Synflorix revisited - April 2012
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Synflorix revisited - April 2012

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Presentation at Ambala & Patiala CME organized by GSK

Presentation at Ambala & Patiala CME organized by GSK

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  • Key PointsAs per the O’Brien report in Lancet 2009, India tops the countries with the greatest number of pneumococcal deaths in children under 5 years, ahead of China which has a higher population.
  • Key PointsThe Millennium Development Goal 4 aims to reduce mortality in children younger than 5 years by two-thirds between 1990 and 2015. However looking at this graph for 60 priority countries (including India), it seems we are still far away from that goal.
  • Although 91 serotypes have been isolated only a few of these serotypes are responsible for invasive pneumococcal disease. According to Johnson et al published in 2010, only 10 serotypes cause 75% of IPD in children under 5 years of age.
  • Key PointsOverall, positive culture growth was obtained in 432 (8.2%) of the 5,249 enrolled subjects. Percentages of total growth were as follows: Salmonella sp. 60 (13.9%); Streptococcus pneumonia 27 (6.3%); Staphylococcbus hominis 41(9.5%); Micrococcus sp. 32 (7.4%); Staphylococcus epidermidis 24 (5.6%); Staphylococcus aureus 19 (4.4%).SP was detected and serotype information obtained in 17 subjects (n=18 serotypes). In 1 subject isolates grown from CSF and blood were of 2 different serotypes (CSF=6A and blood=3).Distribution of the serotypes isolated is shown in Table 3; 6A and 5 were seen most frequently.The serotype coverage offered by PCV7, PCV10, and PCV13 was 27.77%, 55.55%, and 100%, respectively.Four of the 18 isolates were resistant to trimethoprim/sulfamethoxazole, 3 to erythromycin, and 1 to ceftriaxone. Antibiotic resistance was observed for serotypes 6A, 14, 1, 3, and 19A.
  • Based on a compilation paper written by Murphy et al in 2009, NTHi is one of the leading othopathogens and is responsible more than 30% AOM cases in children under 5 years of age.
  • To summarize on these 3 serotypes – Serotype 3 is not commonly isolated in children under 5 yrs of age. It is an atypical serotype and there is inconsistent immune boosting by any of the pneumococcal vaccines. Even the FDA has questioned the effectiveness of ST 3 in Prevenar 13.Serotype 6B-6A cross-protection is now a globally accepted fact and the WHO/GAVI organizations accept that any PCV with ST 6B will provide cross-protection to 6A.Serotype 19A as shown in the earlier slides is not a rising problem across the globe. And 19F-19A cross-reactivity is possible.To conclude – both vaccines have only a marginal difference in their coverage and for India, based on Dr. Nitin Shah’s article, both vaccines offer >70% IPD coverage.

Synflorix revisited - April 2012 Synflorix revisited - April 2012 Presentation Transcript

  • Dr Gaurav Gupta, Pediatrician, Member AAP, IAP,Charak Clinics, Mohali 7th April 2012
  • Overview Pneumococcal Disease Burden – Indian Context Studies from India & abroad NTHi Design, Recommendations & Faqs
  • Overview Pneumococcal Disease Burden – Indian Context Studies from India & abroad NTHi Design, Recommendations & Faqs
  • Description of PCV vaccines PCV 7 (Prevenar) 4, 6B, 9V, 14, 18C, 19F, 23F CRM197 Diphtheria carrier proteinPCV 10 (Synflorix) 4, 6B, 9V, 14, 23F, 18C, 19F 1, 5, 7F NTHi protein D TT DT NTHi protein DPCV 13 (Prevenar13) 4, 6B, 9V, 14, 18C, 19F, 23F, 1, 5, 7F 3, 6A, 19A CRM197 Diphtheria carrier protein 4
  • Strep Pneumoniae in developing countries 1000 X AOM 100 X Non Invasive pneumoneia 10 X Bacteremia Meningitis
  • PNEUMOCOCCAL DISEASE BURDENCountries with the greatest number of pneumococcal deaths among children under 5 years TOP TENO,Brien K, et al. Lancet. 2009;374:893-902.
