1. Dr Gaurav Gupta,
Pediatrician,
Member AAP, IAP,
Charak Clinics, Mohali
Feb 2012

2.  Brief intro about Pneumococcal Disease
 India – Scope of IPD – morbidity &
mortality
 Latest data (including ASIP) regarding
Pneumococcal strains prevalent in Asia/
India
 What about NTHi ?
 Information about the latest dual pathogen
vaccine against S. Pneumoniae and NTHi
 Common Questions regarding using PCV
10

3.  Brief intro about Pneumococcal Disease
 India – Scope of IPD – morbidity &
mortality
 Latest data (including ASIP) regarding
Pneumococcal strains prevalent in Asia/
India
 What about NTHi ?
 Information about the latest dual pathogen
vaccine against S. Pneumoniae and NTHi
 Common Questions regarding using PCV
10

4. Pneumococcal Disease
 S. pneumoniae first isolated by
Pasteur in 1881
 90 known serotypes
 First U.S. vaccine in 1977 (14 valent
PPV)
 PCV 7 launched in 2000
 Type-specific antibody is protective

5. DISEASES CAUSED BY STREPTOCOCCUS
PNEUMONIAE
PNEUMOCOCCAL INFECTION
Non-invasive disease Invasive disease
• Sinusitis • Bacteraemia (blood)
• Otitis media
• Pneumonia
• Meningitis (CNS)
• Endocarditis (heart)
• Peritonitis (body cavity)
• Septic arthritis (bones and joints)
• Others (appendicitis, salpingitis,
soft-tissue infections)
Musher, in Principles and Practice of Infectious
Diseases, 1995

6. Strep Pneumoniae in developing countries
1000 X
AOM
100 X
Non Invasive
pneumoneia
10 X
Bacteremia
Meningitis

7.  Brief intro about Pneumococcal Disease
 India – Scope of IPD – morbidity &
mortality
 Latest data (including ASIP) regarding
Pneumococcal strains prevalent in Asia/
India
 What about NTHi ?
 Information about the latest dual pathogen
vaccine against S. Pneumoniae and NTHi
 Common Questions regarding using PCV
10

8. Each Dot = 5,000 child deaths
Child DEATHS
We are No. 1 Black RE. The Lancet 2003; 361: 2226-2234

9. Pneumococcal Disease Burden
in India
 Meningitis and Sepsis –
 Among Top 10 causes of mortality
in India
Meningitis
 causing 1.53 lakh deaths in
children under 5 yrs
Sepsis
 Pneumonia –
 No. 1 Killer of children in India
 Causing 4 lakh deaths in children Pneumonia
under 5yrs
 Acute Otitis Media (AOM) – Non-invasive diseases
 Most frequent disease of (Otitis media)
Non-invasive diseases
childhood (Otitis media)
 Leading cause of physician visits
and antibiotic therapy
Black RE et al. Lancet 2010; 375: 1969-1987
Pneumonia: The Forgotten killer; WHO September 2008
Rudan et al. Bull World Health org 2008; 86: 408
Gehrard grevers, IJPO Vol 74 Issue 6, June 2010, Pages 572-
577

10. PNEUMOCOCCAL DISEASE BURDEN
Countries with the greatest number of pneumococcal
deaths among children under 5 years
TOP TEN
O,Brien K, et al. Lancet. 2009;374:893-902.

11. PNEUMONIA AND 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 pneumonia1
1. Levine OS et al Indian Pediatrics 2007; 44:491-496
2. Pneumonia – The forgotten killer of children, WHO, UNICEF, 2006
3. Thacker N. IPD burden - An Indian Perspective. Pediatrics Today 2006; 9(4): 208-213

12. 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 goal
Source: UN Population Division World Population Prospects, 2004.
12

13.  Brief intro about Pneumococcal Disease
 India – Scope of IPD – morbidity &
mortality
 Latest data (including ASIP) regarding
Pneumococcal strains prevalent in Asia/
India
 What about NTHi ?
 Information about the latest dual pathogen
vaccine against S. Pneumoniae and NTHi
 Common Questions regarding using PCV
10

14. A limited number of serotypes
cause IPD in young Children
~ 10 Serotypes causes
75% of IPD in children
under 5 years of age
Johnson et al PLOS Medicine 2010

15. PCV 7 - Coverage
References: 1. Johnson et al. Plos Medicine 2010

16. PCV 10 - Coverage

17. PCV 13 - Coverage

18. Pneumococcal Polysaccharide and Non- Typable Haemophilus influenza
(NTHi)
Protein D conjugate vaccine, adsorbed
Europe Asia
North America
Africa
Latin America
oceania
References: 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

