Product Approval Information - Licensing Action

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Review Memorandum

BLA STN 103907 (99-0800)
To: Rolf Taff, PhD, BLA Chair
Theresa Finn, PhD, Primary Reviewer
From: Leslie K. Ball, MD, Clinical Reviewer, VCTB, DVRPA
Through: Antonia Geber, MD, Chief, VCTB
Karen Goldenthal, MD, Director, DVPRA
cc: Karen Farizo, MD, Clinical Reviewer
Henry Hsu, PhD, Statistical Reviewer
Helen Sullivan, Regulatory Coordinator

Date: November 12, 2001

1.0  Clinical Review of BLA STN 103907: InfanrixDTPaHepB-IPV™

GSK's DTPa-HepB-IPV vaccine is a liquid combination vaccine formulated by pooling purified bulk preparations of diphtheria and tetanus toxoids (DT); acellular pertussis (pertussis toxoid [PT], filamentous hemagglutinin [FHA], and pertactin); hepatitis B surface antigen (HBs) and inactivated poliovirus (IPV) types 1, 2, and 3. The DT toxoids adsorbed combined bulk is manufactured by Chiron-Behring GmbH and Co., Marburg, Germany. The acellular pertussis components are manufactured by SmithKline Beecham Biologicals (SBB), Rixensart, Belgium. The combined DTPa components (Infanrix®) were approved for use in the U.S. on January 29, 1997. The hepatitis B surface antigen is similar to that found in Engerix-B® approved by the U.S. FDA on August 29, 1989. The IPV component is not licensed in the U.S.

1.1 Medical Officer's Review

1.1.1 BLA STN 103907
1.1.2 BLA Submission Date: July 2, 1999

1.2 Drug name

1.1.1 Generic or proper name: Diphtheria and Tetanus Toxoids, Acellular Pertussis, Hepatitis B (Recombinant), Inactivated Polio Vaccine
1.2.1 Proposed trade name: InfanrixDTPaHepB-IPV™

1.3 Sponsor: GlaxoSmithKline (SmithKline Beecham Biologicals [SBB])

1.4 Pharmacologic Category: Vaccine

1.5 Proposed Indication: (From BLA Amendment 2/28/01)

Primary Series (Doses 1, 2, 3): Infanrix DTPa HepB-IPV™ is indicated for active immunization against diphtheria, tetanus, pertussis (whooping cough), all known subtypes of hepatitis B virus and poliomyelitis caused by poliovirus types 1, 2, and 3 as a three-dose primary series in infants and children 6 weeks to 7 years (prior to the 7th birthday).

Reviewer Comment: Original BLA submission 7/2/99 stated that the indication was for active immunization from 6 weeks to 7 years and did not specify use of DTPa-HepB-IPV for a 3 dose primary series only, thus leaving open the possibility of use of this product as a booster immunization. However, CBER's IR letter of 2/9/00 noted insufficient data for a booster dose indication (4th or 5th dose). CBER recommended that the indication be revised for primary immunization (doses 1, 2, and 3), and this was the indication brought before the Vaccines and Related Biological Products Advisory Committee on 3/7/01. Further, CBER recommended that prescribing information note that limited data are available describing the use of DTPa-HepB-IPV as a booster dose. In their BLA amendment of 2/28/01, p. 9, the sponsor stated that "[a]n indication for a fourth dose following a primary series is not being sought at this time. The language in the indication providing immunization prior to the 7th birthday is intended to allow for catch up primary immunization."

Data reviewed here cover use of DTPa-HepB-IPV as a primary series. The limited available data on use of DTPa-HepB-IPV as a 4th dose following a primary series of DTPa-HepB-IPV are presented in Appendix 2.

1.6  Dose, Schedule, and Route of Administration:

0.5mL injections containing: 25 Lf diphtheria toxoid; 10 Lf tetanus toxoid; 25 µg PT; 25 µg FHA; 8 µg pertactin; 10 µg HBs; 40 D-antigen units (DU) type 1 poliovirus; 8 DU type 2 poliovirus; 32 DU type 3 poliovirus

Schedule and Route: Three injections at 4 to 8 week intervals (2, 4, 6 months of age, customary) administered intramuscularly.

1.7  Important Related Vaccines/Files

------------------------------------------
PLA 95-1773, ELA 95-1926: Infanrix (DTPa)
PLA 87-0566, ELA 87-0555: Engerix-B
---------------------------------------------

PLA 95-1781: DT Adsorbed Bulk Concentrate for Further Manufacture supplied by Chiron Behring GMBH and Co., Marburg, Germany under a shared manufacturing agreement with GSK

1.8 Related Reviews

Written statistical and product reviews not available to clinical reviewer at time of this memo.

1.9 Abbreviated U.S. Regulatory Timeline

02/29/96 Original Submission IND--------: Safety and immunogenicity "equivalence" study (DTPaHepB-IPV-015, U.S.)
06/25/96 Letter to Sponsor (Advice/IR)
07/19/96 -----------------, Submission of large scale safety trial (DTPa-HepB-IPV-011, Germany)
06/12/97 IPV Meeting with Sponsor
12/02/97 Pre-phase 3 Meeting with Sponsor:
  • Manufacturing Issues: Process modifications
  • Clinical Issues: Discussion of pivotal studies
01/27/98 ---------- – Submission of revised lot consistency/bridging study (DTPa-HepB-IPV-044, U.S.)
10/28/98 End of Phase III/Pre-Biologics License Application (BLA) Meeting
02/23/99 Pre-BLA Meeting
07/02/99 BLA submission
09/99 Pre-Approval Inspection
02/09/00 FDA Information Request Letter
05/01/00 FDA Complete Response Letter
12/18/00 Submission of Complete Response
03/07/01 VRBPAC Review and Vote
04/20/01 Meeting with Sponsor on Remaining Clinical Issues
06/19/01 Meeting with Sponsor on Remaining CMC Issues
06/21/01 Complete Response Letter
09/25/01 IND --------: Submission of Protocols for Clinical Studies –084 (Safety with Concomitant Prevnar) and –085 (Safety and Immunogenicity with Concomitant Prevnar)

2.0   Table of Contents

1.0 Title and General Information

2.0 Table of Contents

3.0 Material Reviewed

4.0 Chemistry Manufacturing and Controls

5.0 Animal Pharmacology/Toxicology

6.0 Clinical Background

6.1 Foreign Experience
6.2 Directions for Use

7.0 Description of Clinical Data Sources (both IND and non-IND)

7.1 Objectives
7.2 Pivotal Trial Summary
7.3 Inclusion/Exclusion Criteria for Pivotal Trials
7.4 Demographics of Pivotal Trials
7.5 Supportive Trial Summary
7.6 Clinical Trial Summary Table (Pivotal +Supportive)

8.0 Clinical Studies

8.1 Efficacy Data (Immunogenicity)

8.1.1 Characterization of the Immune Response
8.1.2 Assessment of Immunogenicity
8.1.3 Pivotal Study: DTPa-HepB-IPV- 015 (Comparative Immunogenicity of DTPa-HepB-IPV vs. Separate Vaccines)
8.1.4 Pivotal Study: DTPa-HepB-IPV- 044 (Lot Consistency and Manufacturing Bridge)
8.1.5 Supportive Data for Lot Consistency: DTPa-HepB-IPV/Hib-027
8.1.6 Hepatitis B Vaccine Schedule Change
8.1.7 Overview of Efficacy (Immunogenicity) Data

8.2 Safety Data

8.2.1 Safety Database
8.2.2 Assessment of Safety
8.2.3 Pivotal Study: DTPa-HepB-IPV-011 (Large Scale Safety Study)
8.2.4 Pivotal Study: DTPa-HepB-IPV-015
8.2.5 Pivotal Study: DTPa-HepB-IPV-044
8.2.6 Safety of DTPa-HepB-IPV Following a Birth Dose of Hepatitis B Vaccine
8.2.7 Overview of Safety Data

8.3 Concurrent Immunizations (Safety and Immunogenicity)

8.3.1 Haemophilus influenzae type b (Hib) Vaccine
8.3.2 7-V Pneumococcal Conjugate Vaccine (Prevnar)

8.4 4th Dose DTPa (Infanrix®) following Primary Series of DTPa-HepB-IPV

8.5 Summary of Available Data

8.6 Summary of Data Not Submitted in BLA

9.0 VRBPAC March 7, 2001: Brief Summary

10.0 Post VRBPAC Meetings/Agreements on Clinical Issues

11.0 Planned Clinical Studies: Co-administration with Prevnar: Summaries of DTPa-HepB-IPV-084 and –085

11.0 Conclusions

12.0 Recommendations/Remaining Issues

Appendix 1: Concurrent Immunization of Prevnar with DTPa/DTPa combinations

Appendix 2: 4th Dose DTPa (Infanrix®) following a Primary Series of DTPa-HepB-IPV

3.0 MATERIAL REVIEWED:

  • eBLA STN 103907 (99-0800):
    • Original Submission 7/2/99: Cover letter; Item 2: Labeling; Item 3: Summary; Item 4: CMC; Item 5: Nonclinical pharmacology and toxicology, Item 8: Clinical, Item 10: Statistical; Item 12, Case Report Forms
    • Amendments 3/3/00, 8/3/00, 9/7/00, 11/10/00, 12/18/00, 2/23/01, 2/28/01. 4/2/01. 4/3/01, 5/11/01, 5/15/01, 6/26/01, 7/26/01, 9/25/01.
  • IND -------

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4.0 Chemistry, Manufacturing, and Controls

The DTPa-HepB-IPV combination consists of the following components in each 0.5 mL dose:

Composition Quantity
(per 0.5 ml dose)
Active Substances
Pertussis toxoid (PT), adsorbed (ads.) 25 µg
Filamentous haemagglutinin (FHA), adsorbed 25 µg
Pertactin (69kDa Outer Membrane Protein, PRN), ads. 8 µg
Diphtheria toxoid (D), ads. ≥ 2 U/ml or 25 Lf
Tetanus toxoid (T), ads. ≥ 2 U/ml or 10 Lf
r-DNA Hepatitis B surface antigen, ads. 10 µg (HBs)
Inactivated Poliovirus Type 1 40 DU
Inactivated Poliovirus Type 2 8 DU
Inactivated Poliovirus Type 3 32 DU
Excipients
2-phenoxyethanol 2.5 mg
Sodium Chloride 4.5 mg
Water for Injection 0.5 ml
Adjuvants
Aluminum salts (Aluminum hydroxide 0.5 mg and aluminum phosphate 0.2 mg) 0.7 mg

The diphtheria and tetanus toxoids, adsorbed combined bulk are produced by Chiron Behring, GmbH and Co., Marburg, Germany. The acellular pertussis antigens, hepatitis B surface antigen, and trivalent inactivated polio virus vaccine are produced by SmithKline Beecham Biologicals (SBB). SBB performs the formulation, filling, testing, packaging and release of the final product.



