synflorix what’s new in preventing pneumococcal disease (feb 2012)

WHAT’S NEW IN PREVENTING PNEUMOCOCCAL DISEASE ?

Dr Gaurav Gupta,

Pediatrician,

Member AAP, IAP,

Charak Clinics, Mohali

Feb 2012

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

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

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

DISEASES CAUSED BY STREPTOCOCCUS PNEUMONIAE

Non-invasive disease• Sinusitis • Otitis media • Pneumonia

Musher, in Principles and Practice of Infectious Diseases, 1995

Invasive disease• Bacteraemia (blood)

• Meningitis (CNS)• Endocarditis (heart)• Peritonitis (body cavity)• Septic arthritis (bones and joints)• Others (appendicitis, salpingitis,

soft-tissue infections)

PNEUMOCOCCAL INFECTION

1000 XAOM

MeningitisStrep Pneumoniae in developing countries

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

Child DEATHS Each Dot = 5,000 child deaths

Black RE. The Lancet 2003; 361: 2226-2234We are No. 1

Pneumococcal Disease Burden in India

Meningitis and Sepsis – Among Top 10 causes of

mortality in India causing 1.53 lakh deaths in

children under 5 yrs Pneumonia –

No. 1 Killer of children in India Causing 4 lakh deaths in children

under 5yrs Acute Otitis Media (AOM) –

Most frequent disease of childhood

Leading cause of physician visits and antibiotic therapy Black RE et al. Lancet 2010; 375: 1969-1987

Pneumonia: The Forgotten killer; WHO September 2008Rudan et al. Bull World Health org 2008; 86: 408Gehrard grevers, IJPO Vol 74 Issue 6, June 2010, Pages 572-577

Non-invasive diseases(Otitis media)

Non-invasive diseases(Otitis media)

Pneumonia

Sepsis

Non

-inva

sive

In

vasi

ve Meningitis

Countries with the greatest number of pneumococcal deaths among children under 5

years

O,Brien K, et al. Lancet. 2009;374:893-902.

PNEUMOCOCCAL DISEASE BURDEN

TOP TEN

PNEUMONIA AND INDIAPNEUMONIA 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; 44:491-4962. Pneumonia – The forgotten killer of children, WHO, UNICEF, 20063. Thacker N. IPD burden - An Indian Perspective. Pediatrics Today 2006; 9(4): 208-213

We are missing the target(Millennium Development Goal 4)

12

AAR =average annual rate of reduction MDG=millennium development goal

U5MR in 2015 at current AAR

MDG Target U5MR in 2015

85

38

Under-five mortality ratio (U5MR) projections 60 priority countries

Source: UN Population Division World Population Prospects, 2004.

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

A limited number of serotypes cause IPD in young Children

Johnson et al PLOS Medicine 2010

~ 10 Serotypes causes 75% of IPD in children under 5 years of age

PCV 7 - Coverage

References: 1. Johnson et al. Plos Medicine 2010

PCV 10 - Coverage

PCV 13 - Coverage

North America

Latin America

oceania

Africa

AsiaEurope

PCV7:<50%1PCV10:>70%1PCV13: 75%1

PCV7:<60%1PCV10:<80%1PCV13:~80%1PCV7:<70%1PCV10:~75%1PCV13:~80%1

PCV7:~70%1PCV10:~80%1PCV13:<90%1

PCV7:>80%1PCV10:~85%1PCV13:~90%1

PCV7:<50%2PCV10: 75%2PCV13: 75%2

PCV7:<50%1PCV10:>70%1PCV13: 75%1

Pneumococcal Polysaccharide and Non- Typable Haemophilus influenza (NTHi)

Protein D conjugate vaccine, adsorbed

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

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)

Table 3: Serotype Distribution

Serotype N

6A 5

5 3

1 2

3 2

14 2

9V 1

19F 1

18C 1

19A 1

a – In 1 subject 2 different serotypes were obtained from blood and CSF (6A in CSF and 3 in blood)

•Study done at 3 hospitals in Bangalore South Zone (Kempegowda Institute of Medical Sciences Hospital, Vanivilas Hospital, and Indira Gandhi Institute of Child Health)

•Limited no. of serotype and only from part of a city of a region hence can not represent a Sub continent like India