19. Epidemiology of Pneumococcal Serotypes in India in Children under 5
yrs :
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 )
19

20. PNEUMONET KIMS study… (1 year data)
•Study done at 3 hospitals in
Table 3: Serotype Distribution
Bangalore South Zone
(Kempegowda Institute of Medical Serotype N
Sciences Hospital, Vanivilas 6A 5
Hospital, and Indira Gandhi 5 3
Institute of Child Health) 1 2
3 2
•Limited no. of serotype and only
from part of a city of a region 14 2
hence can not represent a Sub 9V 1
continent like India 19F 1
18C 1
• No indication of high prevalence
of 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)
20

21. Pressing Need For Robust
Indian Data ……
 Very limited data available from India regarding
Pneumococcal disease causing
 Serotypes
 Prevalence
 Distribution
 Robust data from PAN India will help in
Suitability and choice of PCV in India
 ASIP : ALLIANCE FOR SURVEILLANCE OF
INVASIVE PNEUMOCOCCI IN INDIA can really
help in understanding the prevalence of S.
Pneumonie and serotype

22. CMC CNBC Inclusion
Study Centres Criteria
Ludhian 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 therapy
Mumba 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 Tiruvalla
LTMM
C
Mumba Central
i Monitoring
Lab CMC,
St. AIMS
Vellore
Johns Kochi
Bengalu
19

23. ASIP: Distribution of Serogroup/type
Preliminary 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 23

24. Summary : Prevalence of
Pneumococcal Serotypes in
India
 Available data since 1999 to 2011 suggest that in
children < 5 yrs of age
 Serotype 1,5 and 7 are major cause of IPD in India
across all studies
 In pan India serotype surveillance studies there was no
evidence of ST 3 prevalence in India
 No rise / uptrend seen in serotype 19 A prevalence
in India or no data is available to assume the same

25.  Brief intro about Pneumococcal Disease
 India – Scope of IPD – morbidity &
mortality
 Latest data (including ASIP) regarding
Pneumococcal strains prevalent in Asia/
India
 What about NTHi ?
 Information about the latest dual pathogen
vaccine against S. Pneumoniae and NTHi
 Common Questions regarding using PCV
10

26. Spectrum of disease caused by 2
bacteria
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

27. 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 Catarrhalis
The 3 predominant pathogens in otitis media: S. pneumoniae, NTHi and M. catarrhalis (from 8 different studies involving
tympanocentesis and culture of middle ear fluid from 1990–2007).9–16
Murphy et al The Pediatric Infectious Disease Journal • Volume 28, Number 10, October 2009

28. Indian data on NP carriage of NTHi in
children under 2yrs of age

29. Review of contribution of NTHi (non typable Haemophilus influenzae) and
S pneumonia in children Acute otitis media
Study Journa Year Place Sampl Age group S. pneumoniae Non typable
l e H. influenzae
Alexandr BMC 2011 Colombi 99 3-60 months 30/99 (30%) 31/99 (31%)
a Sierra infect. a
et al. Dis
Parra M Vaccin 2011 Mexico 121 3-59 months 35/121 (29%) 41/121 (34%)
Bacterial e
et al.
Shiping AJ of 2011 Taiwan 225 1-94months --------------- 189/225 (84%)
He. et al med.
Res.
Barkai G. Ped. 2009 Israel 8145 < 60months 4339/8145(53% 4928/8145
et al Infect. ) (60%)
Dis J
Ref: 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

30. Conclusion:
 NTHi (Non Typable Haemophilus influenzae) and S.
pneumonia and are the major causative organism for
AOM among under 5 children worldwide.
 NTHi and S. pneumoniae mixed episodes are more
likely to occur in AOM, & interaction between these two
pathogens contribute to chronicity and complexity of AOM.

31. Pneumococcal Otitis Efficacy Trial (POET)
Vaccine Efficacy Vaccine Efficacy
Acute Otitis Media Endpoint (95% CI) (95% CI)
POET [11Pn-PD] FinOM [PCV-7]
Any (confirmed by presence of middle-ear % 33.6 %6
fluid) (20.8 to 44.3) (-4 to16)
Vaccine pneumococcal serotypes % 57 % 57
(41.4 to 69.3) (44 to 67)
Non-vaccine pneumococcal serotype %8 % -33
(-64.2 to 49) (-80 to 1)
Haemophilus influenzae % 35.6* (-%11)
(3.8 - 57.0) (-34 to 8)
Recurrent AOM % 55 % 16
(-1.9 to 80.7) (-6 to 35)
*Non-Typeable Haemophilus influenzae % 35.3 (1.8 to 57.4)
Synflorix Only new generation PCV offer dual
Note: Results cannot be quantitatively compared due to differences in study population,
Pathogen Protection against S. Pneumoniae and
epidemiology of AOM, case-ascertainment , etc.
NTHi in AOM
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 31

