# Presentation: 667870

## Immunogenicity of Pentacel

- Theresa Finn, Ph.D.
- OVRR, CBER

## Overview of presentation

- Clinical Studies
- Immunogenicity:
- Endpoints
- Diphtheria toxoid
- Tetanus toxoid
- Polioviruses
- Hib
- Pertussis
- Serology bridge to DAPTACEL in Sweden I
- Comparison to DAPTACEL in US-children
- Concurrent Prevnar
- (Concomitant Vaccines)
- Summary

## Controlled Studies

- 494-01 (U.S.)
- Pentacel compared to HCPDT (DTaP) + POLIOVAX + ActHIB (doses 1-4)
- P3T06 (U.S.)
- Pentacel compared to DAPTACEL + IPOL + ActHIB (doses 1-3)
- Pentacel compared to DAPTACEL + ActHIB (dose 4)

## Pentacel Studies which did not include a group receiving control vaccines 

- 494-03 (U.S.) dose 1-4
- 5A9908 (Canada) dose 4
- M5A07 (U.S.)

## Immunogenicity Population: Pentacel Studies

- Population for primary immunogenicity analyses: Per Protocol for Immunogenicity  (PPI) Population:
- Eligible subjects, blood draws and vaccines within protocol specified windows, and serology result for at least one antigen post-dose 3 or 4

## Statistical considerations

- Non-inferiority analyses
- Previously, CBER used 90% CI for difference in sero-protection/seroconversion rates and for ratio of GMCs
- Currently, CBER recommends 95% CI for difference in rates and for ratio of GMCs

## Immunogenicity of Diphtheria, Tetanus, Polio and Hib components 

|  | Post dose 3 endpoint  | Assay |
| --- | --- | --- |
| Diphtheria | % >0.01 IU/mL | VERO |
| Tetanus | % >0.1 IU/mL | ELISA |
| Poliovirus types 1, 2 and 3 | % >1:8  | Neutralization assay |
| PRP | % >0.15 ug/mL
% >1.0 ug/mL
GMC | RIA |

## Immune response to Diphtheria and Tetanus Toxoids

## Study P3T06: Diphtheria and Tetanus seroprotection rates post dose 3

| Endpoint | Pentacel | DAPTACEL |
| --- | --- | --- |
|  | N = 331- 345 | N = 1037- 1099 |
| Diphtheria 
    %  >0.01 IU/mL | 100.0 | 100.0 |
| Tetanus 
    %  >0.1 IU/mL | 99.7 | 100.0 |

## Immune response to Poliovirus types 1, 2 and 3

## P3T06: Polio seroprotection rates post dose 3

|  | Pentacel  | IPOL |
| --- | --- | --- |
|  | N = 338-350 | N = 1050-1097 |
| Polio type 1
% > 1:8 | 99.4 | 100 |
| Polio type 2 
% > 1:8 | 100 | 100 |
| Polio type 3
% > 1:8 | 100 | 100 |

## Immune response to PRP-T

## Study 494-01: PRP antibody levels post-dose 3

|  | Pentacel
N = 1127 | ActHIB
N = 401 | Non-inferiority analyses |
| --- | --- | --- | --- |
| Anti-PRP |  |  | ActHIB - Pentacel (90% CI)1 |
| % >0.15 ug/mL | 95.4  | 98.3  | 2.87 (1.38, 4.36) |
| % >1.0 ug/mL | 79.1  | 88.8  | 9.63 (6.36, 12.90) |
|  |  |  | ActHIB/Pentacel (90% CI)2 |
| GMC | 3.19 | 6.23 | 1.95 (1.68, 2.26) |

- 1Non-inferiority: UL 90% CI difference <10%
- 2Non-inferiority: UL 90% CI ratio <1.5

## Study P3T06: PRP antibody levels post-dose 3

|  | Pentacel
N = 365 | ActHIB
N = 1128 | Non-inferiority analyses |
| --- | --- | --- | --- |
| Anti-PRP |  |  | ActHIB – Pentacel (90% CI)1 |
| % >0.15 ug/mL | 92.3 | 93.3 | 0.93 (-1.67, 3.53) |
| % >1.0 ug/mL | 72.1 | 70.8 | -1.22 (-5.68, 3.24) |
|  |  |  | ActHIB/Pentacel |
| GMC | 2.31 | 2.29 | 0.99 (0.84, 1.17)2 |

- 1Non-inferiority: UL 90% CI difference <10%
- 2Non-inferiority criteria not specified in the protocol

