ug | - |
| FHA | 5 ug | 5 ug | - |
| PRN | 3 ug | 3 ug | - |
| FIM 2/3 | 5 ug | 5 ug | - |
| Aluminum3 | 0.33 mg  | 0.33 mg | 0.33mg |
| Thimerosal | - | - | 0.01% |

- 1DTaP – licensed in U.S. for first 4 doses of primary series; evaluated in Sweden I
- 2Td – manufactured by Aventis Pasteur Inc, U.S. (API)
- 3Aluminum as AlPO4

## Indication Sought

**ADACELTM is indicated for the active immunization for the prevention of diphtheria, tetanus and pertussis in adolescents and adults aged 11 through 64 years as a booster. **
**The dosing schedule is one dose administered intramuscularly (IM).**

## Tdap Trials Submitted to the BLA

**Pivotal**
**Td506 – Comparative study**
** ****Serology Bridge for Efficacy (lab study)**
**Td505 – Lot consistency**
**Non-Pivotal**** (Concomitant immunizations)**
**Td502 – Tdap with influenza vaccine**
**Td501 – Tdap with hepatitis B vaccine**
**Historical Trials**** – 3 abbreviated reports**
**Safety Database****  = 6803 Tdap recipients**

## Pivotal Trial – Td506

**Phase 3, randomized, observer-blinded, controlled trial comparing Tdap (ADACELTM) with Td in adolescents and adults 11-64 years of age **
**No diphtheria-tetanus-pertussis containing vaccines in previous 5 years**
**Stratified within age groups **
**Tdap : Td  ****	****3:2 for 11-17yr  **
**	****	****	****	****3:1 for 18-64yr **
**One 0.5 mL IM dose of Tdap or Td **

## Pivotal Trial – Td506

**Monitoring**
**Immunogenicity **
**Randomly selected subset in each age strata**
** ****Serum - pre-vac and post-vac (35 **_**+**_** 7 days)**
**Safety**** **
**Immediate adverse events (AEs) – 30 min**
**Solicited AEs – diary card x 14 days **
**SAEs, new onset medical conditions – 6 mo**

## Td506 - Objectives

**Tdap vs. Td**** **
**To compare safety **
**To assess the immune responses to diphtheria (dip) and tetanus (tet)**
**Tdap vs. DTaP (DAPTACEL®)**** **
**To compare the immune response to pertussis antigens**
** **
**Separate assessments for adolescents**
**(11-17 yrs) and adults (18-64 yrs)**

## Td506 Results: Enrollment

|  | Vaccine Group |  |  |
| --- | --- | --- | --- |
| 
Population | Tdap
N | Td
N | Total
N |
| Adolescents
(11-17 years) | 1225 | 818 | 2053 |
| Adults
(18-64 years) | 1807 | 600 | 2427 |
| Total
(11-64 years) | 3032 | 1418 | 4480* |

*** 19 were not vaccinated**

## Td506 Results: Populations

**Demographic characteristics**** **
**Similar for Tdap and Td groups**
**Populations for analysis**
**Intent-to-treat, safety (ITTS) – all randomized and received study vaccine (Tdap or Td)**
**ITT, Immunogenicity (ITTI) – randomized, vaccinated and bled**
**Per-Protocol Immunogenicity (PPI) – ITTI subset with no major protocol violations**

## Td506: Endpoints - Dip and Tet Immune Responses

- Tdap vs. Td, % of subjects achieving response non-inferior if lower limit (LL) of 2-sided 95% CI of the difference () in rates is > -10%
- Seroprotective levels
- Defined _>_ 0.1 IU/mL
- Booster responses
- Defined as 4-fold rise if pre-vac level below cut-off and 2-fold rise if above the cut-off level (2.56 IU/mL for dip and 2.7 IU/mL for tet)

