GSK Vaccine Development - Sabin · PHiD-CV + Hib-MenC-TT + DTPa-HBV-IPV 7vCRM + Hib-MenC-TT +...
Transcript of GSK Vaccine Development - Sabin · PHiD-CV + Hib-MenC-TT + DTPa-HBV-IPV 7vCRM + Hib-MenC-TT +...
Sub-regional Symposium on Pneumococcal in the Caribbean
Dominican Republic, Oct 1-2nd, 2008
GSK Vaccine DevelopmentInnovation and new technology
to provide a solution
Alejandro Lepetic, MDMedical Affairs Director for Latin America & the Caribbean,GSK Biologicals
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Outline
GSK Vaccine Candidate Composition§ 10 valent Pneumococcal serotypes§ Innovative carrier protein from H. influenzae (Protein D value)
WHO criteria for licensure new PCVs: § non inferiority immunogenicity criteria§ functional capacity of antibodies
Clinical Efficacy Trial results: POET study
Clinical Otitis Media and Pneumonia Efficacy Study in Latina
Remarks
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Serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, 23F
v Meets WHO/SAGE criteria for a global formulation (contains 1,5,14 & covers >60% of IPD in <5 yr olds)1
v PHiD-CV candidate vaccine actually covers ~80% of IPD2
8 serotypes conjugated to Protein Dv H. influenzae outer membrane protein),
and 2 serotypes on TT y TD
Pneumococcal Haemophilus influenzae Protein D-Conjugate Candidate Vaccine (PHiD-CV)
Whole cell vaccine
Capsular Polysaccharidevaccine
Conjugate vaccineConventional Carrier Protein
Conjugate vaccineActive Carrier Protein
Novel carrier protein D chosen to
minimize risk of carrier- mediated immune interference3
potentially provide protection against H. influenzae1.WHO (SAGE) WER Jan. 2008 2.Hausdorff et al 2008 Pneumococcal Vaccines: The Impact of Conjugate Vaccine; 3. ISPPD6 C. Tejedor
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PHiD-CV Candidate Vaccinedesigned to protect against 10 pneumococcal serotypes
and non-typeable H. influenzae
S.pneumoniae
protein D[carrier protein]
Non-TypeableH. influenzae
Polysaccharides
Design of PHiD-C Candidate Vaccine
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Design of PHiD-C Candidate Vaccine
Surface exposed1 (on encapsulated and non-encapsulated Hi)
Highly conserved2 (Universal Haemophilus OMP)
Virulence factor3-5
Anti-PD antibodies
protective in animal models5-7
also induced in Humans1
1. Akkoyunlu et al. 1991 ; 2. Janson, unpublished ; 3. Janson H et al. J Infect Dis. 1999; 4. Janson et al. Infect Immun 1994; 5. Bakaletz Infect Immun 1999; 6. Novotny et al Vaccine 2006; 7.Poolman Vaccine 2001
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serotypes 1, 5, & 7F
The critical importance of serotypes 1, 5, and 7F
Pneumococcal Serotypes Responsible for IPDin Latin American Children <6 Years of Age
PCV-7 serotypes4, 6B (and 6A), 9V, 14,
18C, 19F, 23F
+
Adapted from SIREVA (THS/EV 2007/002. Technical Report (From 2000 to 2005) WHO/PAHO
PHiD-CV
% o
f all
IPD
isol
ates
55,8%70,5% 70,2%
47,5%
67,2%
83,5% 82,5% 86,9% 83%
70,9%
54,2%
72,8%
0102030405060708090
100
Argenti
naBraz
ilChil
e
Colombia
Mexico
Urugua
y
Serotype 3 (not included):average of 2.25% of IPD (range 0.8-5.4%)
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WHO Licensure criteria for IPD
The GSK candidate vaccine, PHiD CV, meets the criteria proposed by WHO and endorsed by CHMP:1. Non-inferiority of post-primary ELISA antibody responses compared
to PCV-7 (based on % of subjects reaching pre-set thresholds)For non-22F assay, 0.35 µg/ml used as thresholdIf 22F-containing assay used, immunological bridging needed with non-22F assay*WHO and CHMP: non-inferiority should not be seen as an absolute prerequisite for each serotype
2. Demonstration of functional capacity of antibodies (OpsonoPhagocytic Activity - OPA)
3. Induction of immunological memory
*WHO Technical Report Series, No. 927, 2005, Annex 2Jodar et al. Vaccine 2003; 21: 3265-72
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Clinical Development of PHiD-CV Candidate Vaccine
Immunogenicity was compared to PCV-7Functional responses (OPA) evaluatedBoostability
Co-administration with routine vaccines
1. Tejedor et al., ISPPD6, Reykjavik, Iceland 2008; 2. Lagos et al., ISPPD6, Reykjavik, Iceland 2008; 3.Bermal, ICID, Kuala Lumpur, Malaysia 2008 ; 4 Vesikari, ESPID 2008, Graz, Austria
•DTPa-HBV-IPV/Hib, DTPa-HBV-IPV2,4
•DTPa-IPV/Hib•MenC / HibMenC1
•DTPw HepB Hib3
•MMRV (with booster dose)4
•Rotavirus vaccine •OPV3
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Clinical Development of PHiD-CV Candidate Vaccine
1. Knuf et al., ISPPD6, Reykjavik, Iceland 2008 2. Lagos et al., ISPPD6, Reykjavik, Iceland 2008; 3. Prymula R, et al. Lancet 2006; 4.Nurkka et al., Ped Infect Dis J 2004
Safety and tolerability profile appears to be similar to that of PCV71
No safety concerns identified during the clinical development of PHiD-CV based on currently available safety data from >3000 primed subjects1,2
Supportive data from >10,000 doses of related 11-valent pneumococcal conjugate vaccine administrations provide additional reassurance for safety of candidate PHiD-CV vaccine 3,4
> 2500 primed subjects and 2500 boosted subjects
Immunization schedules: 2-3-4m; 3-4-5m; 2-4-6m; 3-5-11m; 6-10-14 wks
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10 Pn-PD-DIT-011 Study design
PHiD-CV + MenC-CRM + DTPa-HBV-IPV/Hib
PHiD-CV + MenC-TT + DTPa-HBV-IPV/Hib
PHiD-CV + Hib-MenC-TT + DTPa-HBV-IPV
7vCRM + Hib-MenC-TT + DTPa-HBV-IPV
RA
ND
OM
ISA
TIO
N
Age:
Dose 1
±2 months
Dose 2
±4 months
Dose 3
±6 months
8.1±2.37174390
8.1±2.19175386
8.1±2.13178387
8.0±2.23171385
TotalVacc
Cohort
ATPImmunoCohort
Age (weeks)± SD
PHiD-CV: PHiD-CV Candidate Vaccine, 7vCRM: Prevenar™/Prevnar™, Wyeth; Menc-CRM: Meningitec™Wyeth; Menc-TT: Neis-Vac C™, Baxter; Hib-MenC-TT: Menitorix™, GSK; DTPa-HBV-IPV/Hib: Infanrix hexa™, GSK; DTPa-HBV-IPV: Infanrix penta™, GSK
Study 10Pn-PD-DIT-011 (107005 / NCT00334334)
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0% 20% 40% 60% 80% 100%
Israel
Finland
France
Czech & Slovak
Chile
Costa Rica
Japan
US
% pathogens isolated
S. pneumoniae H. influenzae M. catarrhalis Others
N=83, PCV7 vacc 8
N=154, ≤5yrs 7
N=235, 6-30 mos 6
N=102, 0-48 mos 5
N=342, 6-27mos 4
N=2149, 3-36 mos 3
N=1267, 6-24 mos 2
N=209, 3-36 mos 1
1. Liebovitz PIDJ 2003; 2. Eskola New Engl J Med 2001; 3. Gehanno PIDJ 2001; 4.Prymula Lancet 2006; 5.Rosenblut PIDJ 2001; 6. Arguedas PIDJ 2005; 7.Nishimura 2003; 8.Block PIDJ 2004
Vast majority of H. influenzaecausing AOM
are non-typeable
S. pneumoniae &
H. influenzae=
the two major bacterial AOM
pathogens
Why a protein carrier derived from H. influenzae?
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POET Study
Czech and Slovak Republics
Double blind, randomized (1:1) study
11-v Pneumococcal conjugate prototype vaccine with H. influenzae Protein D as carrier
1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, 23F1 µg of each PS was conjugated individually to protein D
3 doses (at 3, 4 and 5 mo) + booster (at 12-15 mo)
Control vaccine: Hepatitis A (HavrixTM 720UE)
~ 5 000 infants, with 24 mo follow-up
Co-administered with a acellular pertussis hexavalent vaccine (InfanrixhexaTM)
Prymula R, et al. Lancet 2006;367:740-748.
° Hexavalent diphtheria-tetanus-3-component acellular pertussis-hepatitis B-inactivated poliovirus types 1, 2, and 3-H influenzae type b; Havrix and Infanrix hexa are trade marks of the GlaxoSmithKline Group of Companies
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Vaccine Efficacy Results I Against Pneumococcal AOM
P-value
95% CIVE (%)HAV (n)
11Pn-PD (n)
Vaccine pneumococcal serotypes
0.639-126.5 to 39.5
-17.11720• Serotype 3 only
0.77-64.2 to 498.52523• Non-Vaccine Types
0.0122.4 to 88.765.5238• All Vaccine-related types
<.00141.4 to 69.357.614160• All 11 VT types combined
Prymula et al Lancet 2006
Reduction of 33%
of all AOM inical episodesy del
42% of llbacterial AOM
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Vaccine Efficacy Results IIAgainst Haemophilus influenzae AOM
~4053Other Hi
0.041.8 to 57.435.36341NTHi
P-value95% CIVE %HAV11Pn-PDPathogen
Reduction of Hi carriage(measured at 15-18 mos.)
