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
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
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
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
PHiD-CV Potential for coverage of broader disease spectrum Invasive Disease SPn + NTHi Otitis Media Pneumonia
Invasive Disease SPn + NTHi Otitis Media Pneumonia
100 90 80 70 60 50 40 30 20 10 10 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vaccine Sources for all regions except Asia: adapted from Hausdorff et al CID 2000 Sources for Asia: Hausdorff (2006 unpublished literature analysis)
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
Invasive Disease SPn + NTHi Otitis Media Pneumonia
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 = 278 23% Mix 49% 27% CZECH & SLOVAK Prymula Lancet 2006; n = 306 22% 62% FINLAND Eskola NEJM 2001; n = 1267 23% 33% CHILE Rosenblut PIDJ 2001; n = 102 JAPAN Suzuki PIDJ 2003; n = 70 U.S. Block PIDJ 2004; n = 419 34% 37% 41% 39% 41% 48% PCV-7 Vast majority of H. influenzae causing AOM are non-typeable 56% 31%
AOM efficacy trial (POET) Lancet. 2006; 367:740-8. Czech and Slovak Republics 11-valent PD-conjugate vaccine vs Havrix (HepA--control vaccine) Efficacy follow-up period 3 4 5 12-15 24-27 mo Co-administered with Infanrix Hexa
Vaccine pneumo serotypes Vaccine Efficacy Results I Against Pneumococcal AOM 11Pn-PD HAV VE % VE 95% CI P-value All 11 VT types combined 60 141 57.6 41.4 to 69.3 <.001 Serotype 3 only 20 17-17.1-126.5 to 39.5 0.639 All Vaccine-related types 8 23 65.5 22.4 to 88.7 0.01 Non-Vaccine Types 23 25 8.5-64.2 to 49 0.77 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?)
Vaccine Efficacy Results II Against Haemophilus influenzae AOM Pathogen 11Pn-PD HAV VE % 95% CI P-value NTHi 41 63 35.3 1.8 to 57.4 0.04 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 15-18 mos.) 42.6% (p =.046) 0.0% 0 6 12 18 Time since entry in the protocol defined efficacy follow-up period (months) Prymula et al Lancet 2006 * Not significant
Vaccine Efficacy Results III Impact on Overall AOM* Endpoint Number of episodes Vaccine Efficacy P value 11Pn-PD HAV % 95% CI Clinical episodes 333 499 33.6 20.8 to 44.3 <0.001 Culture confirmed bacterial episodes 178 306 42.1 27.7 to 53.7 <0.001 Recurrent AOM 8 18 55.6-1.9 to 80.7.052 Placement of PE Tubes 4 10 60.2-26.7 to 87.5.119 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
Invasive Disease SPn + NTHi Otitis Media Pneumonia
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.
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: 3265-72