## Td506 Results: Dip and TetSeroprotective Levels in Adolescents

|  | Tdap
N=527
% | Td
N=516
% | 

Diff % (95% CI) |
| --- | --- | --- | --- |
| Diphtheria |  |  |  |
|  > 0.1 IU/mL (pre) | 72.5 | 70.7 | 1.8 (-3.7, 7.3) |
| > 0.1 IU/mL (post) | 99.8 | 99.8 | 0.0 (-0.5, 0.5) |
| > 1.0 IU/mL (pre) | 15.7 | 17.3 | -1.5 (-6.0, 3.0) |
| > 1.0 IU/mL (post) | 98.7 | 98.4 | 0.3 (-1.2, 1.7) |
| Tetanus |  |  |  |
|  > 0.1 IU/mL (pre) | 99.6 | 99.2 | 0.4 (-0.5, 1.3) |
| > 0.1 IU/mL (post) | 100 | 100 | 0.0 (0.0, 0.0) |
| > 1.0 IU/mL (pre) | 44.6 | 43.8 | 0.8 (-5.2, 6.8) |
| > 1.0 IU/mL (post) | 99.6 | 99.4 | 0.2 (-0.6, 1.0) |

## Td506 Results: Dip and TetSeroprotective Levels in Adults

|  | Tdap
N=741
% | Td
N=506
% | 

Diff % (95% CI) |
| --- | --- | --- | --- |
| Diphtheria |  |  |  |
|  > 0.1 IU/mL (pre) | 62.6 | 63.3 | -0.70 (-6.2, 4.8) |
| > 0.1 IU/mL (post) | 94.1 | 95.1 | -1.0 (-3.6, 1.5) |
| > 1.0 IU/mL (pre) | 14.3 | 16.0 | -1.7 (-5.7, 2.4) |
| > 1.0 IU/mL (post) | 78.0 | 79.9 | -0.9 (-3.5, 1.7) |
| Tetanus |  |  |  |
|  > 0.1 IU/mL (pre) | 97.3 | 95.9 | 1.4 (-0.7, 3.5) |
| > 0.1 IU/mL (post) | 100 | 99.8 | 0.2 (-0.2, 0.6) |
| > 1.0 IU/mL (pre) | 73.0 | 70.3 | 2.7 (-2.5, 7.7) |
| > 1.0 IU/mL (post) | 97.8 | 98.2 | -0.1 (-1.0, 0.8) |

## Td506 Results: Dip and TetBooster Response Rates

|  | Adolescents |  |  | Adults |  |  |
| --- | --- | --- | --- | --- | --- | --- |
| 
Booster
Response* | Tdap
N=527
% | Td
N=516
% | 
Diff %
(95% CI) | Tdap
N=741
% | Td
N=506
% | 
Diff %
(95% CI) |
| Diphtheria | 95.1 | 95.0 | 0.1 
(-2.5, 2.8) | 87.4 | 83.4 | 4.0 
(0.0, 8.0) |
| Tetanus | 91.7 | 91.3 | 0.4 
(-3.0, 3.8) | 63.1 | 66.8 | -3.7 
(-9.0, 1.6) |

***Defined as 4-fold rise if pre-vac level below cut-off and 2-fold rise if above the cut-off level (2.56 IU/mL for dip and 2.7 IU/mL for tet)**

## Td506: Endpoints - Pertussis Immune Responses for Efficacy Bridge 

**Tdap vs. DTaP (DAPTACEL®)**** **
**DTaP ~85% efficacy against *****B. pertussis *****infection with 21 days of paroxysmal cough in Sweden I Efficacy Trial**
**Geometric mean concentrations (GMCs) for each antigen (PT, FHA, PRN and FIM), non-inferior if:**
**LL of 2-sided 95% CI ratio of GMC (Tdap/DTaP) > 0.67**

## Serologic Bridge to Efficacy

**DTaP (DAPTACEL®) Samples from Sweden I**
- 80 of original 181 paired samples available (not randomized)
- Samples obtained pre- and 1 mo post-3rd dose from infants immunized at 2, 4 and 6 mo of age
**Laboratory **
- Assayed concurrently with Tdap samples from adolescents in Td505 using ELISA in 2002 at APL
- Antibody values for comparisons with adolescents _and_ adults in Td506 (primary comparisons for efficacy bridge)

## Tdap and DTaP Pertussis Post-Vaccination GMC*

***GMC = geometric mean concentration (ELISA Units/mL)**
**‡ ****1 month after 3 doses (2, 4 and 6 mo) in Sweden I Efficacy Trial**

|  | Infants | Adolescents |  | Adults |
| --- | --- | --- | --- | --- |
| 
Post GMC | DTaP‡
N=80 | Tdap – 505
N=1053 | Tdap - 506
N=526 | Tdap
N=741 |
|     PT | 86.6 | 338.1 | 309.3 | 178.8 |
|     FHA | 39.9 | 265.5 | 214.8 | 192.9 |
|     FIM | 341.1 | 1804.8 | 1792.4 | 852.7 |
|     PRN | 108.1 | 367.3 | 344.5 | 341.9 |

## Efficacy Bridge: Tdap vs. DTaP Post-Vaccination GMC Ratios

| 

Antigen | Adolescents
Tdap/DTaP
GMC Ratio
(95% CIs) | Adults
Tdap/DTaP
GMC Ratio
(95% CIs) |
| --- | --- | --- |
| PT | 3.6    (2.8, 4.5) | 2.1    (1.6, 2.7) |
| FHA | 5.4    (4.5, 6.5) | 4.8    (3.9, 5.9) |
| FIM | 5.3    (3.9, 7.1) | 2.5    (1.8, 3.5) |
| PRN | 3.2    (2.5, 4.1) | 3.2    (2.6, 4.4) |

**All lower limits of 95% CI for GMC ratios for Tdap/DTaP for adolescents and adults exceeded 0.67 criterion **

## Td506: Endpoints – Pertussis Booster Responses 

**Tdap vs. Historical limits for Tdap**
**Booster Responses - % of subjects achieving booster response compared to acceptable rate for each antigen determined in historical studies, non-inferior if the LL 95% CI > acceptable rate (~80%) **

## Td506 Results: Pertussis Booster Responses

***Rates in historical trials used to define rate for each antigen **
** ****Non-inferiority demonstrated, LL of 95% CIs > acceptable rate for each antigen**

|  | 
Adolescents | 
Adults |  |
| --- | --- | --- | --- |
| 
Antigen  | N=524
% (95% CI) | N=739
% (95% CI) | Pre-defined
Acceptable Rate* |
| PT | 92.0 (89.3, 94.2) | 84.4 (81.6, 87.0) | 81.2 |
| FHA | 85.6 (82.3, 88.4) | 82.7 (79.8, 85.3) | 77.6 |
| FIM | 94.9 (92.6, 96.6) | 95.9 (83.2, 88.4) | 82.4 |
| PRN | 94.5 (92.2, 96.3) | 93.8 (91.8, 95.4) | 86.4 |

## Td506: Endpoints - Safety

**Tdap vs. Td – Safety****   **
**Safety comparisons for erythema, swelling, pain and fever from Days 0-14**
**Rates of events, non-inferior if upper limit (UL) of 2-sided 95% CI ******** < 10%**

## Td506: Safety EndpointComparisons in Adolescents

|  | Adolescents |  |  |
| --- | --- | --- | --- |
| 
“Any” Intensity
Solicited AEs (Days 0-14) | Tdap
N=1175
% | Td
N=787
% | 

Diff % (95% CI) |
| Erythema | 20.8 | 19.7 | 1.1 (-2.6, 4.7) |
| Swelling | 20.7 | 18.3 | 2.6 (-0.9, 6.2) |
| Pain | 77.8 | 71.0 | 6.8 (2.8, 10.7) |
| Fever (> 38oC/100.4oF) | 4.9 | 2.7 | 2.2 (0.6, 3.9) |