32. Summary : Importance of NTHi
and dual pathogen protection
 NTHi along with S. Pneumoniae causes non
invasive disease like AOM
 NTHi is one of the leading pathogen in OM
 Managing OM is difficult and challenging and
every children by 3 years of age will have an
episode of AOM
 In POET trial 11 v PNPD vaccine offered dual
pathogen protection against S. Pneumoniae and
NTHi All cause AOM was reduced by 33.6 %

33.  Brief intro about Pneumococcal Disease
 India – Scope of IPD – morbidity &
mortality
 Latest data (including ASIP) regarding
Pneumococcal strains prevalent in Asia/
India
 What about NTHi ?
 Information about the latest dual pathogen
vaccine against S. Pneumoniae and NTHi
 Common Questions regarding using PCV
10

34. Description of PCV vaccines
Prevenar 4, 6B, 9V, 14, 18C, 19F, 23F
CRM197 Diphtheria carrier protein
Synflorix 4, 6B, 9V, 14, 23F, 18C, 19F 1, 5, 7F
NTHi protein D
Prevenar13 4, 6B, 9V, 14, 18C, 19F, 23F, 1, 5, 7F 3, 6A, 19A
CRM197 Diphtheria carrier protein
34

35. 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 35

36. 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

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

38. Synflorix : Only new generation PCV with
Proven Efficacy Against Clinical
Pneumonia
Synflorix™ C-CAP
Alveolar consolidation on
Vaccine efficacy (%) Chest X-ray analyzed acc to
,[95% CIs] , p-value WHO definition
Per-protocol (ATP) 25.7 [8.4;39.6]
Intent-to-treat (TVC) 23.4 [8.8;35.7]
^ 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

39. Synflorix IPD Effectiveness II:
Pneumococcal Meningitis in Brazil, in <2 yr olds
1998-2011
Cumulative number of Pneumococcal meningitis cases in children <2 years of age by month of occurrence, Brazil,
2007-10
Synflorix™ 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

40. Synflorix in Various Countries NIPs
National Immunization Programs Regional High Risk
Imm. Population
Programs s
Finland Brazil New Zealand Sweden Bosnia &
(5 regions) Herzegovina
Iceland Chile Kenya Poland
Netherlands Peru Ethiopia Croatia
Czech Rep Ecuador Saudi Arabia
Slovakia Mexico Oman
Bulgaria Colombia
Austria Caribbean: Aruba, Jamaica,
Bermuda, Gran Cayman,
Cyprus, Albania Trinidad & Tobago, Barbados

41.  Brief intro about Pneumococcal Disease
 India – Scope of IPD – morbidity &
mortality
 Latest data (including ASIP) regarding
Pneumococcal strains prevalent in Asia/
India
 What about NTHi ?
 Information about the latest dual pathogen
vaccine against S. Pneumoniae and NTHi
 Common Questions regarding using PCV
10

42. Q 1. Why should I use Synflorix when prophylactic use
of Paracetamol is not recommended as the immune
response may be lowered?

44. Q 2. Synflorix co-administration with IPV caused a
reduced immune response to IPV 2. Can I still use
Synflorix with IPV?
Answer: Synflorix can safely be co-administered
with IPV and will not cause a reduced antibody
response to the poliovirus antigens

45. Summary
 Pneumococcal disease is the #1 vaccine-preventable cause
of death worldwide in children aged <5 years1
 Data from India clearly points to vaccine preventable
serotypes being common cause of Pneumococcal Disease !
 Convenient transition from PCV 7 to newer vaccines at any
point in the vaccination schedule4
 PCV 10 offers protection against AOM too – unique.
 For high risk cases PCV/ PPSV can be given up to 18 years
1. WHO. http://www.who.int/immunization_monitoring/data/GlobalImmunizationData.pdf. Accessed September 3, 2009.
2. Dinleyici E, et al. Expert Rev Vaccines. 2009;8:977-986.
3. GAVI Pneumococcal AMC TPP, Nov 2008. http://www.vaccineamc.org/files/TPP_codebook.pdf. Accessed September 3, 2009.
4. Prevenar 13. Summary of Product Characteristics. Wyeth Pharmaceuticals.
5. Data on file. Pfizer Inc, New York, NY. 45