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5.0 Animal Pharmacology/Toxicology (BLA Section 5.I)

The sponsor indicates that the active ingredients and excipients used in the manufacture of DTPa-HepB-IPV vaccine are well known and used in other SBB US licensed vaccines: Infanrix, Engerix-B, as well as Infanrix-based combinations licensed in other markets, e.g. Infanrix-HepB, Infanrix-IPV/Hib. Therefore, toxicological studies have been limited to the tests performed for routine release and antigen characterization for the DTPa-HepB-IPV vaccine. Routine release and characterization tests include: specific toxicity in guinea-pigs for diphtheria (D) and tetanus (T) (Ph. Eur. 647) for characterization of D and T components; test in monkeys for active virus (former 21CFR §630.4 (e)) for characterization of the IPV component; test for lymphocytic choriomeningitis in mice (former 21CFR §630.4 (d)) for characterization of the IPV component; residual pertussis toxin activity (histamine sensitization test) for routine release of both Infanrix and DTPa-HepB-IPV vaccine; and general safety test -abnormal toxicity (21CFR §610.11) for routine release of both Infanrix, Engerix-B and DTPa-HepB-IPV vaccine.

Immunogenicity tests for each vaccine component are part of the release specifications for DTPa-HepB-IPV and are thus routinely performed on each lot of final bulk. These tests are as follows: potency in -------------- for tetanus; potency in -------------- for diphtheria; immunogenicity in ------- for pertussis; and immunogenicity in ----- for poliomyelitis. Immunogenicity tests have also been performed on 3 lots or more for the purpose of antigen characterization: immunogenicity in ------- for hepatitis B and immunogenicity in ------------- for poliomyelitis.

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6.0 Clinical Background

In licensing combination vaccines the FDA is directed by the Code of Federal Regulations (CFR). A new license is required when already licensed products are combined or when unlicensed components are added to a licensed vaccine [21CFR 610.17]. In addition, safe and effective products may be combined if each component makes a contribution to the claimed effects and combining does not decrease the purity, potency, safety, or effectiveness of individual components [21CFR 601.25]. In applying the latter regulation, the FDA has relied on the concept that clinical studies of combination vaccines should be designed to rule out clinically meaningful differences, as described in the 1997 guidance document, "Guidance for Industry for the Evaluation of Combination Vaccines for Preventable Diseases: Product, Testing and Clinical Issues".

The approach to licensure of DTPa-HepB-IPV has been to demonstrate non-inferiority of the combination vaccine with respect to efficacy and safety when compared to separate administration of U.S. licensed component vaccines. As mentioned above, the DTPa and hepatitis B components of SBB's DTPa-HepB-IPV vaccine are already licensed in the U.S. as Infanrix® and Engerix-B®, respectively. The IPV component is not currently licensed in the U.S. Licensure of Infanrix® and Engerix-B® was based clinical endpoint efficacy studies. Although there exists no generally accepted immunologic correlate(s) of protection against pertussis, demonstration of a comparable (non-inferior) antibody response between the acellular pertussis components of the combination vaccine to the licensed acellular pertussis vaccine of established efficacy has been used to support efficacy in this application. For antigens with identified correlates of protection (i.e., D, T, HBs, and polio types 1, 2, and 3), evidence for efficacy has been provided by demonstrating that the immune response to these antigens surpasses the level previously established as a protective response. Additional evidence for efficacy of the D, T, HBs and polio types 1, 2, and 3 components has been sought by demonstrating non-inferiority of the immune responses to the combination vaccine compared with separately administered components. However, even if the immune response to an antigen in the combination product is decreased compared to separately administered vaccines, it may still be possible to conclude that the immune response to this component in the new combination is acceptable.

The overall objective of the clinical plan for DTPa-HepB-IPV has been to demonstrate safety and immunogenicity of this vaccine when administered as a 3 dose primary series in infants. Additionally, the manufacturer has sought to demonstrate that the vaccine can be manufactured consistently and produce consistent results with respect to reactogenicity and immunogenicity. Finally, additional studies looked at the effect of concurrent administration of Haemophilus influenzae type b (Hib) vaccine. Of note, no data have been submitted to the FDA to date evaluating DTPa-HepB-IPV with concurrent Prevnar, Wyeth-Lederle's 7 valent pneumococcal conjugate vaccine, as this product was not licensed until after submission of the BLA.

6.1 Foreign Experience

Foreign Marketing: (fax of January 26, 2001)

Infanrix® DTPa: licensed in 118 countries worldwide

DTPa-HepB-IPV/Hib: licensed in 15 European Union Member States

DTPa-HepB: licensed in 15 EU Member States and Argentina, Australia, Columbia, Czech Republic, Estonia, Hong Kong, Italy, Jordan, Kenya. Mexico, New Zealand, Nigeria, Philippines, Romania, Slovakia, Switzerland, Ukraine

DTPa-Hib: Argentina, Australia, Austria, Belgium, Brazil, Canada, Columbia, Czech Republic, Germany, Jamaica, Luxembourg, Malta, New Zealand, Romania, Singapore, Spain, Switzerland, United Kingdom

DTPa-IPV: Canada (booster), France (booster), Morocco, Switzerland (booster)

DTPa-IPV/Hib: Argentina, Austria, Belgium, Brazil, Columbia, Costa Rica, Finland, France (booster), Germany, Iceland, Israel, Italy, Jamaica, Luxembourg, Malta, Morocco, Portugal, Romania, Singapore, Spain, Sweden, Switzerland, Turkey

6.2 Directions for Use See Section 1.5 above. Note that revisions to proposed label have not been submitted to CBER.

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7.0 Description of Clinical Data Sources

Reviewer Comment: IND Studies for DTPa-HepB-IPV consisted of pivotal studies 217744-011, 217744-015 and 217744-044, hereafter referred to as Studies DTPa-HepB-IPV –011, -015, and 015. All other completed DTPa-HepB-IPV studies were not conducted under US IND.

7.1 Objectives of Clinical Studies

  1. Establish the safety of DTPa-HepB-IPV
    • To rule out important differences in the safety and reactogenicity of the combination vaccine compared to separately administered components.
  2. Establish the efficacy of DTPa-HepB-IPV
    • Efficacy to be established via immunogenicity of each component in the combination.
    • Rule out important differences between the immune response to each antigen elicited by DTPa-HepB-IPV compared to the separately administered components.
  3. Establish the safety and efficacy with concurrent immunizations
    • Evaluate immunogenicity of DTPa-HepB-IPV when administered concurrently with routinely recommended U.S. licensed vaccines anticipated to be given on the same schedule (i.e., Haemophilus influenzae type b).
  4. Demonstrate clinical consistency of production lots of DTPa-HepB-IPV.
  5. Demonstrate clinical bridging (comparative immunogenicity) between two sequential series of production lots following a manufacturing change.
  6. Compare the immunogenicity of the hepatitis B surface antigen (HBs) when given in the combination at 2, 4, and 6 months of ageversus the U.S. licensed regimen for hepatitis B (Engerix B) vaccination of 0, 1 and 6 months.

7.2 Pivotal Trial Summary

Three clinical trials, Study DTPa-HBV-IPV-011 (011), Study DTPa-HBV-IPV-015 (-015), and Study DTPa-HBV-IPV-044 (-044), were submitted as pivotal studies in support of the requested indication for DTPa-HepB-IPV as a three dose primary series. Because the DTPa and hepatitis B components of this vaccine are already licensed in the US (as Infanrix® and Engerix-B®, respectively), and generally accepted correlates of immunity exist for the IPV component, evidence of efficacy was based on demonstrating non-inferiority of DTPa-HepB-IPV with respect to immunogenicity of each component compared to separate administration of U.S. licensed component vaccines (Infanrix®, Engerix-B®, and oral or inactivated polio vaccines [OPV or IPV]). Immunogenicity data were obtained from Studies -015 and -044; safety data were obtained from all three pivotal studies. Safety of concurrent immunization with Hib vaccine was studied in all three pivotal studies and immunogenicity of concurrent Hib was studied in -015 and -044. Data on concurrent administration of Prevnar, Wyeth Lederle's 7-valent pneumococcal conjugate vaccine licensed in February 2000, were not part of the DTPa-HepB-IPV BLA (submitted in July 1999).