**Non-inferiority was demonstrated for all comparisons, except pain**

## Td506: Safety EndpointComparisons in Adults

|  | Adults |  |  |
| --- | --- | --- | --- |
| “Any” Intensity
Solicited AEs 
(Days 0-14) | Tdap
N=1698
% | Td
N=561
% | 

Diff % (95% CI) |
| Erythema | 24.7 | 21.6 | 3.2 (-0.8, 7.1) |
| Swelling | 21.0 | 17.3 | 3.7 (0.0, 7.4) |
| Pain | 65.7 | 62.9 | 2.7 (-1.9, 7.3) |
| Fever (> 38oC/100.4oF) | 1.4 | 1.1 | 0.3 (-0.7, 1.4) |

**Non-inferiority was demonstrated for all comparisons**

## Td506 Results: Safety Overview

|  | Adolescents |  | Adults |  |
| --- | --- | --- | --- | --- |
| 
Safety Event | Tdap
N=1175
% | Td
N=792
% | Tdap
N=1752
% | Td
N=573
% |
| Immediate AEs | 0.5 | 0.6 | 0.2 | 0.2 |
| Any Local AEs1 
Day 0-14 | 80.4 | 74.0 | 68.4 | 67.0 |
| Any Systemic AEs2 
Day 0-14 | 65.5 | 61.0 | 50.3 | 47.6 |
| SAEs | 0.9 | 1.0 | 1.9 | 1.9 |

**1 ****Local AE – pain, swelling, erythema; axillary node swelling**
**2 ****Systemic – fever, chills, headache, nausea, vomiting, bodyache, ****	****	****       lethargy, rash, sore/swollen joints**

## Td506 Results: Safety 

- Immediate AEs – no anaphylaxis events
- Solicited systemic AE rates similar in Tdap and Td groups
- Sore/swollen joints reported by ~11.5% Tdap and Td adolescent groups; 9.1% in Tdap and 7% in Td adult groups
- Unsolicited AEs (Days 0-28) – no pattern
- Trend for higher rate of local AEs in Tdap and Td vaccinees in young adolescents (11-14 yrs)

## Td506 Results: Safety

- SAEs
- 83 events in 63 participants
- Rate of 1.5% in both Tdap and Td groups
- No deaths reported
- 2 neuropathic events in adults
- 1 day post-Tdap, 26yo female hospitalized for migraine and unilateral facial paralysis; ↑BP (160/100) at time of vaccination
- 12 days post-Tdap, 49yo female hospitalized for dysasthesia in neck and left arm; evaluated for myocardial infarction and diagnosed as “nerve compression”

## Td506 – Trial Summary

**Safety and immunogenicity endpoints were met for both adolescents and adults:**
**Safety**
**Non-inferiority was demonstrated for AE rates after ADACELTM as compared to AE rates after Td (except “any” pain in adolescents)**

## Td506 – Trial Summary, cont.

**Immunogenicity for dip and tet**
**Non-inferiority was demonstrated for dip and tet following ADACELTM as compared to Td for:**
**Seroprotective rates**
**Booster responses **

## Td506 – Trial Summary, cont.

**Immunogenicity for pertussis antigens**
**Non-inferiority was demonstrated for the immune responses to the pertussis antigens following ADACELTM as compared to the immune responses following 3 doses of DAPTACEL® in infants in the Sweden I Efficacy Trial **
**Booster responses demonstrated**

## Pivotal Trial – Td505 Lot Consistency Study

**Phase 3, randomized, double-blind trial to assess the lot consistency of 3 consecutively produced lots of Tdap, as measured by safety and immunogenicity, when given as a booster to 11-17 year olds**
**99.9% had documented 5 previous doses of dip, tet and pertussis-containing vaccine**
**Received 0.5mL IM dose of one of 3 lots of Tdap**
**Assessments for safety and immunogenicity were performed similar to Td506 (except no 6 mo check)**

