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Synflorix : A New Generation PCV

Synflorix : A New Generation PCV. Pneumococcal Serotypes Surveillance so far . 6 studies in children less than 5 years All the isolates were from normally sterile sites. Asian Network for Surveillance of Resistant Pathogens (ANSORP): 2008-2009. Study was conducted in 10 South Asian countries

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Synflorix : A New Generation PCV

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  1. Synflorix: A New Generation PCV

  2. Pneumococcal Serotypes Surveillance so far • 6 studies in children less than 5 years • All the isolates were from normally sterile sites

  3. Asian Network for Surveillance of Resistant Pathogens (ANSORP): 2008-2009 • Study was conducted in 10 South Asian countries • Total 91 isolates of 19A were collected to see resistance patterns • India had contributed 3 isolates of 19A during this period • Under 5 or more than 5 years is not known or clear • It was retrospective or prospective study and case definition is not defined? As purpose was to see resistance • Most of the isolates were collected from Sputum etc and hence Non-invasive • J AntimicrobChemother Feb 2011; Shin et al

  4. ALLIANCE FOR SURVEILLANCE OF INVASIVE PNEUMOCOCCI (ASIP) IN INDIA ‘When you've got something to prove, there's nothing greater than a challenge.’ -- Terry Bradshaw 12

  5. JAN to NOV 2011 – Key developments Identification of sentinel Drs / Pvt Lab for developing sentinel network in Mumbai , Delhi , Bangalore , Chennai Serotyping and AST work initiated. Consolidation of study data, presentation at 3rd IM Pneumo season - Isolation + serotyping ASIP – Year 2 ZONAL CONSOLIDATION JAN FEB MARCH AUG SEPT OCT – DEC’11 DEC – JAN ‘12 CRC Recruitment for Chennai , Bangalore , Delhi IM Meeting in GOA Sept 2011 Sentinel network initiated in Kolkata , Coimbatore , Hyderabad , Ahmedabad PEDICON ASIP POSTER ASIP website launched e -CRF developed 16

  6. February 2011 – ASIP website launched http://www.asipindia.org 17

  7. Study Centres Study Central Monitoring Laboratory, CMC, Vellore 19

  8. 20

  9. ASIP LOCAL LAB 21

  10. Update on Recruitment and +ve Cultures (as on 23rd Nov 2011) 23

  11. ASIP: Distribution of Serogroup/typePreliminary Results (n=35 out of 42), 2011 • 19 A % : 1/35 ( 2.85 %) • 19F % : 3/35 ( 8.57%) • ------------------------------------ • 19 % : 4/35 (11.4%) • In line with previous studies and • PneumoADIP- Asia: 2009 Data on file: www.asipindia.org

  12. Pneumonia kills 45 children an hour …1095 children a day …7,692 children a week …33,300 children a month Each year pneumonia kills over 400,000 children in India ~50,000 by Hib ~142,000 by pneumococcus Pneumo Hib DRAFT

  13. Serotype 3 • Serotype 3 is an atypical serotype1,2 • Serotype 3 pneumococci are abundantly capsulated, making the bacteria less sensitive to immune interactions1 • Serotype 3 probably behaves differently in vivo (biofilms) 3 • Has tendency to switch off the capsule or express it in an abundant way Polysaccharide capsule 2 Serotype 3 Serotype 19F 1.Poolman J, et al. Vaccine 2009;27: 3213-3222 2.Hammerschmidt et al. Infection and Immunity 2005;73(8):4653-67 3. Waite RD, Struthers JK, Dowson CG. Mol Microbiol 2001;42(5):1223-32

