DTaP-based Pediatric Combination
Vaccine Development:
The core of modern immunization
programs
Outline
• Combination vaccines
– Background
– Vaccine development
• Sanofi Pasteur experience in combination vaccine
development
–
–
–
–
DTaP “backbone”
Tetravalent DTaP/IPV
Pentavalent DTaP/IPV/Hib
Hexavalent DTaP/IPV/Hib/HB
• Summary
Combination Vaccines:
• Include several antigens in a single vaccine
• merge equivalent component vaccines into single products
• prevents more than 1 disease
MMR
DPT
or protects vs multiple strains of pathogens causing the
same disease.
IPV
PCV
• Developed because the increasing number of effective
childhood vaccines à economic and logistical difficulties
• (multiple needle sticks, additional vaccination visits, shipping,
handling, and storage)
Decker MD & al. Combination vaccines. In Vaccines, Sixth Edition. Edited by Stanley A. Plotkin, Walter A
Orenstein, and Paul Offit, WB Saunders Company, Orlando. 2013, 1069-1102
Combination Vaccines: Advantages
– For Vaccinees:
• Fewer injections, less pain
• Reduced costs for extra health-care visits
– For Health Care Providers:
• Optimize implementation of immunization recommendations
• Simplify administration
• Reduced shipping and stocking costs
– For Public Health:
• Improved vaccine coverage rates
• Better timeliness of vaccination
• Facilitate addition of new vaccines into vaccination programs
Decker MD & al. Combination vaccines. In Vaccines, Sixth Edition. Edited by Stanley A. Plotkin, Walter A
Orenstein, and Paul Offit, WB Saunders Company, Orlando. 2013, 1069-1102
Combination Vaccines: Considerations
• Immune Response:
– Immune response to any of the combined antigens is just as
good as response to the individual vaccines
•Exposure to multiple conjugate antigens à enhanced or
diminished immune responses
•Chemical or physical interaction among vaccine components
– Correlates of protection
•Individual antibody level that directly correlates with/ predicts
protection
•Identified for: polio, tetanus, diphtheria, Hep B, Hib
– Evaluating effectiveness
•Non-inferiority trials : investigational product is not inferior
i.e. no more than 10% difference in seroprotection rates
Decker MD & al. Combination vaccines. In Vaccines, Sixth Edition. Edited by Stanley A. Plotkin, Walter A
Orenstein, and Paul Offit, WB Saunders Company, Orlando. 2013, 1069-1102
Combination Vaccines: Considerations
•Rates of adverse reactions
• Same as they would be if the vaccines were administered separately
• Local AEs more common, but offset by less number of injection sites
•Other Considerations
•Patent and proprietary issues
•Combination vaccine price
•Licensure strategies
•Compare new combination vaccine to:
• Each of its major building blocks given alone
DTaP/IPV/Hib
DTaP
IPV
Hib
DTaP-IPV
Hib
•Previously approved combination vaccine
DTaP/IPV/Hib
DTaP/IPV/Hib
(licensed)
Decker MD & al. Combination vaccines. In Vaccines, Sixth Edition. Edited by Stanley A. Plotkin, Walter A
Orenstein, and Paul Offit, WB Saunders Company, Orlando. 2013, 1069-1102
Combination Vaccines:
Development
• Most modern pediatric combination vaccines
begin with: DTwP or DTaP vaccine
+ IPV
+ Hib
+ Hep B
• Large number of combination vaccines available
ACIP General Recommendations on Immunization
states that “the use of a combination vaccine
generally is preferred over separate injections of the
equivalent component vaccines”.