42.6%(p-value = 0.046)
Prymula et al Lancet 2006
0.0%
0.5%
1.0%
1.5%
2.0%
2.5%
0 6 12 18
Time since entry in the protocol defined efficacy follow-up period (months)
Cum
ulat
ive
Haz
ard
for t
he fi
rst N
THi A
OM
epi
sode
PneumococcalPD-conjugate vaccine
Hepatitis A vaccine
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Clinical Otitis Media and PneumoniA Study(COMPAS)
Panama (n= 7000)- Panama City
Argentina(n=14000)- Mendoza- Santiago del Estero- San Juan
Colombia(n= 3000)
- Cali
Double-blind, individually randomized (n=24,000), placebo controlled (Hep. A)
3 primary doses of PHiD-CV (@ 2,4,6 mos) plus one booster (@ 15-18 mos) alongside other routinely administered infant vaccines
Start 2007; last 3 years
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Clinical Otitis Media and PneumoniA Study(COMPAS)
Primary objective:§ Demonstrate efficacy against either “likely bacterial CAP” or against clinical AOM
Definitions: § Likely bacterial CAP: alveolar consolidation (WHO) or abnormal CXR plus CRP
> 40 mg/L. Chosen to provide a better description of the true public health benefit of vaccination.
§ Clinical AOM: standardized clinical case definition confirmed by ENT specialist§ Tympanocentesis will be used to assess specific AOM etiology
An IDMC (Independent Data Monitoring Committee) integrated by vaccineexperts from different countries (Argentina (1), Brazil (1), Switzerland (1),US (2) and Mexico (1) has been monitoring the study from the beginning.
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PHiD-CV file being submitted in parallel in many countries, including EMEA, beginning end-07
EMEA procedure & milestones: Proceeding as planned§ Licensure timing expected early 09
WHO meeting in Ottawa (July 08) with regulators, manufacturers§ reviewed ELISA thresholds & OPA standardization efforts§ draft conclusions of meeting support current regulatory
pathway
International public health agencies: § manufacturing process tailored to produce large capacities§ currently in discussions with to ensure the timely availability of
PHiD-CV for all children in need
Registration status & WHO Prequalification Process and GAVI/Gates Foundation
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PHiD-CV candidate vaccine offers a global formulation that includes 3 additional serotypes of S. pneumoniae (1, 5 and 7F) reaching a high additional impact on IPD in children <5 years of age
11-valent protein D-conjugate (prototype vaccine) showed major clinical impact on AOM, with efficacy against the 2 major bacterial pathogens
POET study demonstrated the proof of innovative carrier concept
A third of all-cause clinical AOM prevented
No evidence of immunological interference when PHiD CV is co-administered with other paediatric vaccines
PHiD-CV: Summary
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Thank you for your attention!!!Thank you for your attention!!!
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BACK up
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Bridging of 22F-ELISA (GSK) to non-22F-ELISA (WHO)
Antibody titer (µg/ml)
0.01 0.1 1 10
perc
enta
ge o
f obs
erva
tions
0
20
40
60
80
100 Non-22F ELISA (WHO reflab)
22F-inhibition ELISA (GSK)
0.2 µg/mL 22F-inhibition ELISA (GSK)
0.35 µg/mL Non-22F ELISA
Henckaerts et al. Clinical and Vaccine Immunology 2006; Vol 13: 356-360
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Different overall impact on AOM in different settingsMuch depends on local epidemiology
57.6%
% o
f Bac
teria
l AO
M c
ases
in c
ontro
l gro
up
8.0%
35.3%
33%42%
57.6%
8.0%
35.3%
18%
33%
57.6%
8.0%
35.3%
18%28%
0
10
20
30
40
50
60
70
80
90
100
contr
ol
VT+VRT NVT Hi
contr
ol
VT+VRT NVT Hi
contr
ol
VT+VRT NVT Hi
M. catarrhalis
H. influenzae
Spn NVT
Spn 11-VT+ CR
Czech/Slovak (POET)Prymula Lancet 2006
Higher Moraxella: FinlandEskola NEJM 2001
Higher Haemophilus: (Hypothetical)
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AOM episodeVaccine Serotypes
AOM episodeany S. pneumoniae
Any ENT Specialist confirmed clinical AOM episode
POET - Vaccine Efficacy*
AOM episodeNon-Vaccine Serotypes
AOM episodeNon-typeable H. influenzae
57.6%
51.5%
33.6%
-80 -60 -40 -20 0 20 40 60%
8.5%
35.3%
*PD-CV treatment group versus HAV control groupP-value from Cox regression model
95%CI
Prymula R, et al. Lancet 2006;367:740-748.