  14. Serotype 3 displays an atypical immunogenicity profile 11Pn-PD post-booster HAV post-booster 11-valent Pn-PD in POET 13-valent-CRM 100 90 80 70 60 50 40 30 20 10 0 11Pn-PD post-primary HAV post-primary Patients (%) PCV 10 vs PCV 13? Or PCV 12 Kieninger et al.,ICAAC 2008 (http://uploads.renegadedigital.com/Istanbul/ kieninger.pdf;) • 0.1 1.0 10.0 100.0 • Antibody concentration (µg/mL) Serotype 3 ELISA immunogenicity: higher responses post-primary than post-booster Adapted from Prymula et al. Lancet 2006;367:740–748

  15. Do 6B conjugates provide cross protection against 6A disease? Synflorix anti-6A functional activity (OPA) appears similar to PCV7CRM Decreases in 6A IPD after PCV7CRM introduction 100 80 PCV 10 vs PCV 13? Or PCV 11 60 Serotype 6A OPA, % >8 IPD cases per 100,000 40 20 0 DiT-001/007 DiT-011/017 DiT-036 DiT-012/018 DiT-012/018 2-3-4 mo 2-4-6 mo 2-4-6 mo 6-10-14 wks 2-4-6 mo Belgium4, 0–5y2002/3 vs. 2008 & 12>18 mo & 11>18 mo & 11>18 mo & 12>18 mo & 12>18 mo Denmark5, 0–2y2000/7 vs. 2008 Norway7, 0–5y2004/5 vs. 2008 Australia8, 0–2y2002/4 vs. 2007 USA10, 0–5y1999 vs. 2003/6 England6, 0–2y2003/6 vs. 2006/9 DTPa-combo DTPw-combo SynflorixPost-primary PCV7 Post-primary Belgium and Denmark 2+1 UMV since 2007; England and Norway: 2+1 UMV since 2006; Australia: 3+0 UMV since 2005; US: 3+1 UMV since 2000 SynflorixPost-booster PCV7 Post-booster Schuerman, et al. ISPPD-7 Tel Aviv, 14–18 March 2010 (Abstract 475) ; 4. Hanquet et al. Vaccine 2011;29:2856-2864; 5. Harboe et al. Vaccine 2010;28:2642-2647; 6. Foster et al. Int J Med Microbiol2011;60:91-97; 7. Vestrheim et al. Vaccine 2010;28:2214-2221; 8. Williams et al. Med J Australia 2011;194:116-120; 9. Pilishvili et al. J Infect Dis 2010;201:32-41; 10. Park J Infect Dis2008;198:1818-22

  16. Vaccine efficacy or effectiveness against 19A invasive disease 80 60 40 20 Vaccine efficacy or effectiveness against 19A 0 -20 -40 -60 1 2 3 5 6 4 7 -80 • 14 v PS: US indirect cohort analysis (1993) (with 19F but not 19A)1 • 7vCRM: US post-marketing surveillance (assessment 2nd year after launch)2 • 7vCRM: US CDC case-control3 • 7vCRM & 9vCRM: meta-analysis of 4 efficacy studies in US, Gambia, South Africa4 • 7vCRM: Quebec post-marketing surveillance5 • 7vCRM: Finland: FinOM6 • 7vOMP: Finland: FinOM6 IPD AOM Every time it has been examined, the efficacy/effectiveness point estimate against 19A has been positive Adapted from Hausdorff et al BMC 2010 1. Butler 1995; 2. Whitney NEJM 2003; Whitney Lancet 2006; 4. Klugman 2008; 5. Deceunick ESPID 2009; 6. Eskola NEJM 2001 PCV7-CRM: Prevenar™/Prevnar™ is a trademark of Pfizer/Wyeth

  17. Synflorix elicits higher functional activity (OPA) against vaccine-related serotype 19A than PCV7 100 80 60 Serotype 19A OPA, % ≥8 40 20 0 DiT-001/007 DiT-011/017 DiT-036 DiT-012/018 DiT-012/018 2-3-4 mo 2-4-6 mo 2-4-6 mo 6-10-14 wks 2-4-6 mo & 12>18 mo & 11>18 mo & 11>18 mo & 12>18 mo & 12>18 mo DTPa-combo DTPw-combo PCV7 Post-primary SynflorixPost-primary SynflorixPost-booster PCV7 Post-booster Schuerman, et al. ISPPD-7 Tel Aviv,14–18 March 2010 (Abstract 475)