Study DTPa-HepB-IPV-011, a large scale comparative safety trial of DTPa-HepB-IPV was conducted in Germany under a 3, 4, 5 month primary immunization schedule with concurrent Haemophilus influenzae type b (Hib) vaccine. This trial was amended after initiation to expand enrollment and include a control group receiving separately administered U.S. licensed vaccines, i.e., DTPa, OPV, and Hib. The separate administration control group did not receive hepatitis B vaccine during the study period.

Study DTPa-HepB-IPV-015, conducted in the U.S. under a 2, 4, and 6 month primary schedule, compared the safety and immunogenicity of 3-dose primary series of DTPa-HepB-IPV and Hib with either a sequential IPV/OPV schedule or separately administered U.S. licensed vaccines, e.g., DTPa, hepatitis B, OPV and Hib.

Study DTPa-HepB-IPV-044, conducted in the U.S. under a 2, 4, 6 month schedule, evaluated lot consistency and manufacturing bridge from the 1st to the 2nd lot series. Hib was administered concurrently in each group.

7.3 Inclusion/Exclusion Criteria for Pivotal Studies

In general, criteria for inclusion were consistent across pivotal studies with minor differences. Study DTPa-HepB-IPV-011 enrolled subjects who were 8-16 weeks of age, while Studies –015 and –044 enrolled subjects who were 6-12 weeks of age at study entry. Study DTPa-HepB-IPV-011 did not exclude subjects born following a preterm (< 36 week) gestation; Studies -015 and -044 excluded former preterm infants. On entry (all pivotal studies) subjects were to be free of obvious health problems, and born to mothers seronegative for HBsAg. Subjects were excluded if they had a known hypersensitivity to any vaccine component, had previously received any vaccines or any blood or blood product (including Hepatitis B Immune Globulin), were born to mothers known to be HIV positive, had temperatures ≥ 38°C (100.4 ° F) rectally at first study visit. In addition, Study –044 specifically excluded subjects with acute disease at the time of enrollment, defined as "presence of a moderate or severe illness with or without fever." In Study-044, vaccines could be administered to persons with minor illness such as diarrhea or mild-upper respiratory infection with or without low-grade febrile illness.

Pivotal Trial Summary

Study/ Location Objectives Endpoints Schedule (mo) Concurrent vaccines N receiving
DTPa-HepB-IPV*		 N in Control Group (Separately Administered Vaccines)*
011
Germany		 Large scale comparative safety vs. separate vaccines Safety only 3, 4, 5 Hib 4695 776**
015
USA		 Comparative vs separate vaccines ( U.S. schedule) Safety and immunogenicity 2, 4, 6 Hib 200 200
044
USA		 Lot consistency; Manufacturing bridge from 1st to 2nd lot series Safety and immunogenicity 2, 4, 6 Hib 484 §
*Total cohort (number enrolled)
** Study-011 was amended after initial enrollment to include a control group receiving separately administered US licensed vaccines.
§There was no control group receiving separately administered vaccines in Study-044.

Study Designs: DTPa-HepB-IPV-011, DTPa-HepB-IPV-015, and DTPa-HepB-IPV-044 (adapted from BLA Table 8.II.9- 1)

DTPa-HepB-IPV-011 DTPa-HepB-IPV-015 DTPa-HepB-IPV-044
Country Germany Country USA Country USA
Schedule 3, 4, 5 months of age Schedule
Group 1		 2, 4, 6 months of age Schedule 2, 4, 6 months of age
Groups 1 - 4 pooled DTPa-HepB-IPV +
Various Hib*		 DTPa-HepB-IPV
+ PM Hib		 Group 1 DTPa-HepB-IPV (Lot A 2nd
lot series)+ PM Hib
    Group 2 DTPa-HepB-IPV + Hib
(2, 4 months)		 Group 2 DTPa-HepB-IPV (Lot B 2nd
lot series ) + PM Hib
DTPa-HepB + PM Hib + Lederle OPV (6 months) Group 3 DTPa-HepB-IPV (Lot C 2nd
lot series ) + PM Hib
Group 3 DTPa-HepB + PM IPV
+ PM Hib
Group 5 SBB DTPa +
PM Hib +
Lederle OPV		 Group 4 SBB DTPa +
SBB HepB + PM Hib +
Lederle OPV		 Group 4 DTPa-HepB-IPV (1st lot
series ) + PM Hib
*Group 1 = SBB Hib; Group 2 = Pasteur Merieux Connaught (PM-now Aventis Pasteur) Hib; Group 3 = Lederle Hib; Group 4 = Merck Hib

 

2.4 Demographics of Pivotal Trials

Study Country N = Total
(DTPa-HepB-IPV)		 Race
White Black Asian Other
011 Germany 5471 (4695) 96.3% 0.5% 2.2% 1.0%
015 USA 400 (200) 46.0% 12.3% 1.0% 40.8%;
Hispanic: 36%
044 USA 484 (484) 87.0% 2.5% 0.6% 9.9%;
Hispanic: 6.2%
Total Pivotal 6355 (5379) 92.4% 1.4% 2.0% 4.2%
Total Pivotal + Supportive 8792 (7028) 91.4% 1.1% 1.5% 3.3%

7.5 Supportive Study Summary

Primary series

In addition to the pivotal trials, safety and immunogenicity data from additional studies were submitted in support of the BLA. These included 1) additional studies of DTPa-HepB-IPV not conducted under US IND; and 2) studies of other Infanrix®-based combination vaccines providing supportive data on safety and immunogenicity. The latter category included Study DTPa-HepB-030 which provided immunogenicity data from SBB's DTPa-HepB combination to support the change in hepatitis B vaccination schedule from 0, 1, and 6 months (Engerix-B®) to the 2, 4, 6 months schedule of DTPa-HepB-IPV. In addition, supportive data on safety of a primary series of DTPa-HepB-IPV following a birth dose of hepatitis B vaccine was submitted in the form of Study DTPa-HepB-IPV-030 and Study DTPa-HepB-IPV/Hib-003. DTPa-HepB-IPV/Hib-003 provided data on SBB's DTPa-HepB-IPV mixed extemporaneously prior to injection with SBB's PRP-T vaccine (not licensed in the U.S.)

DTPa Booster

The license application for DTPa-HepB-IPV requests an indication for primary series immunization. Overall clinical development of DTPa-HepB-IPV included studies evaluating a toddler booster of DTPa (Infanrix®) or a fourth consecutive dose of DTPa-HepB-IPV following a primary series of DTPa-HepB-IPV. While not formally considered under this BLA, SBB has submitted summary safety and immunogenicity data on 4th (toddler) dose of Infanrix® or Infanrix®-based combinations following a primary series with DTPa-HepB-IPV.

7.5 Clinical Trial Summary (Pivotal + Supportive)

Study
Number		 Vaccine
( Lot Series)		 Objective Country Study Arms:
DTPa-HepB-IPV vs Comparator		 N = receiving DTPa-HepB-IPV# N=
Compar.		 Sched-ule
(mo)		 Comment
001 (Pilot) DTPa-HepB-IPV
(1st Lot)		 Feasibility Turkey DTPa-HepB-IPV
vs
DTPa-HepB+IPV		 20 20 3, 4, 5 Research lot
002 (Pilot) DTPa-HepB-IPV
(1st Lot)		 Feasibility Finland DTPa-HepB-IPV 30   2, 4, 6  
004 (Pilot) DTPa-HepB-IPV
(1st Lot)		 Feasibility Canada DTPa-HepB-IPV 50 0 2, 4, 6  
005 (Supportive) DTPa-HepB-IPV
(1st Lot)		 Lot consistency Belgium DTPa-HepB-IPV
(3 consistency lots)		 567 0 3, 4, 5  
011 (Pivotal) DTPa-HepB-IPV
(1st Lot)		 Large scale safety Germany DTPa-HepB-IPV+SBB Hib (1)
vs
DTPa-HepB-IPV +PMC Hib (2)
vs
DTPa-HepB-IPV +Led Hib (3)
vs
DTPa-HepB-IPV +Merck Hib (4)
vs.
DTPa+Hib+OPV (5)		 4695
(Groups 1-4)		 776
(Group 5)		 3, 4, 5 -Original objective to compare different Hib formulations
-Amended to compare to US licensed separate injections
-No serology performed
Not on US schedule of 2, 4, 6 months
012
(Supportive) 		DTPa-HepB-IPV
(1st Lot)		 Hib co-administration Lithuania DTPa-HepB-IPV+SBB Hib
vs
DTPa-HepB-IPV +PMC Hib
vs
DTPa-HepB-IPV +Led Hib
vs
DTPa-HepB-IPV +Merck Hib		 549 0 3, 4.5, 6  
015 (Pivotal) DTPa-HepB-IPV
(1st Lot)		 1) Comparative immunogenicity vs separate injections
2) Safety (common AEs)
3)Simultaneous imm. (Hib)		 USA DTPa-HepB-IPV+Hib @2,4, 6 mo (Group 1)
vs
DTPa-HepB-IPV+Hib @2,4, and DTPa-HepB+OPV+Hib @6mo (Group 2)
vs
DTPa-HepB +IPV+ Hib (Group 3)
vs
DTPa + HepB+OPV+ Hib (Grp 4)		 200 200 2, 4, 6  
016 (Supportive) DTPa-HepB-IPV
(1st Lot)		 1)Safety
2)Immunogenicity		 Germany DTPa-HepB-IPV/Hib
vs
DTPa-IPV/Hib+HepB		 184 368 3, 4, 5  

Manufacturer abbreviation: SBB=SmithKline Beecham Biologicals; PMC=Pasteur Merieux Connaught, now known as Aventis Pasteur; Led=Wyeth Lederle


Clinical Trial Summary (Pivotal + Supportive – cont.)