  • Pneumonia & India Pneumonia remains the leading killer of children1 410,000 children < 5 die of pneumonia every year1,2 25% of all child deaths are due to pneumonia3 Meta-analysis of 4 CTs suggest 30-40% of all severe pneumonia in children is pneumococcal. In Indian context, around 123,000 to 164,000 children <5 years die annually from pneumococcal pneumonia11. Levine OS et al Indian Pediatrics 2007; 44:491-4962. Pneumonia – The forgotten killer of children, WHO, UNICEF, 20063. Thacker N. IPD burden - An Indian Perspective. Pediatrics Today 2006; 9(4): 208-213
  • Strep Pneumoniae & Pneumonia – Indian Disease Burden  Pneumonia is the single most important cause of death among children in the postneonatal period, contributing as much as 27.5% of total under-five mortality  It appears that about 10-15% of childhood pneumonias are caused by H. influenzae and RSV each; and 12-35% by pneumococcus. ** Mathew J et al. ARI & Pneumonia in India – A systematic review . Indian Pediatrics, March2011
  • We are missing the target (Millennium Development Goal 4) Under-five mortality ratio (U5MR) projections 60 priority countries U5MR in 2015 85 at current AAR 38 MDG Target U5MR in 2015 AAR =average annual rate of reduction MDG=millennium development goalSource: UN Population Division World Population Prospects, 2004. 9
  • Overview Pneumococcal Disease Burden – Indian Context Studies from India & abroad NTHi Design, Recommendations & Faqs
  • A limited number of serotypes cause IPD in young Children ~ 10 Serotypes causes 75% of IPD in children under 5 years of ageJohnson et al PLOS Medicine 2010
  • PCV 7 - CoverageReferences: 1. Johnson et al. Plos Medicine 2010
  • PCV 10 - Coverage
  • PCV 13 - Coverage
  • Pneumococcal Polysaccharide and Non- Typable Haemophilus influenza (NTHi) Protein D conjugate vaccine, adsorbed Europe Asia North America Africa Latin America oceaniaReferences: 1. Johnson et al. Plos Medicine 2010 2.Nitin k. shah et al. summary of invasive pneumococcal disease burden among children in Asia-Pacific region. Vaccine 28(2010) 7589-7605
  • Epidemiology of Pneumococcal Serotypes in India in Children under 5yrs :An overview of available data  1999 : IBIS study (Invasive Bacterial Infection Surveillance)  2006-07 :SAPNA network (South Asia Pneumococcal Alliance)  2008 : Asian Network for Surveillance Of Resistant Pathogens ( ANSORP 2008 )  1992-07 : S. Pneumoniae Surveillance for Serotype distribution in Bangladesh:  2008 : KIMS Study (PneumoNET)  2009 :Pneumo ADIP (Pneumococcal vaccine Accelerated Development and Introduction Plan )  2011 : Alliance for Surveillance of Invasive Pneumococci (ASIP) : (Jan – Nov ) 16
  • PNEUMONET KIMS study… (1 year data)•Study done at 3 hospitals in Table 3: Serotype DistributionBangalore South Zone(Kempegowda Institute of Medical Serotype NSciences Hospital, Vanivilas 6A 5Hospital, and Indira Gandhi 5 3Institute of Child Health) 1 2 3 2•Limited no. of serotype and onlyfrom part of a city of a region 14 2hence can not represent a Sub 9V 1continent like India 19F 1 18C 1• No indication of high prevalenceof serotype 19 A 19A 1 a – In 1 subject 2 different serotypes were obtained from blood and CSF (6A in CSF and 3 in blood) 17
  • Burden of Disease –PneumonetDataAge Clinical Incidence X-ray Incidencegroup Pneumonia rates per Pneumonia rates per(months) No. of cases 1,00,000 pop. No. of cases 1,00,000 pop.1 to 6 393 4,800.88 145 1,771.326 to 12 499 3,826.69 214 1,641.1012 to 24 627 2,752.78 318 1,396.1524 to 36 384 1,708.95 175 778.8236 to 60 468 1,017.17 254 552.05Overall 2,371 2,107.87 1,106 983.26 These are total pneumonia cases. Incidence of Pneumococcal pneumonia has to be by extrapolation on possible fraction of S. pneumonae as a cause of pneumonia in this age groups