  18. Pneumococcal 19F polysaccharide conjugation to the carrier proteins Native 19F structure PCV 10 vs PCV 13? Or PCV 10 ½ Reductive amination Cyalinilation Different conjugation chemistries used for the two vaccines 19F structure in Pfizer vaccines 19F structure in Synflorix™ Kim et al. Anal . Biochemistry 2005

  19. Cross-sectional surveys in South IndiaPrevalence and sequelae of otitis media Acute suppurativeotitis media: 1.5% Otitis Media with Effusion: 6% Chronic suppurativeotitis media: 1.4% Eustachian tubal block: 4% Prevalence rate of CSOM was found to be 6% in children 2-10 yrs

  20. S. pneumoniae and H. influenzae account for up to 80% of bacterial AOM cases in children16 % of culture confirmed cases AOM caused by S. pneumoniaeand H. influenzaeare clinically indistinguishable (Liebowitz PIDJ 2004) 1. Broides et al., Clinl Infects Dis 2009;49:1641–7; 2. Eskola J, et al. N Engl J Med 2001;344:4039; 3. Gehanno P, et al. Pediatr Infect Dis J 2001;20:5703; 4.Prymula R, et al. Lancet 2006;367:7408; 5.Del CatilloF, et al. Pediatr Infect Dis J 1996;15:5413; 6.RosenblutA, et al. Pediatr Infect Dis J 2001;20:5017; 7. Guevara et al., Pediatr Infect Dis J 2008;27: 12–6; 8. Suzuki A, et al. Pediatr Infect Dis J 2005;24:6557; 9.Block SL, et al. Pediatr Infect Dis J 2004;23:8293; 10. Aguilar et al Int J Pediatr ORL. 2009; 73:1407-11; 11. Parra M et al., WSPID Buenos Aires, Nov 2009 (Abstract 797); 12. Sierra A et al., 14th ICID, Miami Mar 2009 (abstract 1129); 13. Casey & Pichichero Pediatr Infect Dis J 2010; 29(4):304-9; 14. Intakorn P et al. ISRAOM Seoul, Korea, 2009; 15. Kirkham, et al. ISPPD-7 2010 Tel Aviv, (Abstract 448); 16. Grevers et al. Int J PediatrOtorhinolaryngol 2010;74:572–77 .

  21. NTHi in lower respiratory tract diseaseBronchoalveolar lavage studies (non-CF patients) In contrast, likely minor role for NTHi in consolidated alveolar pneumonias GSK Internal literature review, M. Van dyke; Hausdorff & Dagan Vaccine 2008

  22. Can a protein D conjugate vaccine prevent acute otitis media by NTHi?Pneumococcal Otitis Efficacy Trial (POET) 11-PN-PD (NATP = 2455) Havrix(NATP = 2452) Dose 1 Dose 2 Dose 3 Booster ±3 months ±4 months ±15–18 months ±5 months 24–27 monthsfollow-up RANDOMISATION 1:1 + InfarixHexa in both groups Key endpoints: 1. AOM due to Vaccine types Any pneumococcus NTHi • Nasopharyngeal carriage due to pneumococcus and NTHi Adapted from Prymula, et al. Lancet 2006; 367: 740–48 DTPa-HBV-IPV/Hib: Infanrix hexa™ and HAV: Havrix™ are trademarks of the GlaxoSmithKline group of companies .