Decker MD & al. Combination vaccines. In Vaccines, Sixth Edition. Edited by Stanley A. Plotkin, Walter A
Orenstein, and Paul Offit, WB Saunders Company, Orlando. 2013, 1069-1102
Objectives of Combination Vaccines Clinical
Development Programs (not limitative)
· Equivalence of the reactogenicity profile of combo AB
versus A and B given concomitantly at separate sites during
primary series and booster
· Non-inferiority of the immune response to all AB antigens
between subjects receiving combo AB versus subjects
receiving A and B concomitantly at separate sites after
primary series and after booster
· Equivalence of the immune response to all AB antigens
between subjects receiving three consistency lots of the AB
combo after a primary series
· Safety and immunogenicity of the AB combo in toddlers
when the AB combo is used as a booster in non-AB-primed
toddlers
Pediatric Combination Vaccine General Delopment Plan
10 months
Phase I
14 months
Phase II
First trial
wave
14 months
Phase III
Consistency
Phase III
Large Scale
Safety
Second
trial wave
24-28 months
Phase III
Immunological
interferences
investigation
Phase III
Immunisation
investigation
CTD
Submission
Year 1
Year 2
Year 3
Year 4
Year 5
Year 6
Pediatric Combination Vaccine General Delopment Plan
Phase I
Phase I
• First use in man
• Initial testing in small numbers
• Safety (and first validation of
immunogenicity) of Combo AB given
in toddlers in non-AB primed infants
Pediatric Combination Vaccine General Delopment Plan
Phase I
Phase II
Phase II
• Involves larger number of subjects
• Preliminary information about immunogenicity in
the target population (and its general safety)
• Comparative immunogenicity in infants
• Combo AB versus A + B given in infants as a
primary series and a booster dose in a
comparative study
• Reality check: Do we have a product ?
Pediatric Combination Vaccine General Delopment Plan
Phase I
Phase II
First trial
wave
Phase III
Consistency
Phase III
Large Scale
Safety
Phase III studies
• Pivotal Comparative Immunogenicity
Study
• Non-inferiority of immune response
against all Ags between AB and A + B
Second
trial wave
Phase III
Immunological
interferences
investigation
Phase III
Immunisation
investigation
Phase III studies
• Lot Consistency Study
• Equivalence of the immune response
against all Ags between 3 lots of AB
• Large Scale Comparative Safety Study
• Equivalence of reactogenicity between AB
and A + B
• Schedule Comparison
Study(ies) when relevant
• Safety/Immu. in toddlers
non-AB-primed when
relevant
Pediatric Combination Vaccine General Delopment Plan
Phase I
Phase II
First trial
wave
Some flexibility in
the Clinical
Programs …
Phase III
Consistency
Phase III
Large Scale
Safety
Second
trial wave
Phase III
Phase I : to go directly
into Phase II or III
Immunological
interferences
investigation
Phase III
Phase II : to merge this study
with the Phase III Pivotal
Immunogenicity Study
Immunisation
investigation
Phase III Large Scale Comparative Safety :
to reduce the sample size
CTD
Submission
Pediatric Combination Vaccine General Delopment Plan
10 months
Phase I
14 months
Phase II
First trial
wave
14 months
Long process
Phase III
Consistency
Phase III
Large Scale
Safety
Study preparation (p)
Enrollment (e)
Follow-up (f)
Analysis (a)
Second
trial wave
24-28 months
Phase III
Immunological
interferences
investigation
Total = at least
42 months
(3.5 yrs)
Phase III
Immunisation
investigation
· Ph I: 3 (p) + 5 (e+f) + 4 (a) = 12 months
· Ph II: 3 (p) + 3 (e) + 5 (f) + 4 (a) = 15 months
· Ph III: 3 (p) + 3 (e) + 5 (f) + 4 (a) = 15 months
Year 1
Year 2
Year 3
Year 4
Year 5
CTD
Submission
Year 6
Guidance Documents on Clinical
Developments of Combination Vaccines
• The US FDA guidance for Industry for the Evaluation of
Combination Vaccines for Preventable Diseases:
Production, Testing and Clinical Studies (April 1997)
• EMEA CPMP Note for Guidance on Clinical Evaluation of
Vaccines (May 2005)
• WHO guidelines on clinical evaluation of vaccines; TRS
924 Annex 1
Key principles of developments progressively matured
through collaboration between sponsors and NRAs
US FDA
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/UCM175909.pdf :
EMEA CHMP http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003875.pdf ; WHO
http://www.who.int/biologicals/vaccines/clinical_evaluation/en/
Regulatory Evaluation of Pertussis-based Vaccines:
US Licensure as Example
• Rationale:
– Pertussis: No well established serologic correlate of protection
– Different DTaP combination vaccines available
• “Linked” vaccines – contain same pertussis antigens
produced by the same manufacturer and methods
– US FDA has accepted comparison of pertussis Ab responses
between linked DTaP vaccines with DTaP vaccine shown to be
efficacious in a pertussis clinical efficacy trial
• US-licensed DTaP Combination Vaccines – based on :
Clinical end
Safety &
Post-marketing
point efficacy
Immunogenicity of
Effectiveness data
data on
newer DTaP combo
to corroborate
“linked” DTaP
vaccines compared to
pre-licensure
vaccine
“linked” DTaP vaccine
efficacy estimates
Farizo KM et al. Clinical Evaluation of Pertussis Vaccines: US FDA Regulatory Considerations. Journal of Infectious Diseases 2014 209 Suppl 1 pp S28-31.
