Two-in-one: GSK s candidate PHiD-CV dual pathogen vaccine

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1 Two-in-one: GSK s candidate PHiD-CV dual pathogen vaccine Dr. Bernard Hoet Director, Medical affairs GlaxoSmithKline Biologicals Rixensart, Belgium Istanbul, Feb 13, 2008

2 PHiD-CV: A novel concept in Bacterial Vaccine Design Whole cell vaccine Capsular Polysaccharides vaccine Non-Typeable Haemophilus influenzae Streptococcus pneumoniae Dual approach Conjugate vaccine Passive Carrier Protein Conjugate vaccine Active Carrier Protein Conjugation of pneumococcal serotypes to NTHi-protein D offers the potential to expand the protection beyond pneumococcal diseases

3 Protein D 42kDa lipo-protein, Surface exposed Highly Conserved Expressed in all H. influenzae and NTHi strains Genetically stable Akkoyunlu Inf. & Imm. 1991; van Alphen Gene 1997 Virulence factor Inhibits ciliary beating Important pathogenicity factor in otitis media Janson Inf & Imm 1994 Anti-protein D antibodies are protective in animal models Increase bacterial lung clearance in Rat model Poolman Vaccine 2001 Prevent AOM in Chinchilla model Bakaletz Infect & Imm 1999 Immunogenic in Humans Protein D

4 PHiD-CV: Serotype Composition Serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, 23F 8 pneumococcal serotypes conjugated to NTHi-Protein D and two serotypes on DT and TT. Proposed trade name: Synflorix TM

5 PHiD-CV Potential for coverage of broader disease spectrum Invasive Disease SPn + NTHi Otitis Media Pneumonia

6 Invasive Disease SPn + NTHi Otitis Media Pneumonia

7 Pneumococcal serogroups are responsible for most IPD in young children 0 91% 88% US/Canada 87% 87% 85% 86% 87% 84% 71% Pacific Rim 49% Other Asia 67% Africa 74% Europe 63% Latina 78% Oceania Pacific Rim: China, Hong Kong, Japan, Korea, Singapore, Taiwan Other Asia: Bangladesh, India, Israel, Malaysia, Pakistan, Philippines, Saudi Arabia, Thailand serogroups 1, 5, & 7 + PCV-7 serogroups 4, 6, 9, 14, 18, 19, 23 PHiD-CV Pneumococcal H. influenzae protein D conjugate vaccine Sources for all regions except Asia: adapted from Hausdorff et al CID 2000 Sources for Asia: Hausdorff (2006 unpublished literature analysis)

8 10 serogroups cover most invasive disease everywhere 7-valent (4, 6B, 9V, 14, 18C, 19F, 23F) plus cross reactive types are always important Serotypes 1, 5, 7F are relevant Highly invasive serotypes Implicated in serious and complicated disease (Empyema) Serotype 1 an important cause of epidemic meningitis with high case fatality rates in children and young adults (Africa) *Sniadack 1995 PIDJ; Fraser 2001 CID

9 Invasive Disease SPn + NTHi Otitis Media Pneumonia

10 S. pneumoniae and Non-Typeable H. influenzae are two major pathogens in Otitis Media) S. pneumoniae H. influenzae M. catarrhalis other ISRAEL Liebovitz PIDJ 2003; n = % Mix 49% 27% CZECH & SLOVAK Prymula Lancet 2006; n = % 62% FINLAND Eskola NEJM 2001; n = % 33% CHILE Rosenblut PIDJ 2001; n = 102 JAPAN Suzuki PIDJ 2003; n = 70 U.S. Block PIDJ 2004; n = % 37% 41% 39% 41% 48% PCV-7 Vast majority of H. influenzae causing AOM are non-typeable 56% 31%

11 AOM efficacy trial (POET) Lancet. 2006; 367: Czech and Slovak Republics 11-valent PD-conjugate vaccine vs Havrix (HepA--control vaccine) Efficacy follow-up period mo Co-administered with Infanrix Hexa

12 Vaccine pneumo serotypes Vaccine Efficacy Results I Against Pneumococcal AOM 11Pn-PD HAV VE % 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 Prymula et al Lancet 2006 Why no protection against serotype 3? Not clear Antibody response had seemed satisfactory ELISA, OPA rises But serotype 3 PS, even unconjugated, is immunogenic in infants Serotype 3 may behave differently from other pneumococci Heavy mucoidal PS makes it difficult to kill in vitro Does it behave differently in vivo (biofilms?)

13 Vaccine Efficacy Results II Against Haemophilus influenzae AOM Pathogen 11Pn-PD HAV VE % 95% CI P-value NTHi to Other Hi 3 5 ~40* Sustained Efficacy against First AOM Episode 2.5% (per protocol analysis) 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 =.046) 0.0% Time since entry in the protocol defined efficacy follow-up period (months) Prymula et al Lancet 2006 * Not significant

14 Vaccine Efficacy Results III Impact on Overall AOM* Endpoint Number of episodes Vaccine Efficacy P value 11Pn-PD HAV % 95% CI Clinical episodes to 44.3 <0.001 Culture confirmed bacterial episodes to 53.7 <0.001 Recurrent AOM to Placement of PE Tubes to Due to trial design, referral & setting differences, one CANNOT directly compare results in POET to those in any other trials Prymula et al Lancet 2006 *As confirmed by both pediatrician and ENT

15 Invasive Disease SPn + NTHi Otitis Media Pneumonia

16 COMPAS Clinical Otitis Media and PneumoniA Study Likely bacterial pneumonia Panama with abnormal chest X-ray (CXR) showing alveolar consolidation (=WHO case definition) Argentina with abnormal CXR but without alveolar consolidation The first pneumococccal conjugate vaccine efficacy data from Latina.

17 PHiD-CV: Summary & implications Potential Implications: IPD: likely to cover upto 80% of disease in most parts of the world. Otitis Media: 11PnPD demonstrated clinically significant efficacy against AOM caused by S. pneumoniae and by H. influenzae Pneumonia: Clinical AOM and Pneumonia efficacy trial with PHiD-CV underway in Panama and Argentina PHiD-CV s dual pathogen approach offers the potential for a bigger impact on Antibiotic Resistance *WHO Technical Report Series, No. 927, 2005, Annex 2 Jodar et al. Vaccine 2003; 21: