GSK Vaccine Development

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1 GSK Vaccine Development Innovation and new technology to provide a solution Sub-regional Symposium on Pneumococcal in the Caribbean Dominican Republic, Oct 1-2 nd, 2008 Alejandro Lepetic, MD Medical Affairs Director for Latin America & the Caribbean, GSK Biologicals

2 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

3 Pneumococcal Haemophilus influenzae Protein D- Conjugate Candidate Vaccine (PHiD-CV) Whole cell vaccine Serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, 23F Capsular Polysaccharide vaccine v Meets WHO/SAGE criteria for a global formulation (contains 1,5,14 & covers >60% of IPD in <5 yr olds) 1 Conjugate vaccine Conventional Carrier Protein Conjugate vaccine Active Carrier Protein v PHiD-CV candidate vaccine actually covers ~80% of IPD 2 8 serotypes conjugated to Protein D v H. influenzae outer membrane protein), and 2 serotypes on TT y TD Novel carrier protein D chosen to minimize risk of carrier- mediated immune interference 3 potentially provide protection against H. influenzae 1.WHO (SAGE) WER Jan Hausdorff et al 2008 Pneumococcal Vaccines: The Impact of Conjugate Vaccine; 3. ISPPD6 C. Tejedor

4 Design of PHiD-C Candidate Vaccine S.pneumoniae Non-Typeable H. influenzae Polysaccharides protein D [carrier protein] PHiD-CV Candidate Vaccine designed to protect against 10 pneumococcal serotypes and non-typeable H. influenzae 4

5 Design of PHiD-C Candidate Vaccine Surface exposed 1 (on encapsulated and non-encapsulated Hi) Highly conserved 2 (Universal Haemophilus OMP) Virulence factor 3-5 Anti-PD antibodies protective in animal models 5-7 also induced in Humans 1 1. Akkoyunlu et al ; 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 Janson, unpublished ; 3.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

6 The critical importance of serotypes 1, 5, and 7F % of all IPD isolates Argentina Pneumococcal Serotypes Responsible for IPD in Latin American Children <6 Years of Age 83,5% 82,5% 86,9% 83% 55,8% Brazil 72,8% 70,5% 70,2% Chile 54,2% Colombia Mexico 70,9% 67,2% Uruguay 47,5% serotypes 1, 5, & 7F + PCV-7 serotypes 4, 6B (and 6A), 9V, 14, 18C, 19F, 23F PHiD-CV Serotype 3 (not included): average of 2.25% of IPD (range %) Adapted from SIREVA (THS/EV 2007/002. Technical Report (From 2000 to 2005) WHO/PAHO

7 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 threshold If 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 2 Jodar et al. Vaccine 2003; 21:

8 Clinical Development of PHiD-CV Candidate Vaccine Immunogenicity was compared to PCV-7 Functional responses (OPA) evaluated Boostability Co-administration with routine vaccines DTPa-HBV-IPV/Hib, DTPa-HBV-IPV 2,4 DTPa-IPV/Hib MenC / HibMenC 1 DTPw HepB Hib 3 MMRV (with booster dose) 4 Rotavirus vaccine OPV3 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

9 Clinical Development of PHiD-CV Candidate Vaccine Safety and tolerability profile appears to be similar to that of PCV7 1 No safety concerns identified during the clinical development of PHiD- CV based on currently available safety data from >3000 primed subjects 1,2 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; m; wks 1. Knuf et al., ISPPD6, Reykjavik, Iceland Lagos et al., ISPPD6, Reykjavik, Iceland 2008; 3. Prymula R, et al. Lancet 2006; 4.Nurkka et al., Ped Infect Dis J 2004

10 10 Pn-PD-DIT-011 Study design Study 10Pn-PD-DIT-011 ( / NCT ) Total Vacc Cohort ATP Immuno Cohort Age (weeks) ± SD PHiD-CV + MenC-CRM + DTPa-HBV-IPV/Hib ±2.23 RANDOMISATION PHiD-CV + MenC-TT + DTPa-HBV-IPV/Hib PHiD-CV + Hib-MenC-TT + DTPa-HBV-IPV 7vCRM + Hib-MenC-TT + DTPa-HBV-IPV ± ± ±2.37 Dose 1 Dose 2 Dose 3 Age: ±2 months ±4 months ±6 months 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

11 Why a protein carrier derived from H. influenzae? US N=83, PCV7 vacc 8 Japan N=154, 5yrs 7 Costa Rica N=235, 6-30 mos 6 Chile N=102, 0-48 mos 5 Czech & Slovak N=342, 6-27mos 4 France N=2149, 3-36 mos 3 Finland N=1267, 6-24 mos 2 Israel N=209, 3-36 mos 1 S. pneumoniae H. influenzae M. catarrhalis Others 0% 20% 40% 60% 80% 100% S. pneumoniae & H. influenzae = the two major bacterial AOM pathogens Vast majority of H. influenzae causing AOM are nontypeable % pathogens isolated 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

12 POET Study Czech and Slovak Republics Prymula R, et al. Lancet 2006;367: 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, 23F 1 µg of each PS was conjugated individually to protein D 3 doses (at 3, 4 and 5 mo) + booster (at mo) Control vaccine: Hepatitis A (Havrix TM 720UE) ~ infants, with 24 mo follow-up Co-administered with a acellular pertussis hexavalent vaccine (Infanrix hexa TM ) 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

13 Vaccine Efficacy Results I Against Pneumococcal AOM Vaccine pneumococcal serotypes 11Pn-PD (n) HAV (n) VE (%) 95% CI P- value All 11 VT types combined to 69.3 <.001 Serotype 3 only to All Vaccine-related types to Non-Vaccine Types to Reduction of 33% of all AOM inical episodes y del 42% of llbacterial AOM Prymula et al Lancet 2006

14 Vaccine Efficacy Results II Against Haemophilus influenzae AOM Pathogen 11Pn-PD HAV VE % 95% CI P-value NTHi to Other Hi 3 5 ~40 2.5% Cumulative Hazard for the first NTHi AOM episode 2.0% 1.5% 1.0% 0.5% Hepatitis A vaccine Pneumococcal PD-conjugate vaccine Reduction of Hi carriage (measured at mos.) 42.6% (p-value = 0.046) 0.0% Time since entry in the protocol defined efficacy follow-up period (months) Prymula et al Lancet 2006

15 Clinical Otitis Media and PneumoniA Study (COMPAS) Double-blind, individually randomized (n=24,000), placebo controlled (Hep. A) 3 primary doses of PHiD-CV (@ 2,4,6 mos) plus one booster (@ mos) alongside other routinely administered infant vaccines Start 2007; last 3 years Colombia (n= 3000) - Cali Argentina (n=14000) - Mendoza - Santiago del Estero - San Juan Panama (n= 7000) - Panama City

16 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 vaccine experts from different countries (Argentina (1), Brazil (1), Switzerland (1), US (2) and Mexico (1) has been monitoring the study from the beginning.

17 Registration status & WHO Prequalification Process and GAVI/Gates Foundation 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

18 PHiD-CV: Summary 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 coadministered with other paediatric vaccines

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21 Bridging of 22F-ELISA (GSK) to non-22f-elisa (WHO) 100 Non-22F ELISA (WHO reflab) percentage of observations F-inhibition ELISA (GSK) Antibody titer (µg/ml) 0.35 µg/ml Non-22F ELISA 0.2 µg/ml 22F-inhibition ELISA (GSK) Henckaerts et al. Clinical and Vaccine Immunology 2006; Vol 13:

22 Different overall impact on AOM in different settings Much depends on local epidemiology 100 % of Bacterial AOM cases in control group % 33% 8.0% 35.3% 42% 57.6% 8.0% 18% 35.3% 33% M. catarrhalis H. influenzae Spn NVT Spn 11-VT + CR 57.6% 18% 28% 35.3% 8.0% 0 control VT+VRT NVT Hi Czech/Slovak (POET) Prymula Lancet 2006 control VT+VRT NVT Hi Higher Haemophilus: (Hypothetical) control VT+VRT NVT Hi Higher Moraxella: Finland Eskola NEJM 2001

23 POET - Vaccine Efficacy* % 8.5% 57.6% AOM episode Vaccine Serotypes AOM episode Non-Vaccine Serotypes 35.3% 51.5% AOM episode any S. pneumoniae AOM episode Non-typeable H. influenzae 95%CI 33.6% Prymula R, et al. Lancet 2006;367: Any ENT Specialist confirmed clinical AOM episode *PD-CV treatment group versus HAV control group P-value from Cox regression model