Study
Number		 Vaccine / Lot Series Objective Country Study Arms:
DTPa-HepB-IPV vs Comparator		 N = receiving DTPa-HepB-IPV# N=Compar Sched-ule
(mo)		 Comment
017 (Supportive) DTPa-HepB-IPV
(1st Lot)		 1)Safety
2)Immunogenicity		 France DTPa-HepB-IPV+Hib
vs
DTPa-HepB-IPV/Hib
vs
DTPa-IPV/Hib+HepB		 29 180 2, 3, 4  
019
(Supportive)		 DTPa-HepB-IPV
(1st Lot)		 1)Safety
2)Immunogenicity		 Estonia DTPa-HepB-IPV
vs
DTPa-HepB +IPV		 60 60 3,4.5,6  
030
(Supportive)		 DTPa-HepB-IPV
(2nd Lot)		 Safety after birth dose HepB Moldova birth dose HepB+ DTPa-HepB-IPV
@ 6, 10, 14 wks
vs
birth dose HepB+DTPw-IPV-Hib +HepB @ 6, 10, 14 weeks		 160 160 6,10,14 weeks -All infants received birth dose of hepB
-Compressed schedule (6, 10, 14 wks)
-Comparator includes whole cell pertussis vaccine
044
(Pivotal)		 DTPa-HepB-IPV
(1st Lot) and DTPa-HepB-IPV(2nd Lot)		 1) Lot consistency
2)Bridge from 1st lot to 2nd lot for safety and immunogenicity		 USA DTPa-HepB-IPV (Groups 1-3) (3 lots of 2nd lot series)
vs
DTPa-HepB-IPV (Group 4)
(1 lot of 1st lot series)		 484
1:1:1:1		 0 2, 4, 6 No separate injection control arm
DTPa-HepB-IPV/Hib-027
(Supportive)		 DTPa-HepB-IPV/Hib Lotconsistency (Safety and immunogenicity) USA DTPa+HepB+OPV+Hib (Group 1)
vs
DTPa-HepB-IPV/Hib
(3 lots of DTPa-HepB-IPV 2nd lot series, same lots as -044)
(Groups 2-4) 		 1085 358 2, 4, 6 Note: Study evaluated DTPa-HepB-IPV/Hib
DTPa-HepB -030
(Supportive) 		DTPa-HepB Support schedule change HepB USA DTPa-HepB + Hib + OPV
@ 2, 4, 6 mo
vs
DTPa + Hib +OPV @2,4,6 mo
HepB @0, 1, 6 mo 		N.A. N.A. 2, 4, 6 Note: Study evaluated DTPa-HepB
DTPa-HepB-IPV/HIB-003
(Supportive) 		DTPa-HepB-IPV/Hib Safety after birth dose HepB USA DTPa-HepB-IPV/Hib (no birth dose HepB) (Group 1)
vs
DTPa-HepB-IPV + birth dose HepB (Group 2) 		N.A. N.A. 2,4,6 Note: Study evaluated DTPa-HepB-IPV/Hib
Total Cohort
Safety Immunogen-icity		 all studies
Studies 011+015+044

Studies 015+044		 Pivotal + Supportive
Pivotal

Pivotal		 7028
5379

684		 1764  


#Numbers from Electronic Submission BLA 99-0800 Item 8.1.1 Summary of Studies Table 8.I.6-1

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8.0   Clinical Studies

8.1 Efficacy Data (Immunogenicity)

8.1.1 Characterization of the Immune Response: Clinical Serology

All assays were performed blinded to vaccination status. Assays were conducted in either of two laboratories: SBB Laboratories in Rixensart, Belgium or in the labs of Dr. Michael Pichichero (MEP) at the University of Rochester. Data to support the comparability of the procedures employed and the results obtained from the two laboratories were reported in the BLA.

Antigen Serological
Method		 Endpoints**
DTPa-HepB-IPV antigens
Diphtheria Toxoid (D) ELISA 0.1 IU/mL
Tetanus Toxoid (T) ELISA 0.1 IU/mL
Pertussis Toxoid (PT) ELISA 5 EL.U/mL
Filamentous Haemagglutinin (FHA) ELISA 5 EL.U/mL
Pertactin (PRN) ELISA 5 EL.U/mL
Hepatitis B surface antigen (HBs) RIA 10 mIU/mL
Poliovirus types 1, 2, 3 (IPV) Cell culture neutralization 1/8
Concurrent administration
Haemophilus influenzae type b (Hib) ELISA* 0.15 and 1.0 mcg/mL

*In studies DTPa-HepB-IPV-002, 004, -005, and -012, anti-PRP antibodies were measured using radiolabeled antigen-binding assay (RABA).

**For D, T, HBs, "seroprotection" rates (i.e., the % of infants with antibody titers equal or above the assay cut-off) were set such that subjects who had titers above the cut off could be considered protected from disease.

For polio types 1, 3, and 3, subjects with detectable neutralizing antibody were considered protected from disease.

For pertussis antigens, "vaccine response" rates (i.e., the % of infants showing a vaccine response to each pertussis antigen (PT, FHA and PRN) was defined as antibody titers equal to or above the assay cut-off in subjects who were seronegative prior to vaccination and at least maintenance of prevaccination antibody titers in those who were seropositive prior to vaccination.

8.1.2  Assessment of Immunogenicity

Subjects evaluated for immunogenicity had serum samples for measurement of antibody response obtained before vaccination and approximately one month after the third vaccine dose.

Study cohorts for immunogenicity:

Intent-to-treat (ITT) cohort for analysis of immunogenicity: All subjects enrolled in the study for whom assay results were available for antibodies against at least one study antigen either pre- or post-vaccination.

According-to-Protocol (ATP) cohort for analysis of immunogenicity:

Studies DTPa-HepB-IPV-016, -030, and -044: All evaluable subjects (i.e, those meeting all inclusion/exclusion criteria and complying with the procedures defined in the protocol, and fulfilling requirements for analysis) for whom assay results were available for antibodies against at least one study vaccine antigen post-vaccination.

All other studies: same criteria as above but must have assay results available for antibodies against at least one study antigen both pre- and post-vaccination.

Criteria for evaluation of immunogenicity:

Primary endpoints for immunogenicity were defined as seroprotection rates for D, T, HBsAg, and poliovirus (Types 1, 2, 3) and in terms of vaccine response rates and GMTs for the pertussis components (PT, FHA, and PRN). Seroprotection rates for PRP, seropositivity rates for PT, FHA and PRN, and GMTs for D, T, HBsAg, poliovirus (Types 1, 2, 3) and PRP were considered secondary endpoints.

Endpoints:

The following immunogenicity endpoints were evaluated.

  • Seroprotection rates: i.e., the % of infants with antibody titers equal to or above the assay cut-off. D, T, HepB, Polio, Hib
    • D, T, hepatitis B: % infants with antibody titers ≥ the predefined levels (see table below)
    • Polio types 1, 2, 3 : % infants with neutralizing antibodies ≥ 1:8
    • Hib: % infants with anti-PRP antibodies ≥ 0.15 and 1.0 mcg/mL
  • Vaccine response rates: Pertussis
    • % infants showing response to PT, FHA, PRN
    • Defined as: ≥ 5 EL.U/mL in subjects who were seronegative prior to vaccination or at least maintenance of pre-vaccination antibody titers in those "seropositive" prior to vaccination
  • Geometric mean antibody titers (GMTs): The anti-log of the mean of the log titer transformation.
  • Distribution of antibody responses by reverse cumulative distribution curves (RCD curves)

Statistical methodology: (From BLA 8.III.1.3)

The statistical methodology used to evaluate the immunogenicity of the study vaccine evolved during clinical development, from testing of the null hypothesis of no vaccination difference in the earlier studies to testing for non-inferiority or equivalence in later studies (ICH E-9 Statistical principles for clinical trials, Final, February, 1998: Section 3.3.2).

Three statistical approaches were used:

  1. Descriptive analyses within each vaccine group: all studies

    For each treatment group, seroprotection rates and GMTs were calculated with their 95% confidence intervals (CI) for all time points for which serum was titrated. Vaccine response rates and their 95% CI were also tabulated by treatment group.

    Antibody titer distributions, approximately one month after the vaccination course, were displayed by means of reverse cumulative distribution curves.

  2. Hypothesis testing of no difference between the SBB DTPa-HepB-IPV vaccine and control, or for lot-to-lot consistency (studies DTPa-HepB-IPV-005, -012).

    Seroprotection/ vaccine response rates were compared between vaccine groups using Fisher's Exact test, whereas GMTs were compared using one-way ANOVA test. P-values less than 0.05 (two-sided test of the null hypothesis of no difference) were considered as indicative of statistical significance.

  3. Equivalence testing between the SBB DTPa-HepB-IPV vaccine and commercial control or for lot-to-lot consistency (studies DTPa-HepB-IPV-015, -016,-030, -044, and -005 [a posteriori analysis]).

    The clinical limits defining non-inferiority of the SBB DTPa-HepB-IPV vaccine relative to a control, and consistency between lots of the SBB DTPa-HepB-IPV vaccine, were as follows:

Specified limits for non-inferiority of DTPa-HepB-IPV* relative to a control and consistency between lots of the SBB DTPa-HepB-IPV vaccine (8.III.1.3.2)

Seroprotection/vaccine response rate Max difference
% subjects with anti D ≥0.1 IU/mL 10%
% subjects with anti T ≥0.1 IU/mL 10%
% subjects with anti-PT vaccine response 10%
% subjects with anti-FHA vaccine response 10%
% subjects with anti-PRN vaccine response 10%
% subjects with anti-HBS ≥ 10 mIU/ml 10%
% subjects with anti-polio 1 ≥ 1:8 10%
% subjects with anti-polio 2 ≥ 1:8 10%
% subjects with anti-polio 3 ≥ 1:8 10%
Geometric Mean Titers (GMTs) Max Ratio
Anti-PT GMT 1.5
Anti-FHA GMT 1.5
Anti-PRN GMT 1.5
Anti-HBs GMT 2.0*
* Secondary endpoint

According to the study objectives, non-inferiority was demonstrated when, for all study primary endpoints, the upper limit of the 90% CI for the vaccine difference was below the specified clinical limit of non-inferiority (one-sided equivalence test; alpha = 5%).