SP has accumulated >30 years of experience in the
development & licensure of combinations
DTaP/IPV/Hib/HB
DTaP/IPV/Hib
>3.4 M doses
>75 countries
(DTaP)
DTaP/IPV
IPV
Hib
Over 25 years of experience in acellular pertussis (aP)
combination vaccines
[2] & [3] Data on file: registration dates and Finance data
[4] Vidor. Hum Vacc, 2008;4(5)
SP has accumulated >30 years of experience in the
development & licensure of combinations
Several families of products have been developed (some are still
in development) in different regions based on the historical
roots of the company and on multiple partnerships:
• The AcXim family: DTaP2Fr-backboned products
• The Acel family: DTaP5Ca-backboned products
• The partnership with MRL on hexavalents
• One DTaP5Ca-backboned hexavalent under development
• The partnership with Shantha Biotechnics in India
• DTwP-HepB-Hib (Shan-5) and DTwP-IPV-HepB-Hib (Shan-6;
under development)
Sanofi Pasteur’s Trivalent DTaP :
Backbone of AcXim family
• DTaP*:
– Core of various combinations with other pediatric antigens
– Phase I: safety and immunogenicity in healthy adults
– Phase II trials: dose-response (for pertussis Ags) in infants,
toddlers, and children; safety and immunogenicity of 2
dosages;
• Established optimal content of PT and FHA
– Phase III trials: Clinical end point efficacy trial: Senegal
pertussis efficacy trial (wP versus aP) to establish the
performance of this valence against B. pertussis infections
– i.e. the ‘Link’ vaccine
*Not licensed
Sanofi Pasteur’s Trivalent DTaP :
Backbone of AcXim family
• The Relative Efficacy Pertussis Senegal Trial
– Prospective, randomized, double-blinded, study of the relative efficacy of
the DTaP versus the DTwP
– Clinical outcome: measured during a mean of 21 months of follow up
starting one month after the last pertussis vaccination (schedule 2 – 4 – 6
months of age)
• Household case-contact study for Absolute Vaccine Efficacy
determination:
Using the WHO pertussis case
definition
• 92% for DTwP (95% CI: 81% - 97%)
• 74% for DTaP (95% CI: 51% - 86%)
+ contact with a culture positive
person
• 96% for DTwP (95% CI: 86% - 99%)
• 85% for DTaP (95% CI: 66% - 93%)
Simondon F et al. A randomized double-blind trial comparing a two-component acellular to a whole-cell pertussis vaccine in Senegal. Vaccine,
vol 15 no 12 pp 1606-1612, 1997.
Sanofi Pasteur’s Combination DTaP-based
Vaccines : Compositions
TETRAVALENT: DTaP-IPV
•
•
•
•
Diphtheria toxoid:
D
Tetanus toxoid:
T
Acellular pertussis:
– Pertussis toxoid
PT
– Filamentous haemagglutinin FHA
Inactivated Polio Virus (IPV) antigens:
– Poliovirus type 1 (Mahoney)
– Poliovirus type 2 (MEF1)
– Poliovirus type 3 (Saukett)
≥ 30 IU/dose
≥40 IU/dose
25 µg/dose
25 µg/dose
40 DU/dose
8 DU/dose
32 DU/dose
PENTAVALENT: DTaP-IPV-Hib
DTaP-IPV
•
Hib antigen:
• Polyribosylribitol phosphate PRP
conjugated to tetanus protein
10 µg/dose
HEXAVALENT: DTaP-IPV-Hib-HB
DTaP-IPV-HiB
• Purified recombinant Hep B surface antigen 10 µg/dose
Sanofi Pasteur’s Combination DTaP-based
Vaccines : Evaluation of Biopharmaceutics
• Primary immunogenicity endpoints:
– Seroprotective rates: (correlates of protection) as used
by all NRAs (National Regulatory Authorities)
•
•
•
•
•
Tetanus: Ab titers >0.01 IU/mL
Diphtheria: Ab titers >0.01 IU/mL
Poliovirus: types 1, 2, 3 neutralizing Ab titers > 8 (1/dilution)
Hib PRP Ag: Ab titers > 0.15 µg/mL
HBs: Ab titers >10 mIU/mL
– Seroconversion rates: Pertussis
• PT and FHA: 4-fold rise of Ab titers (EIA) in EU/mL or vaccine
response rates
Sanofi Pasteur’s Combination DTaP-based
Vaccines : Evaluation of Biopharmaceutics
• Assays (Pertussis):
– Based on well-established neutralization assays
developed/validated years ago
– Laboratories: Sanofi Pasteur, NRAs, academic
institutions (Vanderbilt Univ. Nashville TN USA; CAMR, UK)
– PT and FHA EIA techniques validated for concordance in
a comparative inter-laboratory study (Vanderbilt Univ.