## Td505: Endpoints – Immunogenicity

**Immunogenicity  - Consistency demonstrated (equivalence testing) if:**
**Dip and tet – 2-sided 95% CI of difference in seroprotection rates and booster rates between any 2 lots were within interval    (-10%, 10%)**
**Pertussis antigens – 2-sided 90% CI for the ratio of GMCs for any 2 lots within interval (0.67, 1.5)**

## Td505: Results

**Enrolled N=1811 (~equal in each lot)**
**Demographic characteristics similar for each lot**
**Lot consistency demonstrated**
**Immunogenicity - similar results for each of the 3 lots for dip, tet and pertussis responses; similar to Td506 adolescents**

## Td505: Safety Endpoints and Results

**Safety**
**Erythema, swelling, pain and fever from Days 0-14 for “any” or “moderate & severe”, equivalence testing**
**Safety evaluations ******** contributed to safety database**
**Results similar between lots and similar to adolescents in Td506 **
**No anaphylaxis events **
**4 SAEs, not vaccine related**

## Td505 Summary

**Consistency of manufacturing of 3 production lots was demonstrated**
**Contributed ~1800 adolescents to the safety database of the BLA**
**Serum samples were assayed at the same time as Sweden I trial samples (Serology Bridging Study)**

## Td502 – Concomitant Study of ADACELTM and Influenza Vaccine

- Open-labeled, randomized, controlled trial of the safety and immunogenicity of Tdap and influenza vaccines when given concurrently or separately in adults, 19-64 years of age
- Group A – Tdap and Flu concurrently (Tdap+flu)
- Group B – Flu then Tdap 4-6 weeks later (flu, Tdap)
- Assessments were performed similar to Td506
- No active safety monitoring after flu vaccine alone

## Td502: Comparisons for Group A (Tdap + flu) vs. Group B (flu, Tdap)

- Dip and Tet
- Endpoints similar to Td506
- Pertussis Antigens
- GMC ratio A/B, if LL of 2-sided 90% CI > 0.67
- Influenza Strains (A/H3N2, A/H1N1, B)
- Seroprotection rates (defined as HAI* _>_ 1:40)
- Seroconverison (defined as _>_ 4-fold rise)
- Non-inferior if UL of 2-sided 95% CI  in
- rates (B-A) < 10%

- *HAI = hemagglutination inhibition

## Td502 Results: Enrollment

**Total =720**
**Group A = 359 and Group B = 361**
**Discontinued = 24**
**21 in Group B after flu but prior to Tdap**
**Demographics were similar for both groups**
**69% reported history of 5 previous dip-tet-pertussis containing vaccines **

## Td502 Results: Immune ResponsesDip, Tet and Pertussis

| 
Immune
Response | Group A
Tdap + Flu
N=354 | Group B
Flu, Tdap
N=324 |  |
| --- | --- | --- | --- |
| Seroprotection 
> 0.1 IU/mL | 
% | 
% | 
Diff % |
|     Diphtheria | 86.2 | 87 | 0.9 (-4.3, 6.0) |
|     Tetanus | 99.7 | 98.1 | -1.6 (-3.1, 0.0) |
| Post-GMC |  |  | GMC Ratio A/B (90% CI) |
|     PT | 186.4 | 234.5 | 0.79 (0.70, 0.90) |
|     FHA | 200.6 | 242.2 | 0.83 (0.75, 0.91) |
|     FIM | 925.8 | 1136.3 | 0.81 (0.68, 0.98) |
|     PRN | 191.7 | 260.3 | 0.74 (0.61, 0.88) |