Likewise, consistency was demonstrated when, for all study primary endpoints, and for all pair-wise comparisons of vaccines (lots), the 90% CI for the difference between vaccines (lots) was included in the specified clinical limits of equivalence (two-sided equivalence test; alpha =5%).

For the differences in seroprotection and vaccine response rates, exact 90% CIs were calculated using "StatXact 3.0". For GMT ratios, the 90% CIs were derived from a one-way ANOVA model on the logarithm of the titers, assuming that the logarithm of the titers were normally distributed and had a common variance across groups. The robustness of the GMT analysis with respect to the parametric assumptions was evaluated using a Cox regression model. Both ANOVA and Cox models included the group effect as the only regressor.

8.1.3 Pivotal Study for Immunogenicity: DTPa-HepB-IPV-015 (Comparative Immunogenicity vs. Separately Administered U.S. Licensed Vaccines)

Title: An open study of the safety and immunogenicity of DTPa-HepB-IPV vaccine administered as a three dose series or in a sequential IPV/OPV schedule at 2, 4, and 6 months of age.

Objectives:

Primary Objective: To evaluate the immune response and potential interactions to each of the 10 antigens (D, T, PT, FHA, Pertactin, PRP, Hepatitis B, and polio virus types 1, 2, and 3) in infants who receive three doses of DTPa-HepB-IPV vaccine and Hib (OmniHIB™) simultaneously at separate sites compared to DTPa-HepB (SBB) administered with IPV (IPOL®) and Hib (OmniHIB™) simultaneously at separate injection sites and compared to DTPa (Infanrix®), Hepatitis B (Engerix-B®) and Hib (OmniHIB™) vaccines simultaneously at separate sites along with OPV (ORIMUNE™).

Secondary objective: To evaluate the safety and immunogenicity of the IPV component of the DTPa-HepB-IPV administered as a single injection relative to the safety and immunogenicity of OPV (ORIMUNE®) or IPV (IPOL®) administered separately along with DTPa (Infanrix®) Hepatitis B (Engerix-B®), Hib (OmniHIB™ or DTPa-HepB (SBB) and Hib (OmniHIB™). Note SBB's DTPa-HepB vaccine is not licensed in the U.S.

To compare the safety and immunogenicity of the sequential administration of DTPa-HepB-IPV vaccine at 2 and 4 months followed by OPV (ORIMUNE®) at 6 months of age with a three dose series of DTPa-HepB-IPV vaccine.

Design: Open, randomized

Schedule: 2, 4, 6 months

Group 1: DTPa-HepB-IPV + Hib at 2, 4, 6 mo
Group 2: DTPa-HepB-IPV at 2, 4 mo; DTPa-HepB + Hib + OPV at 6 months
Group 3: DTPa-HepB + Hib + IPV at 2, 4, 6 mo
Group 4: DTPa + HepB + OPV + Hib at 2, 4, 6 mo

Number of subjects

Total enrolled (ITT cohort): 400 (100 per group)
Completed: 347

ATP for safety cohort: 399
ATP immunogenicity cohort: 332

Data analysis

As defined by SBB, the primary objective was demonstrated if the upper limits of all the 90% CIs for the difference in the primary endpoints (see section 8.1.2: specified limits of non-inferiority) between Group 1 and Group 4, were below the limit defining clinical non-inferiority.

In the review of DTPa-HepB-IPV, Group 1 ( DTPa-HepB-IPV + Hib at 2, 4, and 6 months of age) and Group 4 (DTPa + HepB + Hib + OPV at 2, 4, and 6 months of age) considered. Group 2 included the sequential IPV/OPV schedule which is no longer part of the U.S. Recommended Childhood Immunization Schedule, and Group 3 evaluated SBB's DTPa-HepB combination (unlicensed in the U.S). Therefore, data presented below concentrate on groups 1 and 4.

DTPa-HepB-IPV-015: Comparison of the immunogenicity of DTPa-HepB-IPV and U.S. licensed vaccines administered separately, i.e., Group 1 vs Group 4 (ATP cohort for immunogenicity)

Antigens Seroprotection/Vaccine Response‡ GMTs§
Group 1 Group 4 Difference (Group 4
minus Group 1)		 Group 1 Group 4 Group 4 Divided by Group 1
N % N % 90% CI 90% CI
  LL UL   LL UL
Diphtheria 90 98.9 78 100 1.1 -5.2 8.2* 1.294** 0.805 0.62 0.50 0.77
Tetanus 90 100 78 100 0.0 -7.0 5.5* 3.730** 2.345 0.63 0.51 0.77
Hepatitis B 89 100 77 100 0.0 -7.1 5.5* 1661.2 804.9 0.48 0.35 0.67*
PT 91 98.9 78 98.7 -0.2 -8.1 6.2* 97.1 47.5 0.49 0.41 0.58*
FHA 91 95.6 77 100 4.4 -2.6 12.8 119.1 153.2 1.29 1.12 1.48*
PRN 91 95.6 78 91.0 -4.6 -15.0 4.3* 150.4 108.6 0.72 0.58 0.90*
Polio 1 86 100 73 98.6 -1.4 -9.7 4.7* 415.3** 819.2 1.97 1.48 2.63
Polio 2 86 98.8 73 100 1.2 -5.6 8.6* 514.2** 1261.8 2.45 1.83 3.29
Polio 3 86 100 73 100 0.0 -7.4 5.7* 1729.2** 452.6 0.26 0.20 0.34
PRP** ≥ 1.0 mcg/ml 90 94.4 78 94.9 0.4 -8.5 10.1* 6.165** 7.822 1.27 0.95 1.69
≥ 0.15 mcg/ml 90 98.9 78 100 1.1 -8.2 5.2*
Group 1: DTPa-HepB-IPV + Hib at 2, 4, and 6 months of age
Group 4: DTPa + HepB + Hib + OPV at 2, 4, and 6 months of age
N = number of subjects tested
‡ Definition of s eroprotection/vaccine response provided in Section 3.2.2.
§ Clinical limit = GMT ratio of 1.5 for all anti-pertussis antibodies (anti-PT, anti-FHA, and anti-PRN); 2.0 for anti-HBs
*Upper limit of 90% CI below clinical limit for non-inferiority
**supportive parameter of secondary interest (clinical limit for non-inferiority was not specified for these antigens)

Reviewer comment: Differences in seroprotection/vaccine response rates between Group 1 and Group 4 as well as GMT ratios between Group 1 and Group 4 one month after completion of the three-dose primary vaccination course in subjects included in the according to protocol (ATP) immunogenicity analyses were within the pre-specified clinical limits for non-inferiority with the exception of vaccine response rates for FHA (bolded).

8.1.4 Pivotal Study: DTPa-HepB-IPV-044 (Lot Consistency and Manufacturing Bridge)

Title: A double-blind randomized primary vaccination study to evaluate the lot-to-lot consistency of DTPa-HepB-IPV vaccine manufactured according to the new manufacturing process and to bridge the DTPa-HepB-IPV vaccine manufactured according to the new manufacturing process with the DTPa-HepB-IPV vaccine manufactured by the initial manufacturing process administered to infants at 2, 4, and 6 months of age co-administered with Hib vaccine (OmniHIB™) in a separate injection.

Location: USA

Study Period: 2/11/98-2/3/99

Investigators:

Mark M. Blatter, MD: Pittsburgh Pediatric Research
Douglas Eisert, MD: Wenatchee Valley Clinic, WA
Gerald W. Bottenfield, MD: R/D Clinical Research, Inc., Lake Jackson, TX
James M. McCarty, MD: Hill Top Research, Inc., Fresno, CA
Kathryn M. Edwards, MD: Vanderbilt University School of Medicine, TN
Beth W. Nauert, MD: Center for Clinical Research, Austin, TX

Objectives:

Primary Objective:

  • To evaluate the lot-to-lot consistency in terms of immunogenicity for three production lots of DTPa-HepB-IPV vaccine manufactured according to the new manufacturing process (second lot series)

Secondary Objectives:

  • To evaluate the lot-to-lot consistency in terms of reactogenicity for three production lots of DTPa-HepB-IPV vaccine manufactured according to the new manufacturing process (second lot series)
  • To evaluate whether DTPa-HepB-IPV vaccine manufactured according to the new manufacturing process (second lot series) results in decreased immunogenicity as compared to DTPa-HepB-IPV vaccine manufactured according to the initial manufacturing process (first lot series): Manufacturing bridge from first to second lot series for immunogenicity
  • To evaluate whether DTPa-HepB-IPV vaccine manufactured according to the new manufacturing process (second lot series) results in increased reactogenicity as compared to DTPa-HepB-IPV vaccine manufactured according to the initial manufacturing process (first lot series): Manufacturing bridge from first to second lot series for safety

Schedule: 2, 4, 6 months of age
(6-12 weeks at time of first vaccination)

Group 1: DTPa-HepB-IPV, Lot A 2nd lot series + Hib (OmniHIB™)
Group 2: DTPa-HepB-IPV, Lot B 2nd lot series + Hib (OmniHIB™)
Group 3: DTPa-HepB-IPV, Lot C 2nd lot series + Hib (OmniHIB™)
Group 4: DTPa-HepB-IPV, 1st lot series + Hib (OmniHIB™)

Number of subjects

Number of subjects: Enrolled (ITT Cohort): 484 at five centers (Note: six centers were initiated but one of the six centers did not enroll any subjects)

According-to-Protocol (ATP) safety analysis: 477

ATP Immunogenicity analysis (primary analysis): 434

Population group: Healthy infants, 6 to 12 weeks of age at the time of the first vaccination

Data analysis for immunogenicity

For each treatment group, and for the pooled second series lots, the seropositivity rates/seroprotection rates/vaccine response rates one month after the third vaccination and their exact 95% CIs were calculated. Antibody titers were summarized by GMTs with their 95% CIs and Reverse Cumulative Distribution Curves.