Nashville TN USA; N. Guiso Institut Pasteur, Paris; Clinical Seroimmunological Laboratory, Val de Reuil, France)
Sanofi Pasteur’s Combination DTaP-based
Vaccines : Evaluation of Biopharmaceutics
• Safety Endpoints:
– Immediate Reactions
• Unsolicited, within 30 mins.
– Local Reactions
• Solicited daily for 3 days after vaccination
• Redness, swelling, induration, pain
– Systemic Reactions
• Solicited daily for 3 days after vaccination
• Fever, vomiting, diarrhea, drowsiness, irritability, anorexia,
HHE
ü Described for severity (mild; moderate; severe), duration, outcome, seriousness, action taken
ü Unsolicited local AEs coded (MedDRA) and documented similarly
Pediatric Combination Vaccine General Delopment Plan
Phase I
SP tetravalent DTaP-IPV Experience:
Phase II
Phase
III trials: DTaP (“link” vaccine)
Phase III
Consistency
Phase I trial: DTaP
• safety and
immunogenicity in
adult volunteers
• Clinical end point efficacy trial: safety and
immunogenicity
Phase
III
Large Scale
Safety
Phase III
Immunological
interferences
investigation
Phase III trials: DTaP-IPV
Phase II trials: DTaP
• Dose response in
infants
• Compared to DTwP
• Different schedules
• Different populations
•
•
•
•
•
•
•
•
•
Primary series inPhase
infants
III
Immunisation
Compared to DTwP-IPV,
DTaP + IPV, DTaP-IPV/HiB
investigation
Compared to DTaP + Hib + OPV or IPV
CTD
Lot-to-lot consistency
Large scale safety
Submission
Co-administered with Hib, Hib-HB
Different schedules, different populations
Antibody persistence, immunobridging
Trials in pre-schoolers and adolescents as boosters
Sanofi Pasteur’s Tetravalent DTaP-IPV Vaccine :
Large clinical database since 1986
• Multitude pre- and post-licensure clinical trials
• Safety and Immunogenicity when used in several conditions,
schedule flexibility
– As routine 3-dose primary immunization in infants from 6 wks of age
– As booster (toddler, pre-school, adolescents up to 13 yrs old)
following wP-primed or aP-primed infants
•
Different comparators
• vs DTwP-IPV, vs DTaP-IPV/Hib or vs DTaP + Hib + OPV or IPV
• vs TdaP-IPV or Tdap + OPV in pre-schoolers
•
Different populations including trial in Rep. of Korean
infants
• DTaP-IPV compared with a locally licensed DTaP + IPV as
primary vaccination at 2-4-6 months of age
•
Antibody persistence, co-administration
Sanofi Pasteur’s Pentavalent DTaP-IPV/Hib Vaccine
Large clinical database since 1994
• Multitude pre- and post-licensure clinical trials
• Several countries
– France, Sweden, Chile, US, Turkey, Philippines, Thailand, India, China,
South Africa, South Korea, Vietnam and Argentina
• As 2-dose (3-5) or 3-dose (6-10-14 weeks; 2-3-4; 3-4-5; 2-46 months) primary series vaccination regimen, +/- 2nd year
of life booster
• As 2nd year of life booster following wP-primed infants
• Assessed in comparison to separate vaccines in 4 studies
– (vs DTaP-IPV + Hib and/or vs DTaP + IPV + Hib)
• Assessed when co-administered with Hep B vaccine
– With Hep B vaccine given at birth: 0-6-14 weeks; 0-1-6 or 0-2-6 months
– Without Hep B vaccine at birth: 6-10-14 months
Plotkin et al. Exper. Rev. Vaccines 10(7). (2011)
Sanofi Pasteur’s Pentavalent DTaP-IPV/Hib Vaccine
Evidence of acP Vaccine Effectiveness in the Swedish
Experience (10-yr follow up)
Age-specific incidence of pertussis in children
in National vs. SP DTaP-IPV/Hib cohorts, 1997-2007
SP DTaP-IPV/Hib
Swedish counties exclusively
using SP’s DTaP-IPV/Hib since
2007
Gustafsson & Carlsson. SMITTSKYDDSINSTITUTETS RAPPORT SERIE, 2008;4
Gustafsson L, Carlsson RM. Appendix 2 to Ten-year Report; October 1, 1997 until December 31, 2007.
Sanofi Pasteur’s Pentavalent DTaP-IPV/Hib
Vaccine : Worldwide Experience
•
•
•
•
1st licensed in Sweden in 1997
Approved in >100 countries worldwide
>150 million doses distributed
Used in private and public national immunization programs
• Indication:
– 3-dose primary vaccination series during 1st year of life
– And/or a booster vaccination during 2nd year of life
• Vaccination schedule can be adapted to the immunization program
of individual countries
Plotkin et al. Exper. Rev. Vaccines 10(7). (2011)
SP’s Hexavalent DPT-IPV-Hib-HB vaccine
Supported by thorough international clinical development
Mexico9
A3L11: 2,4,6 mo Primo
vs. DTaP-IPV-HBV//Hib
Turkey4
Colombia & Costa Rica11
A3L24: 2,4,6 mo Primo
vs. DTaP-IPV-HBV//Hib
A3L10: 2,3,4 mo Primo
vs. Pentaxim® + Hep B
A3L22: 15-18 mo Booster4
A3L21: 15-18 mo Booster
(subjects of A3L11)9
Thailand8
Argentina7
A3L12: 2,4,6 mo Primo
vs. DTaP-IPV-HBV//Hib
A3L01: 16-19 mo Booster
vs. DTaP-IPV-HepB-Hib§
Argentina5
A3L02: 2,4,6 mo Primo
vs. Pentaxim® + Hep B*
Mexico & Peru3
A3L04: 2,4,6 mo Primo
vs. DTwP-HepB//Hib + OPV
A3L16: 18 mo Pentaxim® Booster
(subjects of A3L02)6
South Africa1
Peru10
A3L15: 6,10,14 wk Primo (w & w/o Hep B at birth)
vs. DTwP-Hib + OPV +Hep B*
A3L17: 2,4,6 mo Primo
vs. DTaP-IPV-HBV//Hib10
South Africa2
A3L15: 15-18 mo Booster
Primary series study
•
•
Booster study
§ no longer marketed
* Pediatric formulation (10µg HBsAg)
13 clinical studies in 8 countries
~ 5,000 subjects who received at least 1 dose of SP’s DTaP-IPV-Hib-HB
SP’s Hexavalent DTaP-IPV-Hib-HB
Worldwide Experience
• Clinical trials in 4 continents, different schedules, as primary
series and/or booster, +/- Hep b birth dose
• Compared to
– Whole cell based vaccines
– Pentavalent aP + Heb B co-administered
– Another licensed hexavalent vaccine
Licensed in 80 countries
Used in private and public immunization programs
>3.4 million doses distributed
The only hexavalent combination vaccine that is WHO Prequalified
• Indication
– Primary and booster vaccination of infants and toddlers from 6
weeks to 24 months of age
•
•
•
•
[30] Sanofi Pasteur. HEXAXIM®. Summary of Product Characteristics
Conclusions
• Pediatric combination vaccines provide advantages to
individuals, HCPs, and public health
• Vaccine Development progressively matured through constant
collaboration with stakeholders and NRAs
• Sanofi Pasteur has > 30 years experience in developing
combination vaccines widely used in private and public
immunization programs
• SP’s clinical development strategy is designed to gain
confidence on the ability of our combination vaccines to
safely induce consistent clinical protection against the targeted
diseases
• SP’s tetra-, penta-, and hexa valent acP-based combos have
broad global experience and are supported by robust licensure
and post-licensure data
Thank You