  23. AOM Efficacy Trial Results *Non-TypeableHaemophilusinfluenzae% 35.3(1.8to57.4) Note: Results cannot be quantitatively compared due to differences in study population, epidemiology of AOM, case-ascertainment , etc. 1.Eskola J, et al. N Engl J Med 2001; 344:403-409; FinOM: Finnish Otitis Media; 2. Prymula R, et al. Lancet 2006; 367:740–748

  24. PCV 10 vs PCV 10 ½ ? Or 2 (pathogens) vs 1 (pathogen)

  25. Synflorix has undergone an extensive clinical development programme 30 clinical studies completed by August 2011 6,730 infants; 5,098 toddlers; ~26,000 doses of PHiD-CVadministered Immunogenicity profile documented for 10 vaccine serotypes, cross-reactive serotypes 6A and 19A, andprotein D1–5,7–12 Multiple immunization schedules1–14 Vaccine interchangeability at booster age1 Catch-up schedules in older children not primed at younger age15 Six studies included PCV-7 as control1–5 Immunological non-inferiority demonstrated versus PCV-71–5 Safety and tolerability profile similar to PCV-74,6,7 Co-administration with routine paediatric vaccines1–14 DTPa-IPV/Hib, DTPa-HBV-IPV, DTPa-HBV-IPV/Hib, DTPw-HBV/Hib (Tritanrix-HepB or Zilbrix), OPV, IPV, MenC-CRM197, MenC-TT, Hib-MenC, Hiberix, HRV, MMRV and Pediacel 1. Vesikari T, et al. Pediatr Infect Dis J 2009; 28: S66–S76; 2. Wysocki J, et al. Pediatr Infect Dis J 2009; 28: S77–S88; 3. Bermal N, et al. Pediatr Infect Dis J 2009; 28: S89–S96; 4. Knuf M, et al. Pediatr Infect Dis J2009; 28: S97–S108; 5. Kim CH, et al. ISPPD-7 Tel Aviv, 2010 (Abstract 472); 6. Kim CH, et al. ISPPD-7 Tel Aviv, 2010 (Abstract 159); 7. Chevallier B, et al. Pediatr Infect Dis J 2009; 28: S109–S118; 8. van den Bergh MR, et al. 28th ESPID, Nice, June 2010 (Abstract 1163); 9. Lagos R, et al. ISPPD-6 Reykjavik, 8–12 June 2008 (Abstract 486); 10. Vesikari T et al. ISPPD-7 Tel Aviv, 2010 (Abstract 474); 11. Prymula R, et al. Lancet 2009; 374: 1339–50; 12. Silfverdal SA, et al. Pediatr Infect Dis J 2009; 28: e276–e82; 13. Omenaca F, et al. ESPID 2009; Nice, France, abstract 505; 14. Omenaca F, et al. WSPID 2009; Buenos Aires, Argentina; abstract 51; 15. ClinicalTrials.gov http://clinicaltrials.gov/ct2/show/NCT00345358 [accessed 31 Jan 2011].

  26. PHiD-CV effectiveness against pneumonia – Brazil • PHiD-CV was introduced into the Brazilian National Immunization Programme in 2010 • A case-control study evaluating a randomly selected cohort of 1,284 children 7–18 months of age was conducted to determine the effectiveness of PHiD-CV against community-acquired pneumonia (CAP)* Approximately 1 year after the introduction of routine PHiD-CV vaccination, vaccine effectiveness against CAP was 40% (95% CI 1.4, 63.0) *PHiD-CV is not currently indicated for the prevention of pneumococcal pneumonia in Brazil. Andrade A, et al. WSPID 2011, Melbourne, Australia, Abstract 670.