Primary objective: For evaluation of the lot-to-lot consistency, the pairwise differences between Group 1 and Group 2, Group 1 and Group 3, and Group 2 and Group 3 were evaluated using 90% CIs for primary and secondary parameters. The primary objective, i.e., consistency of the three second series production lots of DTPa-HepB-IPV vaccine, was reached if for all primary parameters each set of 90% confidence intervals for pairwise differences were within the clinical limits defining equivalence for differences in vaccine response/ seroprotection rates [-10%; +10%] and for GMT ratios for anti-PT, anti-PRN and anti-FHA [0.67; 1.5].

Secondary objective: The non-inferiority of the second series formulation (pooled Groups 1, 2 and 3) as compared to the first series formulation (Group 4) was also evaluated using 90% CIs for primary parameters and secondary parameters. If the primary objective was reached, the second series formulation was considered at least as immunogenic as the first series formulation, if the upper limits of the exact 90% CI of treatment effect were below the clinical limits defining non-inferiority for all primary parameters.

Primary objective: Lot-to-lot consistency

DTPa-HepB-IPV-044: Seroprotection/vaccine response rates for Group 1, Group 2 and Group 3 with maximum 90% CI limits of pairwise differences for subjects (ATP cohort for immunogenicity)

Endpoints Group 1 Group 2 Group 3 Maximum 90% CI
limit of pairwise
differences*
N Rate N Rate N Rate
  (%)   (%)   (%)
anti-D > 0.1 IU/mL‡ 107 100 112 100 109 99.1 7.0%**
anti-T > 0.1 IU/mL‡ 107 100 112 100 109 100 5.5%**
Vaccine response to PT‡ 107 100 112 99.1 109 100 6.8%**
Vaccine response to FHA‡ 97 99.0 104 96.2 102 100 11.4%
Vaccine response to PRN‡ 107 91.6 112 83.9 109 91.7 17.8%
anti-HBs > 10 mIU/mL‡ 107 99.1 112 98.2 109 100 8.2%**
anti-Polio 1 > 8‡ 107 100 111 100 108 100 5.6%**
anti-Polio 2 > 8‡ 107 100 111 100 108 100 5.6%**
anti-Polio 3 > 8‡ 107 100 110 100 108 100 5.6%**
anti-PRP > 1.0 mcg/mL† 107 92.5 112 89.3 109 90.8 12.5%
anti-PRP > 0.15 mcg/mL† 107 100 112 100 109 100 5.5%
Group 1: DTPa-HBV-IPV, second series Lot A + Hib
Group 2: DTPa-HBV-IPV, second series Lot B + Hib
Group 3: DTPa-HBV-IPV, second series Lot C + Hib
N = number of subjects tested
* highest value among the limits of exact 90% CIs for all pairwise differences between groups 1, 2, and 3
**Maximum 90% CI limit of pairwise differences below clinical limit for equivalence
Clinical limit = 10% difference in seroprotection rates except for anti-PRP > 0.15 mcg/mL where limit = 5% difference
Vaccine response to PT, FHA, and PRN was defined as appearance of antibodies in subjects who were initially seronegative,
and at least maintenance of prevaccination antibody titers in those who were initially seropositive.
‡: parameter of primary interest
† supportive parameter of secondary interest

Reviewer comment: When the immune response in terms of seroresponse/vaccine response rates to lots A, B, and C in the second lot series underwent pairwise comparison, the difference in seroresponse/vaccine response rate was within the prespecified limit of 10% for equivalence (lot consistency), with the exception of the response rates to pertactin and FHA (bolded).

DTPa-HepB-IPV-044: Post-vaccination GMTs in Group 1, Group 2 and Group 3 with maximum 90% CI limits of pairwise ratios (ATP cohort for immunogenicity)

Endpoints Group 1 Group 2 Group 3 Maximum 90% CI limit of
pairwise ratio*
N GMT N GMT N GMT
anti-D† 107 1.050 112 1.049 109 1.047 1.22
anti-T† 107 2.651 112 2.561 109 2.910 1.34
anti-PT‡ 107 93.1 112 99.1 109 105.3 1.30**
anti-FHA‡ 97 164.4 104 151.0 102 190.2 1.41**
anti-PRN‡ 107 115.4 112 95.9 109 126.7 1.59
anti-HBs§ 107 1563.8 112 1575.5 109 1930.4 1.73**
anti-Polio 1† 107 295.3 111 320.6 108 371.5 1.60
anti-Polio 2† 107 277.7 111 288.3 108 406.4 1.86
anti-Polio 3† 107 848.3 110 800.9 108 1057.4 1.69
anti-PRP† 107 5.107 112 4.955 109 6.431 1.67
Group 1: DTPa-HBV-IPV, second series Lot A + Hib
Group 2: DTPa-HBV-IPV, second series Lot B + Hib
Group 3: DTPa-HBV-IPV, second series Lot C + Hib
N = number of subjects tested
* highest value among the limits of 90% CIs for all pairwise ratios between groups 1, 2 and 3
** Maximum 90% CI limit of pairwise ratios below clinical limit for equivalence
Clinical limit = GMT ratio of 1.5 for all anti-pertussis antibodies (anti-PT, anti-FHA, and anti-PRN); 2.0 for anti-HBs
‡: parameter of primary interest
§: main parameter of secondary interest
† supportive parameter of secondary interest (clinical limit for non-inferiority was not specified for these endpoints)

Reviewer comment:With respect to the pairwise ratios of GMTs, the prespecified endpoints for non-inferiority between the three lots were met, with the exception of the GMTs to pertactin (bolded).

To address the fact that the a priori clinical limits defining equivalence for lot-to-lot consistency were not met with respect to all pertussis antigens, the manufacturer hypothesized that high prevaccination titers affected the immune response to pertussis components. A reanalysis of the data was performed as follows:

Study DTPa-HepB-IPV-044: Re-analysis of the consistency of the Second Lot Series of the SBB DTPa-HepB-IPV vaccine in terms of the immune response to the pertussis antigens after adjustment for pre-vaccination titer: vaccine response calculated after elimination of subjects with high* pre-vaccination titers; GMT analyzed after adjustment for pre-vaccination titer (ANCOVA) (BLA Table 8.III.1.7)

Antigen Vaccine Response† GMT‡
Group 1 Group 2 Group 3 Max 90% CI limit for difference between lots Group 1 Group 2 Group 3 Max 90% CI limit for ratio between lots
N % N % N % N   N   N  
PT 106 100 109 100 111 99.1 6.9§ 107 93 109 104 112 101 1.3§
FHA 97 99.0 101 100 104 96.2 11.4 97 165 102 187 104 152 1.4§
PRN 97 96.9 104 95.2 101 92.1 14.9 107 116 109 121 112 100 1.4§
Group 1: DTPa-HBV-IPV, second series Lot A+ Hib
Group 2: DTPa-HBV-IPV, second series Lot B + Hib
Group 3: DTPa-HBV-IPV, second series Lot C+ Hib
% = Percentage of subjects with VR
*Anti-PT titer ³ 54 EL.U/ml; Anti-FHA titer ³ 119 EL.U/ml; Anti-PRN titer ³ 56 EL.U/ml
†VR definition: for pertussis antibodies: initially seronegative subjects with post-vaccination titer ³ cut-off (5 EL.U/ml) or
initially seropositive subjects with post-vaccination titer ³ pre-vaccination titer
‡Units for Pertussis antibodies: EL.U/ml §Limit within clinical limits of equivalence

Reviewer comment: The sponsor hypothesized that failure to meet the equivalence criteria for demonstrating lot consistency with respect to pertactin and FHA may be due to an imbalance in the groups in the number of subjects with high prevaccination titers (from maternal antibodies) to pertussis antigens. However, even after excluding subjects with high pre-vaccination titers, the maximum difference between the lots still falls outside the prespecified limit of 10% with respect to vaccine response rates to FHA and pertactin (bolded). The adjusted GMTs, however, are within prespecified limits.

Manufacturing bridge: 1st to 2nd lot series

DTPa-HepB-IPV-044: Comparison of the immunogenicity of the First and Second Lot Series vaccine (BLA Table 8.III.1-10)

Antigen Seroprotection/Vaccine response* GMT†
2nd Lot Series‡ 1st lot Series§ 1st minus
2nd Lot Series		 2nd Lot Series‡ 1st lot Series§ 1st divided by
2nd Lot Series
  N % N % % 90% CI N % N %   90% CI
          LL UL           LL UL
Diphtheria 328 99.7 106 99.1 -0.6 -5.4 1.9 ¶ — — — — — — —
Tetanus 328 100 106 100 0 -4.2 1.9 ¶ — — — — — — —
PT 328 99.7 104 99.0 -0.7 -5.6 1.8 ¶ 328 99 106 101 1.0 0.9 1.1¶
FHA 303 98.3 99 96.0 -2.4 -8.7 1.8 ¶ 303 168 101 163 1.0 0.9 1.1¶
PRN 328 89.0 104 95.2 6.2 -0.5 12.3 328 112 106 133 1.2 1.0 1.4¶
HBs 328 99.1 106 99.1 0 -5.1 2.8 ¶ 328 1682 106 1455 0.9 0.7 1.1¶
Polio 1 326 100 105 100 0 -4.3 1.9 ¶ — — — — — — —
Polio 2 326 100 105 100 0 -4.3 1.9 ¶ — — — — — — —
Polio 3 325 100 105 100 0 -4.3 1.9 ¶ — — — — — — —
% = Percentage of subjects with SP/ VR
— = No pre-specified limit of non-inferiority
†Units: •Pertussis antibodies: EL.U/ml
•HBs antibodies: mIU/ml
•Polio: None
‡Pooled data from lots Second Lot Series (Lots A, B, C) §First Lot Series   ¶Upper limit below clinical limit for non-inferiority

Reviewer comment: With respect to manufacturing bridging from the 1st lot series to 2nd lot series, SBB met their prespecified endpoints with the exception of vaccine response rates to pertactin (bolded).

To address the fact that the a priori clinical limits defining equivalence for manufacturing bridging were not met with respect to all pertussis antigens, the manufacturer hypothesized that high prevaccination titers (from maternal antibodies) affected the immune response to pertussis components. A reanalysis of the data was performed as follows:

Study DTPa-HepB-IPV-044: Re-analysis of the comparison of the immunogenicity of the First and Second Lot Series of the SBB DTPa-HepB-IPV vaccine in terms of the immune response to the pertussis antigens after adjustment for pre-vaccination titer: vaccine response calculated after elimination of subjects with high* pre-vaccination titers; GMT analyzed after adjustment for pre-vaccination titer (ANCOVA) (Table 8.III.1- 11)

Antigen VR† GMT (EL.U/ml)
2nd Lot Series‡ 1st lot
Series		 1st minus
2nd Lot Series		 2nd Lot
Series‡		 1st lot
Series		 1st divided by
2nd Lot Series
N % N % % 90% CI N  

 N

 

 

 90% CI
LL UL LL UL
PT 326 99.7 103 100 0.3 -3.9 2.9¶ 328 99 104 102 1.0 1.0 1.2¶
FHA 302 98.3 94 100 1.7 -3.1 5.2¶ 303 167 99 165 1.0 0.9 1.1¶
PRN 302 94.7 98 99.0 5.3 0.4 9.8¶ 328 112 104 132 1.2 1.0 1.3¶
% = Percentage of subjects with VR
*Anti-PT titer ³54 EL.U/ml; Anti-FHA titer ³119 EL.U/ml; Anti-PRN titer ³56 EL.U/ml
†VR definition:
•Pertussis antibodies:
– initially seronegative subjects with post-vaccination titer ³ cut-off (5 EL.U/ml)
– initially seropositive subjects with post-vaccination titer ³ pre-vaccination titer
‡Pooled data from A, B, C
¶Upper limit below clinical limit for non-inferiority

Reviewer comment: As was done in the evaluation of lot consistency, SBB performed a reanalysis of vaccine response rates adjusting for high prevaccination antibody titers. Under this reanalysis, the prespecified criteria for non-inferiority with respect to the pertussis antigens were met for the comparison between the first and second lot series.

8.1.5  Supportive Data for Immunogenicity: Non-inferiority of DTPa-HepB-IPV Compared with
Separately Administered Vaccines and Lot Consistency of Second Lot Series: Study
DTPa-HepB-IPV/Hib-027

Additional data to support the non-inferiority of the immune response to DTPa-HepB-IPV compared with separately administered vaccines, as well as the lot-to-lot consistency of the second lot series were provided by study DTPa-HepB-IPV/Hib-027 conducted under IND -------- in the US under a 2, 4, 6 month schedule. This study evaluated the same lots of DTPa-HepB-IPV used in DTPa-HepB-IPV-044 but evaluated SBB's DTPa-HepB-IPV/Hib vaccine (DTPa-HepB-IPV admixed with SBB's PRP-T prior to injection). DTPa-HepB-IPV/Hib is not licensed in the U.S. Unlike Study DTPa-HepB-IPV-044, Study DTPa-HepB-IPV/Hib-027 included a control group receiving separately administered vaccines. Lot-to-lot consistency testing for the three pertussis antigens PT, FHA, and pertactin was performed using an equivalence approach and the same prespecified criteria as in Study DTPa-HepB-IPV-044. Results are shown below.

DTPa-HepB-IPV/Hib-027 – Comparative Immunogenicity: DTPa-HepB-IPV/Hib vs. Separately Administered vaccines--Vaccine response rates and GMTs to pertussis antigens-ATP cohort

Vaccine Response GMT
Antibody Group 1
  N %  95% CI
 LL UL		   95% CI
 LL   UL
Anti-PT 216 99.1 96.7 99.9 54.2 50.3 58.3
Anti-FHA 203 99.5 97.3 100 332.9 309.5 358.1
Anti-PRN 217 97.7 94.7 99.2 112.0 100.5 124.7
  Group 2
Anti-PT 252 99.2 97.2 99.9 70.7 65.9 75.9
Anti-FHA 226 98.7 96.2 99.7 321.7 299.6 345.5
Anti-PRN 253 96.8 93.9 98.6 116.1 104.8 128.8
  Group 3
Anti-PT 227 97.8 94.9 99.3 82.3 76.7 88.4
Anti-FHA 206 99 96.5 99.9 296.2 275.4 318.6
Anti-PRN 230 94.3 90.5 97 122.8 110.8 136.0
  Group 4
Anti-PT 249 98.4 95.9 99.6 70.7 65.5 76.3
Anti-FHA 241 99.2 97 99.9 322.5 301.6 344.8
Anti-PRN 251 95.6 92.3 97.8 114.6 104.3 125.9
  Pooled groups 2, 3, 4
Anti-PT 728 98.5 97.3 99.2 74.2 71.1 77.4
Anti-FHA 673 99 97.9 99.6 313.9 301.4 326.8
Anti-PRN 734 95.6 93.9 97 117.7 111.1 124.7
Group 1: DTPa + HepB + OPV + Hib
Group 2: DTPa-HepB-IPV lot A mixed with Hib lot A
Group 3: DTPa-HepB-IPV lot B mixed with Hib lot B
Group 4: DTPa-HepB-IPV lot C mixed with Hib lot C
N = number of subjects with results available
%=percentage of subjects with a vaccine response
Vaccine response defined as appearance of antibodies in initially seronegative subjects and at least maintenance of pre-vaccination titers in initially seropositive subjects

Reviewer comment: Unlike Study DTPa-HepB-IPV-044, Study DTPa-HepB-IPV/Hib-027 included a control group receiving separately administered Infanrix®. Study DTPa-HepB-IPVHib-027 utilized a larger sample size than Study DTPa-HepB-IPV-044. For purposes of evaluating the immune responses to the pertussis components of DTPa-HepB-IPV, supportive data using the related product DTPa-HepB-IPV admixed with Hib is appears reasonable. Immune responses to pertussis components (vaccine response and GMTs) were comparable between individual lots of DTPa-HepB-IPV/Hib as well pooled lots of DTPa-HepB-IPV/Hib and separately administered DTPa, HepB, OPV and Hib. For all other immunogenicity endpoints, non-inferiority of the immune response to the combination compared with separately administered vaccines was demonstrated with the exception of the Hib component (data not shown). The fact that non-inferiority of the immune response to the Hib component of DTPa-HepB-IPV/Hib was not demonstrated in Study DTPa-HepB-IPV/Hib-027 is of significance in the evaluation of DTP-HepB-IPV/Hib, but not of direct relevance to DTP-HepB-IPV where Hib is administered via a separate injection.

Study DTPa-HepB-IPV/Hib-027: Lot Consistency: Differences in vaccine response rates to PT, FHA and PRN with their 90% CIs between paired consistency lots (Group 2 and Group 3, Group 2 and Group 4, and Group 3 and Group 4) -- ATP cohort for Immunogenicity (BLA amendment 8/3/00, Table 23.b-1)

Endpoints Group 3 Group 2 Difference (Group 2 minus Group 3)
N Rate
(%)		  N Rate
(%)		 Difference of
rates (%)		 90% CI
LL UL
Vaccine response to PT 227 97.80 252 99.21 1.41 -1.48 5.09*
Vaccine response to FHA 206 99.03 226 98.67 -0.36 -3.88 2.85*
Vaccine response to PRN 230 94.35 253 96.84 2.49 -1.53 7.13*
  Group 4 Group 2 Difference
(Group 2 minus Group 4)
Vaccine response to PT 249 98.39 252 99.21 0.81 -2.09 3.94*
Vaccine response to FHA 241 99.17 226 98.67 -0.50 -3.85 2.40*
Vaccine response to PRN 251 95.62 253 96.84 1.22 -2.73 5.32*
  Group 4 Group 3 Difference
(Group 3 minus Group 4)
Vaccine response to PT 249 98.39 227 97.80 -0.59 -4.40 2.59*
Vaccine response to FHA 241 99.17 206 99.03 -0.14 -3.56 2.70*
Vaccine response to PRN 251 95.62 230 94.35 -1.27 -6.06 2.98*
Group 2: DTPa-HepB-IPV lot A mixed with Hib lot A
Group 3: DTPa-HepB-IPV lot B mixed with Hib lot B
Group 4: DTPa-HepB-IPV lot C mixed with Hib lot C
N = number of subjects with pre- and post-vaccination results available
Vaccine response defined as appearance of antibodies in initially seronegative subjects and at least maintenance of pre-vaccination titers in initially seropositive subjects
*Upper and lower limits of 90% CIs within clinical limits for equivalence
Clinical limits = -10%, +10% difference in vaccine response rates