## Td502:  Influenza Immune Responses

|  | Group A
Tdap+flu
N=354 | Group B
Flu, Tdap
N=324 | 

B-A | 
 |
| --- | --- | --- | --- | --- |
| Immune Response | % | % | Diff % | 95% CI |
| Seroprotection (HAI > 1:40) |  |  |  |  |
| A/Panama/2007/99 (H3N2)  | 86.5 | 88.8 | 2.3 | -2.9, 7.4 |
| A/New Caledonia/20/99 (H1N1) | 54.0 | 46.9 | -7.0 | -14.8, 0.8 |
| B/Yamanashi/166/98 | 80.6 | 80.3 | -0.3 | -6.5, 5.9 |
| Seroconversion Rate (4-fold rise) |  |  |  |  |
| A/Panama/2007/99 (H3N2)  | 69.5 | 69.4 | -0.1 | -7.3, 7.1 |
| A/New Caledonia/20/99 (H1N1) | 68.3 | 67.7 | -0.6 | -7.9, 6.6 |
| B/Yamanashi/166/98 | 62.8 | 65.1 | 2.3 | -5.1, 9.8 |

## Td502 Results: Safety

- Non-inferiority of AE rates for concomitant vs. separate was demonstrated for erythema, swelling, and fever but _not_ for pain (‘any” and “moderate & severe” intensity)
- _>_ 1 local AEs were frequent (A=69% and B=64%)
- Solicited systemic AE rates higher for concomitant
- No anaphylaxis events
- Two SAEs (one in each group) reported, not vaccine related; no deaths reported

## Td502: Trial Summary

- Not all endpoints were met:
- Safety
- Pain – more frequent with concomitant
- Immunogenicity – for pertussis
- Non-inferiority of responses (GMCs) for concomitant vs. separate was demonstrated for PT, FHA and FIM, but not PRN
- Robust rises in antibodies for both groups, though responses lower for concomitant administration
- Clinical significance of failed endpoints not clear; should be considered in the context of risks and benefits of concomitant immunization

## Trial Td501 – Concomitant Study of ADACELTM and Hepatitis B Vaccine

- Open-labeled, randomized, controlled trial of safety and immune responses of Tdap and hepatitis B vaccines in adolescents 11-14 years of age
- Study Groups:
- 1 dose of Tdap and 2 dose regimen (1.0 mL per dose) of Hep B vaccine given ~ 4 months apart:
- Group A – Tdap and Hep B #1 concurrently
- (Tdap + Hep B)
- Group B – Tdap then Hep B dose #1, 4-6 weeks later (Tdap, Hep B)

## Td501: Comparisons for Group A (Tdap + Hep B) vs. Group B (Tdap, Hep B)

- Dip, Tet and Pertussis Comparisons
- Similar to Td502
- Hepatitis B
- Seroprotection rates (_>_ 10 mIU/mL, Abbott RIA Kit), non-inferior if UL of 2-sided 95% CI  in rates (B-A) < 10%
- Safety (monitoring after Tdap similar to other trials)
- Erythema, swelling, pain and fever, non-inferior if rates of events A vs. B, if UL of 95% CI  (A-B)        < 10%

## Td501 Results: Enrollment

**Total = 410**
**Group A (Tdap + Hep B) = 206**
**Group B (Tdap, Hep B) = 204**
**Demographics comparable for 2 groups**
**89% with 5 previous dip-tet-pertussis vaccines **

## Td501 Results: Immune Responses to Diphtheria, Tetanus and Pertussis

| 
Immune Responses | Group A
Tdap + Hep B
N=161 | Group B
Tdap, Hep B
N=151 |  |
| --- | --- | --- | --- |
| Seroprotection 
> 0.1 IU/mL | 
% | 
% | 
Diff % |
|     Diphtheria | 100 | 99.3 | -0.7 (-1.9, 0.6) |
|     Tetanus | 100 | 100 | 0.0 (0.0, 0.0) |
| Post-GMC |  |  | GMC Ratio A/B (90% CI) |
|     PT | 303.5 | 321.6 | 0.94 (0.8, 1.1) |
|     FHA | 301.5 | 305.4 | 0.99 (0.8, 1.2) |
|     FIM | 1906.4 | 1926.7 | 0.99 (0.8, 1.2) |
|     PRN | 292.9 | 284.6 | 1.03 (0.8, 1.3) |