## Study 494-01 and Study P3T06: Exploratory analysis – PRP antibody levels pre-dose 4

| Anti-PRP | Study 494-01 |  | Study P3T06 |  |
| --- | --- | --- | --- | --- |
|  | Pentacel | ActHIB | Pentacel | ActHIB* |
|  | N = 829 | N = 276 | N = 335 | N = 323 |
| % >0.15ug/mL
(95% CI) | 68.6
(65.4, 71.8) | 80.8
(75.6, 85.3) | 65.4
(60.0, 70.5) | 60.7
(55.1, 66.0) |

- *Study P3T06 Group 1 (DAPTACEL + ActHIB)

## Immune response to PT, FHA, Fimbriae 2&3 and Pertactin

## Efficacy of Pertussis Component

- Serology bridge:
- Pentacel Study 494-01 compared to DAPTACEL Sweden I
- Comparison to DAPTACEL in US children:
- Study P3T06
- Endpoints:
- % _>_4-fold rise relative to pre-dose 1 antibody levels
- GMC

## Sweden I Efficacy Trial

- March 1992-January 1995
- ~ 2500 infants administered DAPTACEL at 2, 4 and 6 months of age
- Compared to DT control vaccine efficacy of three doses of DAPTACEL against WHO defined pertussis (_>_ 21 days cough with culture/serologic confirmation/epi link 84.9% (95% CI 80.1, 88.6)

## Basis for DAPTACEL efficacy in U.S.

- Serology bridge post-dose 3 DAPTACEL in US children to post-dose 3 Sweden I:
- pertactin seroconversion rates and GMCs significantly lower in US infants
- response to PT, FHA and FIM similar in US and Swedish infants
- Serology bridge post-dose 4 DAPTACEL in Canada to post-dose 3 Sweden I:
- post-dose 4 GMCs were at least as high as those of Swedish infants

## Serology bridge:  Non-inferiority of GMCs

| Antigen | Post dose 3 
DAPTACEL
Sweden I
GMC (EU/mL) | Post dose 4 
Pentacel 
Study 494-01
GMC (EU/mL) | Non-inferiority 
DAPTACEL/Pentacel
(90% CI)1 |
| --- | --- | --- | --- |
|  | N = 80 | N = 553-554 |  |
| PT  | 87.50 | 195.10 | 0.45 (0.38, 0.53) |
| FHA  | 40.70 | 129.85 | 0.31 (0.27, 0.36) |
| FIM  | 339.31 | 506.57 | 0.67 (0.54, 0.82) |
| PRN  | 111.26 | 90.82 | 1.23 (1.01, 1.49) |

- 1Non-inferiority: UL 90% CI ratio <1.5

## Serology bridge: Non-inferiority of seroconversion rates

| Antigen | Post dose 3 
DAPTACEL Sweden I
% ≥4-fold rise1 | Post dose 4 
Pentacel 
Study 494-01
% ≥4-fold rise2 | Non-Inferiority 
DAPTACEL - Pentacel
% (95% CI)3  |
| --- | --- | --- | --- |
|  | N = 80 | N = 507-508 |  |
| PT  | 86.3 | 94.9 | -8.63 (-16.42, -0.85) |
| FHA | 68.8 | 91.7 | -22.97 (-33.40, -12.53) |
| FIM  | 86.3 | 91.5 | -5.27 (-13.20, 2.66) |
| PRN  | 98.8 | 89.2 | 9.60 (5.96, 13.24) |

- 1Post dose 3/pre-dose 1,
- 2Post dose 4/pre-dose 1,
- 3Non-inferiority: UL 95% CI <10%

## Serology bridge: CBER Exploratory Analyses - Seroconversion rates post-dose 3

| Antigen | Post dose 3 
DAPTACEL
Sweden I
% ≥ 4 fold rise  | Post dose 3
Pentacel 
Study 494-01
% ≥4 fold rise  | Difference DAPTACEL – Pentacel
% (95% CI)* |
| --- | --- | --- | --- |
|  | N = 80 | N = 650-652** |  |
| PT  | 86.3 | 89.7 | -3.44 (-12.89, 3.04)  |
| FHA  | 68.8 | 79.8 | -11.0 (-22.23, -1.32)  |
| FIM  | 86.3 | 86.5 | -0.23 (-9.75, 6.38)  |
| Pertactin | 98.8 | 74.4 | 24.36 (18.44, 28.20)  |

- *CBER generated 95% CI (STAT EXACT)
- **Subjects in Study 494-01 had 3 concurrently administered doses of Prevnar with Pentacel

## Serology bridge: CBER Exploratory Analysis - GMCs post-dose 3

| Antigen | Post dose 3 
DAPTACEL 
Sweden I
EU/mL | Post dose 3
Pentacel 
Study 494-01
EU/mL | Ratio DAPTACEL/Pentacel
(90% CI)* |
| --- | --- | --- | --- |
|  | N = 80 | N =730-731 |  |
| PT | 87.50 |  93.38 | 0.94 (0.80, 1.09)  |
| FHA | 40.70 | 71.46 | 0.57 (0.50, 0.65)  |
| FIM | 339.31 | 265.02 | 1.28 (1.04, 1.58)  |
| Pertactin | 111.26 | 38.11 | 2.92 (2.50, 3.40)  |

