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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4

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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5

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 Janson, unpublished ; 3.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.