  27. 1400 400 2007 2007 2008 2008 2009 2009 2010 2010 2011 2011 350 1200 300 1000 250 Cumulative cases Cumulative cases 800 200 600 150 400 100 200 50 0 0 Month Month Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec PHiD-CV effectiveness against IPD – Brazil • Recent surveillance data from Brazil has shown that PHiD-CV has reduced the incidence of meningitis Cumulative number in children <2 years of age, by month of occurrence, 2007-10 Cumulative number in all ages, by month of occurrence, 2007-10 PHiD-CV introduced March-June 2010. UMV, 3+1 schedule ~48% reduction any pneumococcal meningitis Jun11 vs. Jun10 Brazil National Pneumococcal meningitis reporting. MoH - SAUDE : http://portal.saude.gov.br/portal/saude/profissional/visualizar_texto.cfm?idtxt=37811 accessed 21 Nov 2011

  28. Interim Analysis: COMPAS study Clinical OtitisMedia & PneumoniAStudy Dr. Shailesh MEHTA Clinical R & D and Medical affairs, South Asia

  29. COMPAS design summary • COMPAS is the most comprehensive Synflorixstudy to date and was designed to: • Assess the public health value of Synflorix • Confirm and quantify impact of Synflorixagainst pneumonia • Assess the impact of Synflorixagainst acute otitis media Sáez-Llorens X, et al. ESPID 2011, The Hague, The Netherlands, Abstract 1412

  30. Clinical OtitisMedia and PneumoniaStudy (COMPAS) • Multicentre, double-blind, randomised, controlled trial • Sample Size = 24,000 • Synflorix™ vs. control(Randomised 1:1) • 3 Latin American countries • Urban Setting • Good access to health care system Panama: 7 centres N= 7.000 subjects Colombia: 3 centres N= 3.000 subjects Argentina: 17 centres N=14.000 subjects

  31. Study design relative to CAP surveillance Double Blind randomized Controlled Multi center study in Argentina (3), Colombia, Panama All subjects received vaccines within the routine immunization program with in addition: Panama: opportunity for ALL subjects to receive Varilrix™ Argentina: opportunity for ALL subjects to receive MenC-CV Colombia: opportunity for ALL subjects to receive HRV SynflorixTMGroup N=~12,000 + DTPa-HBV-IPV/Hib + DTPa-IPV/Hib Randomisation 1:1 Control Group N=~12,000 Age (Months) (HBV) + DTPa-IPV/Hib (HAV) + DTPa-IPV/Hib 15-18 ~2 ~4 ~6 Vaccine 3-Dose primary Booster CAP Suspected CAP (X-ray request) Independent Data Monitoring Committee (IDMC) of experts overviewed ethical, safety aspects Synflorix™, PHiD-CV; DTPa-HBV-IPV/Hib: Infanrix™ hexa; DTPa-IPV/Hib: Infanrix™ penta; HAV, Havrix™ ; Varilrix™, Varicella vaccine, are trademarks of the GlaxoSmithKline group of companies. MenC-CV : licensed meningococcal serogroup C conjugate vaccine 1. Tregnaghi et al., XIV SLIPE, May 2011; 2.Tregnaghi et al., 29th ESPID, June 2011; 3 . Saez-Llorenz et al., 29th ESPID, June 2011; 4. 10PN-PD-DIT-028; NCT00466947

  32. CAP definitions in COMPAS Suspected CAP (S-CAP) Case definitionX-ray request Clinical suspicion of CAP or child with ARI Suspected CAP (S-CAP) Normal (no pneumonia) or non-interpretable X-ray readers panel Any abnormality on chest x-ray (CXR-CAP) Any abnormality on chest x-ray (CXR-CAP) Alveolar consolidationNon-consolidationNo pneumoniaNon-interpretable Consolidated (CXR-AC-CAP) Non-consolidated(CXR-NAC-CAP) Consolidated (CXR-AC-CAP) Primary endpointlikely bacterial CAP (B-CAP) Primary endpointlikely bacterial CAP (B-CAP) CXR-NAC-CAPwith CRP ≥ 40 g/mL Lab resultsCRP value g/mL CXR-NAC-CAPwith CRP < 40 g/mL CXR-NAC-CAPwith CRP ≥ 40 g/mL Sáez-Llorens X. et al. ESPID 2011; The Hague, The Netherlands. abstract 1412