- *CBER generated 90% CI (STAT EXACT)
- **Subjects in Study 494-01 had 3 concurrently administered doses of Prevnar with Pentacel

## Comparison to DAPTACEL in Study P3T06

## Comparison to DAPTACEL, Study P3T06: Non-inferiority of seroconversion rates post dose 3

| Antigen  | Post dose 3
DAPTACEL
% ≥ 4-fold rise1 | Post dose 3
Pentacel
% ≥ 4-fold rise1 | Non-inferiority
DAPTACEL - Pentacel
%(90% CI) 2 |
| --- | --- | --- | --- |
|  | N = 712-724 | N = 218-221 |  |
| PT  | 86.1 | 93.6 | -7.51 (-10.97, -4.06)  |
| FHA  | 60.9 | 81.9 | -20.99 (-26.19, -15.79)  |
| FIM  | 86.3 | 91.7 | -5.47 (-9.19, -1.74)  |
| PRN  | 75.4 | 74.2 | 1.21 (-4.31, 6.73) |

- 1Post-dose3/pre-dose1
- 2Non-inferiority: UL 90% CI difference <10%

## Comparison to DAPTACEL, Study P3T06: Non-inferiority of GMCs post-dose 3

| Antigen  | Post dose 3
DAPTACEL
GMC (EU/mL) | Post dose 3 
Pentacel
GMC (EU/mL) | Non-inferiority 
DAPTACEL/Pentacel
(90% CI)1  |
| --- | --- | --- | --- |
|  | N = 1015-1016 | N = 318 |  |
| PT  | 63.82 | 89.98 | 0.71 (0.66, 0.76) |
| FHA  | 29.22 | 73.68 | 0.40 (0.37, 0.43) |
| FIM  | 267.18 | 268.15 | 1.00 (0.91, 1.09) |
| PRN  | 43.25 | 36.05 | 1.20 (1.08, 1.33) |

- 1Non-inferiority is demonstrated when UL 90% CI ratio <1.5

## Comparison to DAPTACEL, Study P3T06: Non-inferiority of seroconversion rates post-dose 4

| Antigen | Post dose 4
DAPTACEL
% ≥ 4-fold rise1
 | Post dose 4
Pentacel
% ≥ 4-fold rise1
 | Non-inferiority 
DAPTACEL -  Pentacel
(90% CI)2 |
| --- | --- | --- | --- |
|  | N=237-242 | N = 230-232 |  |
| PT  | 97.1 | 97.4 | -0.34 (-2.84, 2.15) |
| FHA  | 79.3 | 88.4 | -9.02 (-14.53, -3.52) |
| FIM  | 91.6 | 93.5 | -1.92 (-5.92, 2.08) |
| PRN  | 98.3 | 92.7 | 5.67 (2.55, 8.79) |

- 1Post-dose4/pre-dose1
- 2Non-inferiority is demonstrated when UL 90% CI difference <10%

## Comparison to DAPTACEL, Study P3T06 : Non-inferiority of GMCs post-dose 4

| Pertussis Antigen  | Post dose 4 
DAPTACEL 
GMC (EU/mL) | Post dose 4 
Pentacel 
GMC (EU/mL) | Non-inferiority
DAPTACEL/Pentacel
(90% CI)1 |
| --- | --- | --- | --- |
|  | N = 345-347 | N = 366-367 |  |
| PT  | 168.48 | 174.03 | 0.97 (0.87, 1.08) |
| FHA  | 64.02 | 107.94 | 0.59 (0.54, 0.66) |
| FIM  | 513.54 | 553.39 | 0.93 (0.81, 1.06) |
| PRN  | 186.07 | 93.59 | 1.99 (1.76, 2.25) |

- 1Non-inferiority is demonstrated when UL 90% CI ratio <1.5

## Effect of Prevnar

- Study 494-01 exploratory analyses
- Post-dose 4 across pivotal studies

## Effect of Prevnar:  Pertussis GMCs following four doses of Pentacel in pivotal studies 

| # of  concurrent Prevnar doses: | 5A9908 | 494-01 | P3T06 | 494-03 |  |
| --- | --- | --- | --- | --- | --- |
|  | N=191 | N = 853-854 | N = 366-367 | Group 1
N = 203 | Group 3
N = 202 |
| at 2, 4 and 6 months | 0 | 0-3 | 3 | 3 | 3 |
| at 15 months | 0 | 0 | 0 | 0 | 1 |
| PT (EU/mL)  | 249.85 | 202.18 | 174.03 | 161.87 | 138.83 |
| FHA (EU/mL) | 172.42 | 134.59 | 107.94 | 134.47 | 128.12 |
| FIM (EU/mL) | 833.37 | 514.19 | 553.39 | 434.35 | 324.96 |
| Pertactin (EU/mL) | 187.52 | 94.91 | 93.59 | 76.44 | 69.63 |

## Effect of Prevnar

- Study M5A07
- Pentacel + Prevnar at 2, 4, 6, 15 months of age
- Pentacel at 2, 4, 6 and 15 months of age, Prevnar at 3, 5, 7 and 12 months of age
- Summary post-dose 3 data in BLA

## Effect of Prevnar, Study M5A07:  Non-inferiority of seroconversion rates post-dose 3 

| Antigen  | Pentacel + Prevnar
% ≥ 4-fold rise1 | Pentacel staggered Prevnar
 %  ≥ 4-fold rise1 | Non-inferiority  
Group 2 - Group 1 
% (95% CI)2  |
| --- | --- | --- | --- |
|  | N = 422-445  | N = 436-438 |  |
| PT  | 89.7  | 90.4  | 0.73 (-3.23, 4.68) |
| FHA   | 81.6  | 81.9  | 0.25 (-4.86, 5.36) |
| FIM  | 87.6  | 87.7  | 0.11 (-4.24, 4.47) |
| PRN  | 73.6  | 71.7  | -1.96 (-7.84, 3.92) |

- 1The fold rise Post-Dose 3/Pre-Dose 1 antibody level (EU/mL).
- 2Non-inferiority: UL 95% CI <10%

## Effect of Prevnar, Study M5A07:Non-inferiority of GMCs post-dose 3

| Antigen  | Pentacel + Prevnar 
GMC (EU/mL) | Pentacel staggered Prevnar 
GMC (EU/mL)  | Non-Inferiority 
Group 2/Group 1 
(90% CI)1  |
| --- | --- | --- | --- |
|  | N = 446-447 | N = 439 |  |
| PT  | 103.58  | 102.78  | 0.99 (0.93, 1.06)  |
| FHA  | 82.41  | 77.80  | 0.94 (0.87, 1.02)  |
| FIM  | 272.47  | 280.97  | 1.03 (0.93, 1.14)  |
| PRN  | 45.70  | 44.28  | 0.97 (0.86, 1.09)  |

- 1Non-inferiority: UL 90% CI ratio is <1.5.

## Response to concomitantly administered vaccines

- Hepatitis B
- % _>_10mIU/mL and GMC similar when given with Pentacel or Control vaccines
- Prevnar
- Post dose 3:  % _>_0.15 ug/mL, _>_0.5ug/mL and GMC similar when given with Pentacel or Control vaccines
- Post-dose 4: Non-inferiority demonstrated (% _>_0.15 ug/mL, _>_0.5 ug/mL and GMC) when given with Pentacel or MMR + Varivax (Study 494-03)
- MMR
- Varicella

- Non-inferiority demonstrated for
- seroresponse rates

## Summary Pentacel immunogenicity concerns: PRP-T

- PRP-T component:
- Study 494-01:
- diminished % _>_1.0 ug/mL vs. ActHIB
- diminished GMC vs. ActHIB
- Study P3T06:
- similar % >1.0 ug/mL vs. ActHIB
- similar GMC vs. ActHIB

## Summary Pentacel immunogenicity concerns:  Pertussis antigens

- Post dose 3:
-  Serology bridge to Sweden I (exploratory):
- diminished anti-FIM (GMC),
- diminished anti-pertactin (4x rise and GMC)
- Post dose 4:
- Serology bridge to Sweden I:
- diminished anti-pertactin (4x rise)
- Study P3T06:
- diminished anti-pertactin (GMC)

## Questions and Discussion Items

- Are the available data adequate to support the safety of four doses of Pentacel administered at 2, 4, 6 and 15-18 months of age?
**	****(Voting Item)**
- 	If the available data are not adequate, what additional data are needed?

## Questions and Discussion Items cont’d.

- Please discuss whether the available data are adequate to support the efficacy of:
- 	a) The diphtheria, tetanus and polio components of Pentacel,
- 	b) The Hib (PRP-T) component of Pentacel, and
- 	c) The pertussis component of Pentacel.
- 	Are the available data adequate to support the efficacy of Pentacel?
- 	(**Voting Item)**
- 	If the available data are not adequate, what additional data are needed?

## Questions and Discussion Items cont’d.

- 3.		If Pentacel is licensed, please identify any issues which should be addressed in post-licensure studies.