Study DTPa-HepB-IPV/Hib-027: Lot Consistency: Ratios of post-vaccination GMTs for anti-PT, anti-FHA, and anti-PRN with their 90% CIs between paired consistency lots (Group 2 and Group 3, Group 2 and Group 4, and Group 3 and Group 4) -- ATP cohort for immunogenicity (BLA amendment 8/3/00-Table 23.b-2)

Antibody Group 2 Group 3 Group 2 divided by Group 3
  90% CI
N GMT N GMT Ratio of GMTs LL UL
anti-PT 302 70.7 274 82.3 0.86 0.79 0.94*
anti-FHA 273 321.7 248 296.2 1.09 1.00 1.18*
anti-PRN 303 116.1 276 122.8 0.95 0.84 1.07*
  Group 2 Group 4 Group 2 divided by Group 4
anti-PT 302 70.7 289 70.7 1.00 0.92 1.09*
anti-FHA 273 321.7 281 322.5 1.00 0.92 1.08*
anti-PRN 303 116.1 290 114.6 1.01 0.90 1.14*
  Group 3 Group 4 Group 3 divided by Group 4
anti-PT 274 82.3 289 70.7 1.16 1.07 1.27*
anti-FHA 248 296.2 281 322.5 0.92 0.84 1.00*
anti-PRN 276 122.8 290 114.6 1.07 0.95 1.21*
Group 2: DTPa-HepB-IPV lot A mixed with Hib lot A
Group 3: DTPa-HepB-IPV lot B mixed with Hib lot B
Group 4: DTPa-HepB-IPV lot C mixed with Hib lot C
N = number of subjects with available results
*Upper and lower limits of 90% CIs within clinical limits for equivalence
Clinical limits = GMT ratio between 0.67, 1.5

Reviewer comment: Data from Study DTPa-HepB-IPV/Hib-027 utilized the same lots of DTPa-HepB-IPV as in DTPa-HepB-IPV. In these studies, all prespecified pertussis immunogenicity endpoints for demonstrating lot-to-lot consistency of the second lot series were met.

Summary of data supporting lot-to-lot consistency and manufacturing bridge: In Study DTPa-HepB-IPV-044, SBB met all prespecified endpoints for demonstrating lot-to-lot consistency of the 2nd lot series, with the exception of the immune response to FHA (vaccine response rate) pertactin (vaccine response rate and GMT). SBB also did not meet their prespecified immunogenicity endpoints with respect to pertactin for the manufacturing bridge between the 1st and 2nd lot series. When a re-analysis was performed eliminating those subjects with high prevaccination titers to pertussis components, prespecified criteria for manufacturing bridging from the first to second lot series were met. However, for lot consistency, comparison between the three lots with respect to the vaccine response to pertactin and FHA exceeded the prespecified limit.

Of note, Reverse Cumulative Distribution (RCD) curves (not shown) of the immune responses to pertussis antigens shows that virtually all infants (regardless of lot administered) demonstrated an immune response to each pertussis component. Pairwise comparison of the three lots demonstrates that one lot of the second lot series appeared to elicit lower immune response to FHA and pertactin than the other two lots; this lot may account at least in part for the failure to meet prespecified criteria for lot consistency and manufacturing bridging.

To provide further support for consistency of the second lot series, SBB submitted data from DTPa-HepB-IPV/Hib-027 (lot consistency study of SBB's DTPa-HepB-IPV admixed with Hib prior to injection) utilized identical lots of DTPa-HepB-IPV as those used in Study DTPa-HepB-IPV-044. DTPa-HepB-IPV/Hib-027 met all pre-specified endpoints for pertussis antigens for demonstrating lot-to-lot consistency. In addition, DTPa-HepB-IPV/Hib included a comparison arm with separately administered vaccines including DTPa (Infanrix®). The immune response to pertussis components elicited by the three lots of DTPa-HepB-IPV admixed with Hib demonstrated comparable immune response to those of Infanrix®.

The clinical relevance of the observed difference in the immune response to FHA and pertactin is unclear because there exists no generally accepted immunologic correlate(s) of protection against pertussis. One U.S. licensed acellular pertussis vaccine (Certiva) contains only pertussis toxoid. For all studies in the BLA, the database was searched for the occurrence of pertussis disease. Only one subject was diagnosed with pertussis (subject # 4255 from DTPa-HepB-IPV-011) based on clinical symptomatology. This infant received DTPa-HepB-IPV at approximately 2, 3 and 4 months of age. Fifteen days after the third dose she was hospitalized for 3 days for apnea, cyanosis and a pertussis-like cough. No confirmatory testing was performed. One DTPa-HepB-IPV recipient experienced a "pertussoid fit of coughing" 3 days after the first dose. No confirmatory testing was performed. The patient recovered and went on to receive two subsequent doses uneventfully.

8.1.6 Hepatitis B Vaccine Schedule Change

The recommended schedule for administration of Engerix-B®, SBB's U.S. licensed hepatitis B vaccine, in infants is a 0, 1 and 6 month schedule. Under this BLA, SBB seeks an indication for DTPa-HepB-IPV administration on a 2, 4, and 6 month schedule. Summary data on the immune response to HBs for all studies submitted as part of the BLA are presented below.

A. Summary BLA Studies: Hepatitis B immunogenicity in infants receiving DTPa-HepB-IPV -
Effect of Variations in Schedule on Seroprotection and GMT

Study Lab N Seroprotection % [95%CI] GMT [95%CI]
2, 4, 6 months
002 SBB 19 100 [79.1-100] 1517 [875-2630]
004 SBB 46 100 [90.4-100] 1398 [952-2054]
015 MEP 89 100 [95.9-100] 1661 [1256-2198]
044 (pooled 2nd lot) MEP 328 99.1 [97.4-99.8] 1682 [1428-1980]
044 (1st lot) MEP 106 99.1 [94.9-100] 1455 [1108-1911]
3, 4, 5 months
001 SBB 17 100 [77.1-100] 707 [448-1115]
005 SBB 343 97.7 [95.3-98.9] 376 [320-441]
016 MEP 161 98.8 [98.8-99.8] 484 [386-608]
3, 4.5, 6 months
012 SBB 507 99.6 [98.6-100] 890 [798-992]
019 MEP 45 100 [90.2-100] 2070 [1515-2829]
2, 3, 4 months
017 MEP 23 95.7 [76.0-99.8] 472 [231-964]
1.5, 2.5, 3.5 months
>030 MEP 150 98.7 [95.3-99.8] 1016 [835-1237]

Reviewer comment:Clinical studies of hepatitis B vaccines have defined a protective antibody (anti-HBs) level as ≥ 10 mIU/mL. The observed anti-HBs response in infants receiving DTPa-HepB-IPV was significantly greater than the level considered protective against hepatitis B disease. In the three BLA studies administering DTPa-HepB-IPV on the proposed 2, 4, 6 month schedule, 99.1- 100% considered seroprotective, with GMTs from 1455 to 1661 mIU/mL.

Because administration of DTPa-HepB-IPV on a 2, 4, 6 month schedule differs from the licensed schedule of its hepatitis B vaccine component, Engerix-B®, data were sought demonstrating that the HBs immune responses for both schedules were comparable. Study DTPa-HepB-IPV-015 (see section 3.2.3) compared DTPa-HepB-IPV + Hib (group 1) with separately administered DTPa, HepB, OPV and Hib (group 4), but both groups received vaccinations on a 2, 4, and 6 schedule. Both groups achieved 100% seroprotection, but the GMTs for the group receiving DTPa-HepB-IPV (group 1) were 1661 mIU/mL compared with 805 mIU/mL for the group receiving separately administered Engerix-B® (group 4). No data were submitted as part of the BLA directly comparing the anti-HBs immune response of DTPa-HepB-IPV to the immune response Engerix-B® administered at birth, 1 and 6 months. Supportive data for the change in schedule for the hepatitis B component, were submitted from Study DTPa-HepB-030 which evaluated SBB's DTPa-HepB combination (not licensed in the U.S.)

B. DTPa-HepB-030: Supportive Study for Schedule Change for Hepatitis B Component

Title: An Open Study of the Safety and Immunogenicity of DTPa-HepB Vaccine Administered as a Single Injection at 2, 4, and 6 Months of Age as
 Compared to Engerix-B® [Hepatitis B Vaccine (Recombinant)] Administered at Birth, 1, and 6 Months of Age and DTPa Vaccine Administered
 at 2, 4, and 6 Months of Age.

Location: USA

Investigators: Joel Ward, MD

Study Date (Started/Completed): April 1996-March 1997

Objective:

Primary Objective: (Immunogenicity)

To evaluate the immune response to the hepatitis B component of the combined DTPa-HB vaccine administered as a single injection at 2, 4, and 6 months of age as compared to the response to Engerix-B® administered at birth, 1, and 6 months of age.

Methodology:

Open, randomized, controlled trial

Number of subjects

Enrolled (ITT cohort): 280 (140 each group)
Completed: 210
ATP cohort for safety: 265
ATP cohort for immunogenicity: 204

Population: Healthy infants, between birth and 7 days of age at time of enrollment.

Schedule:

Group 1 - DTPa-HepB + Hib + OPV (at 2, 4, and 6 months of age):
Group 2 - DTPa + Hib + OPV (at 2, 4, and 6 months of age) and HepB (at birt