  33. COMPAS timeline 2007 2008 2009 2010 2011 2012 Enrolment Jun 2007 – Dec 2008 Observation period Observation period Interim analysis B-CAP Nov 2010 – Jan 2011≥ 535 B-CAP ATP cases Conclusive Initiate final analysis End-of-study results Spring 2012

  34. Pneumonia aetiology is difficult to establish and can be caused by both viruses and bacteria1  Aetiology of pneumonia in 99 hospitalised children <5 years old in Switzerland2 • Limitations of microbiological diagnostic methods make exact aetiology difficult to establish3 • Viral pneumonia may suppress immune responses, and result in bacterial pneumonia super-infections4 Samples from blood culture and nasopharyngeal aspirates 1. UNICEF, 2006. Pneumonia: the forgotten killer of children; 2. Cevey-Macherelet al. Eur J Pediatr 2009; 168: 1429–36; 3. Brown. Respirology 2009;14:1068–71; 4. Warr & Jakab. Inflammation 1983; 7: 93–104

  35. Primary objective is met. Efficacy for other CAP endpoints (first episodes) also observed ^ p-value significant if lower than 0.0175 *first episodes of pneumonia by Data Lock Point 31Aug2010 Per-protocol : Vaccine Efficacy for time to first occurrence of CAP anytime from 2 weeks after the administration of dose III and part of the ATP cohort. Intent-to-treat: Vaccine Efficacy for time to first occurrence of likely bacterial CAP (B-CAP) anytime from the administration of dose I 1.Tregnaghi et al., XIV SLIPE, Punta Cana, May 2011; 2.Tregnaghi et al., 29th ESPID, The Hague, June 2011 3.10PN-PD-DIT-028; NCT00466947

  36. COMPAS – efficacy of Synflorix™ against Pneumonia (First Episodes) Intent-to-treat: Vaccine Efficacy for time to first occurrence of likely bacterial CAP (B-CAP) anytime from the administration of dose I 1. Tregnaghi et al., 29th ESPID, The Hague, June 2011; 2.10PN-PD-DIT-028; NCT00466947

  37. PCV effectiveness against IPD – Quebec • PCVs have been used in Quebec since 2002 • In 2009, PHiD-CV replaced PCV-7 in the infant routine immunization programme • In 2010, PCV-13 was introduced in place of PHiD-CV for universal mass vaccination Quebec Universal mass vaccination programme 2+1 schedule (2, 4 + 12 months) High-risk & indigenous children 3+1 schedule (2, 4, 6 + 12 mo) HIGH VACCINATION COVERAGE (~97% of children vaccinated) December 2004 PCV-7 (including catch up for ≤ 5 years of age) October 2002 PCV-7 (including catch up for ≤ 5 years of age) December 2010 PCV-13 (transition in January 2011, no catch-up) June 2009 PHiD-CV(transition in July–August 2008, no catch-up) Institut national de santé publique du Québec, Programme de surveillance du Pneumocoque, RAPPORT 2009 http://209.171.32.187/gouvqc/communiques/GPQF/Decembre2010/10/c4447.html.

  38. PCV effectiveness against IPD – Quebec • A recent effectiveness study examined the rates of IPD in children immunised with PCV-7 or PHiD-CV p = 0.02 p < 0.05 56% reduction 42% reduction IPD rate/100,0000 person years • The results demonstrated the effectiveness of PHiD-CV at reducing the number of IPD cases compared with PCV-7 • A significant reduction in IPD cases was also observed in children who received PCV-7 as the primary series and PHiD-CV as the booster De Wals P, et al. ESPID 2011; The Hague, The Netherlands. Abstract P763.

  39. PCV effectiveness against IPD – Quebec De Wals P, et al. ESPID 2011; The Hague, The Netherlands. Abstract P763.

  40. Thank you

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