## Td501 Results: Hepatitis B Post-VaccinationSeroprotection Levels

| 

Seroprotection 
> 10 mIU/mL | Group A
Tdap + Hep B
N=161
% | Group B
Tdap, Hep B
N=151
% | 

Diff %
(95% CI) |
| --- | --- | --- | --- |
|     Hepatitis B | 96.3 | 97.3 | 1.0 (-2.8, 4.9) |

## Td501 Results: Safety

**Safety endpoints were met for fever and “any” pain but **_**not**_** for “any” erythema , and “any” and “moderate & severe” swelling  **
**Local AEs were common in both groups (concomitant = 88% and separate = 86.6%)**

## Td501 Results: Safety

**Solicited systemic AEs after Tdap generally  higher for concomitant group**
**Sore and/or swollen joints - frequent in both concomitant (22.5%) and separate (18%); higher rates than other trials**
**No anaphylaxis events **
**Two SAEs, one in each group, reported - not vaccine related; no deaths reported**

## Td501: Trial Summary

**All of the immunogenicity, but not all of the safety endpoints (local AEs) were met**
**The clinical significance of the failed safety endpoints not clear; should be considered in the context of risks and benefits of concomitant immunization**

## Safety Events of InterestAcross Trials

**Whole limb swelling**
**No occurrences reported in 4 main trials**
**Seizures**
**3 seizure events **
**15 yo male 135 days post-Tdap (known Sz) **
**17 yo male 133 days post-Td (known Sz) **
**51 yo female 22 days post-Tdap (substance abuse)**

## Safety Events of InterestAcross Trials

**Diabetes and Autoimmune Disorders**** **
**1 new-onset insulin-dependent diabetes mellitus (IDDM) in 11yo 23 days post-Tdap (sibling with IDDM)**
**1 non-IDDM in 56yo 13 days post-Tdap with suprasellar mass and trauma **
**1 IDDM in 11yo 105 days post-Td**
**No other autoimmune disorders identified**

## Safety Events of Interest 

**Pregnancy (Td506, 6 month follow-up)**
**30 women with 31 pregnancies, data for 29:**
**19 of 29 healthy full-term infants**
**5 spontaneous abortions (Tdap=4, Td=1)**
**1 therapeutic abortion**
**4 premature infants, otherwise healthy**
**No congenital abnormalities**

## Safety Events  Exploratory Analyses of Local AEs

**Age at Immunization**
**Trend for higher rates of local AEs for younger adolescents (11 - 13 yrs) compared to older adolescents (14 - 17 yrs) **
**Gender**
**Trend for higher rates of local AEs in females than in males (in adolescents and adults) **

## ADACELTM BLA Summary

**Data submitted support:**
**Similar safety profile of ADACELTM as compared to a U.S. licensed Td **
**Non-inferiority of the immune responses to dip and tet as compared to a U.S. licensed Td **

## ADACELTM BLA Summary

**Data submitted support:**
**Non-inferiority of the immune responses to the pertussis antigens following ADACELTM as compared to those observed after three doses of DAPTACEL ® in infants in Sweden I Efficacy Trial**
**A booster response to all of the vaccine antigens**
**Consistency of manufacture of ADACELTM **
**Additionally, data to assess concomitant use of Tdap with influenza and hepatitis B vaccines were provided **

## Douglas Pratt, M.D.

**Douglas Pratt, M.D.**
**Ms. Martha Monser**
**Bruce Meade, Ph.D.**
**Henry Hsu, Ph.D.**
**DVRPA**