  • CMC CNBC Inclusion Study Centres CriteriaLudhian Delhi a • PAN India • Age: Safdar <5 years Network • JungClinically suspected case of pneumonia, meningitis Delhior bacteremia (as per modified WHO case Institutes • 12 definition) KEM • Without previous antibiotic therapyMumba KEM • After informed consent by parent • 48 Sentinel i Pune • Microbiology protocol as per modified WHO/CDC Pediatricians surveillance manual BVP SRMC Pune Chenn • 7 Sentinel MGIM ai local labs S Pushpag Wardh iri a TiruvallaLTMM CMumba Central i Monitoring Lab CMC, St. AIMS Vellore Johns Kochi Bengalu 19
  • ASIP: Distribution of Serogroup/typePreliminary Results (n=35), 2011 Serogroup / No. of Serotype isolates 1 01 4 01 19 A % : 1/35 ( 2.85 %) 19F % : 3/35 ( 8.57%) 5 02 ------------------------------------ 10 04 19 % : 4/35 (11.4%) 7F - • In line with previous studies and 9V - PneumoADIP- Asia: 2009 14 (F) 01 18C - • Others: includes serogroups with 1 isolates 19F 03 23F 02 No case of ST 3 in India, 3 - results in line with 6 03 Previous large multicentric trials 19A 01 Others 17 20
  • Indian Data – A brief SynopsisStudy Total number Top 3 Isolates of IsolatesIBIS – 1999 307 6, 1, 19SAPNA 4 1, 6 BPneumonet * 17 6 A, 5, 1/ 3/ 14ASIP * 35 10, 19 F/ 6, 23F/ 5
  • Ongoing clinical trials COMPAS study  Being conducted in 24,000 children in 3 Latin American Countries; 4 year follow-up  Aim is to study the efficacy in preventing clinical and radiological pneumonia in study group  PCV10 (with NTHi D protein) in study arm with control (Hep. B and Hep. A)  Interim data – vaccine efficacy rate of 22% (clinical pneumonia i.e. features of LRTI with CRP > 40 mg/L) and 25.7% (Consolidation on X-ray Chest)  Likely to be officially published by June 2012
  • PCV 10 IPD Effectiveness II: Pneumococcal Meningitis in Brazil, in <2 yr olds 1998-2011Cumulative number of Pneumococcal meningitis cases in children <2 years of age by month of occurrence, Brazil,2007-10 PCV 10 introduction March-June 2010. 2009 UMV, 3+1 schedule 2010 ~48% reduction any Pn. meningitis 2011 Jun11 vs Jun10 Brazil National Pneumococcal menigitis reporting. MoH - SAUDE : http://portal.saude.gov.br/portal/saude/profissional/visualizar_texto.cfm?idtxt=37811 accessed 21Nov2011
  • Overview Pneumococcal Disease Burden – Indian Context Studies from India & abroad NTHi Design, Recommendations & Faqs
  • Spectrum of disease caused by 2bacteria H. influenzae S. pneumoniae Meningitis Sepsis Incidence of invasive H. influenzae disease drastically reduced—but not eliminated--where Hib vaccination introduced Pneumonia Non-invasive diseases + NTHi (Otitis media) (non-invasive & invasive diseases) 26 26
  • NTHi is one of the leading pathogen in Otitis Media 40.0% 36.7% 35.0% 31.7% 30.0% 25.0% 20.0% 18.7% 15.0% 10.0% 5.0% 0.0% S. NTHi M. Pneumoniae CatarrhalisThe 3 predominant pathogens in otitis media: S. pneumoniae, NTHi and M. catarrhalis (from 8 different studies involvingtympanocentesis and culture of middle ear fluid from 1990–2007).9–16Murphy et al The Pediatric Infectious Disease Journal • Volume 28, Number 10, October 2009
  • Indian data on NP carriage of NTHi in children under 2yrs of age
  • Review of contribution of NTHi (non typable Haemophilus influenzae) and S pneumonia in children Acute otitis mediaStudy Journal Year Place Sample Age group S. Non typable pneumoniae H. influenzaeAlexandr BMC 2011 Colombia 99 3-60 months 30/99 (30%) 31/99 (31%)a Sierra Infect.et al. DisParra M Vaccine 2011 Mexico 121 3-59 months 35/121 41/121 (34%)Bacterial (29%)et al.Shiping AJ of 2011 Taiwan 225 1-94months --------------- 189/225 (84%)He. et al med. Res.Barkai G. Ped. 200 Israel 8145 < 60months 4339/8145 4928/8145et al Infect. 9 (53%) (60%) Dis JRef: Alexandra Sierra et al.,BMC infectious diesease,2011 Parra M Bacterial et al., Vaccine. 2011 (29) 5544– 5549 Shiping He. African Journal of Microbiology Research Vol. 5(17), pp. 2407-2412 Barkai G. Pediatr Infect Dis J.2009 Jun;28(6):466-71
  • Conclusion: NTHi (Non Typable Haemophilus influenzae) and S.pneumonia and are the major causative organism forAOM among under 5 children worldwide. NTHi and S. pneumoniae mixed episodes are morelikely to occur in AOM, & interaction between these twopathogens contribute to chronicity and complexity of AOM.
  • Synflorix Only new generation PCV offer dualPathogen Protection against S. Pneumoniae and NTHi in AOM
  • Overview Pneumococcal Disease Burden – Indian Context Studies from India & abroad NTHi Design, Recommendations & Faqs
  • Design of Synflorix Why use a carrier protein derived from H. influenzae? Synflorix designed to potentially: • protect against most prevelent 10 pneumococcal serotypes • minimize risk of interference with co-administered vaccines • provide protection against NTHi disease S.pneumoniae Non-Typeable H. influenzae protein D [carrier protein] Polysaccharides (10 serotypes*)* 2 polysaccharides conjugated on tetanus and diphtheria toxoid respectively 33
  • Summary : What about Serotype 3, 6A and 19A?Is there any difference between these 2 Vaccines? Serotype 3 (not a common pediatric serotype)  is an atypical serotype and non boostable  In large muticentric clinical studies, Serotype 3 has not been isolated in children < 5 years of age in India ( IBIS 1999 TO ASIP 2011) Serotype 6A (globally accepted 6B-6A cross-protection)  PCV 7 which included only ST 6B, reduced 90% of serotype 6A IPD cases as per CDC surveillance data Serotype 19A (not rising in India)  Data from pan India studies confirms that, there is no rise / upward trend observed in serotype 19 A IPD cases Both the vaccine in India will offer > 70% IPD coverage
  • New recommendations for PCV 10 Iceland – PCV10 April 20111 EMA(CMPH) – PCV10 June 20112 (extension of use for 2 to 5 year age group) Brazil, Chile, Mexico, Colombia Finland, Sweden, Netherlands Albania, Bulgaria, Austria, Cyprus Kenya1. EPI-ICE 7:2 Apr-Jun 2011 2. NELM News Service June 2011
  • New recommendations – PCV10 vs PCV13 Switch from PCV 10 to PCV 13  Hong Kong Nov 20111  Australia Aug 20112  Canada Sep 20103 Simultaneous use of PCV10 and PCV 13  Korea Apr 20114 ○ No comment of superiority or otherwise of either vaccine ○ No special recommendation for use of either vaccine in any specific group  New Zealand May 20115 ○ Use of PCV10 routinely and PCV13 for ―high-risk‖ group1. Press Release: Health Dept. HK. Nov 29, 2011. 2. Dept. Memo dated 30th Aug, 20113. CCDR: Nov 2010. 4. Korean J Pediatr 2011;54(4):146-151 5. IAC – Univ. of Auckland
  • Q 1. Why should I use Synflorix when prophylactic useof Paracetamol is not recommended as the immuneresponse may be lowered?
  • Q 2. Synflorix co-administration with IPV caused areduced immune response to IPV 2. Can I still useSynflorix with IPV?Answer: Synflorix can safely be co-administered with IPV and will not cause a reduced antibody response to the poliovirus antigens
  • Conclusion Pneumococcal disease is the #1 vaccine-preventable cause of death worldwide in children aged <5 years1 High Pneumococcal disease burden in India, excellent safety and improved efficacy profile, pneumococcal vaccine should be offered to all affording children. PCV 10 offers good protection at better price, with additional significant benefit of protecting against AOM due to NTHi.