• No indication of high prevalence of serotype 19 A

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

Study Centres

19

KEM Mumba

i

LTMMC

Mumbai

BVP Pune

KEMPune

MGIMS

Wardha

St. Johns

Bengaluru

Pushpagiri

Tiruvalla

SRMCChenn

ai

Safdar Jung Delhi

CNBCDelhi

CMCLudhian

a • PAN India Network

• 12 Institutes

• 48 Sentinel Pediatricians

• 7 Sentinel local labs

Central Monitoring Lab CMC,

Vellore

Inclusion Criteria

• Age: <5 years• Clinically suspected case of pneumonia, meningitis

or bacteremia (as per modified WHO case definition)

• Without previous antibiotic therapy• After informed consent by parent• Microbiology protocol as per modified WHO/CDC

surveillance manual

AIMSKochi

ASIP: Distribution of Serogroup/typePreliminary Results (n=35), 2011

Serogroup / Serotype

No. of isolates

1 01

4 01

5 02

10 04

7F -

9V -

14 (F) 01

18C -

19F 03

23F 02

3 -

6 03

19A 01

Others 17 23

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

• Others: includes serogroups with 1 isolates

No case of ST 3 in India,

results in line with Previous large

multicentric trials

Summary : Prevalence of Pneumococcal Serotypes in India

Available data since 1999 to 2011 suggest that in children < 5 yrs of ageSerotype 1,5 and 7 are major cause of IPD in India

across all studiesIn pan India serotype surveillance studies there was no

evidence of ST 3 prevalence in IndiaNo rise / uptrend seen in serotype 19 A prevalence

in India or no data is available to assume the same

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

Non-invasive diseases(Otitis media)

Pneumonia

Sepsis

Non

-inva

sive

Inva

sive

S. pneumoniae

26

Spectrum of disease caused by 2 bacteria

Meningitis

H. influenzae

Incidence of invasive H. influenzae disease drastically reduced—but

not eliminated--where Hib vaccination introduced

+ NTHi(non-invasive &

invasive diseases)

S. Pneu-moniae

NTHi M. Catarrhalis

0.0%

5.0%

10.0%

15.0%

20.0%

25.0%

30.0%

35.0%

40.0% 36.7%

31.7%

18.7%

NTHi is one of the leading pathogen in Otitis Media

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).9–16Murphy 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

Study Journal Year Place Sample Age group S. pneumoniae Non typable H. influenzae

Alexandra Sierra et al.

BMC infect.Dis

2011 Colombia

99 3-60 months 30/99 (30%) 31/99 (31%)

Parra M Bacterial et al.

Vaccine

2011 Mexico 121 3-59 months 35/121 (29%) 41/121 (34%)

Shiping He. et al

AJ of med. Res.

2011 Taiwan 225 1-94months --------------- 189/225 (84%)

Barkai G. et al

Ped. Infect. Dis J

2009 Israel 8145 < 60months 4339/8145(53%)

4928/8145 (60%)

Review of contribution of NTHi (non typable Haemophilus influenzae) and S pneumonia in children Acute otitis media

Ref: Alexandra Sierra et al.,BMC infectious diesease,2011Parra M Bacterial et al., Vaccine. 2011 (29) 5544– 5549 Shiping He. African Journal of Microbiology Research Vol. 5(17), pp. 2407-2412Barkai 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 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.

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

Acute Otitis Media EndpointVaccine Efficacy

(95% CI)POET [11Pn-PD]

Vaccine Efficacy (95% CI)

FinOM [PCV-7]

Any (confirmed by presence of middle-ear fluid)

% 33.6(20.8 to 44.3)

% 6(-4 to16)

Vaccine pneumococcal serotypes % 57(41.4 to 69.3)

% 57(44 to 67)

Non-vaccine pneumococcal serotype % 8(-64.2 to 49)

% -33(-80 to 1)

Haemophilus influenzae % 35.6*(3.8 - 57.0)

(-%11)(-34 to 8)

Recurrent AOM % 55(-1.9 to 80.7)

% 16(-6 to 35)

Pneumococcal Otitis Efficacy Trial (POET)

*Non-Typeable Haemophilus influenzae % 35.3 (1.8 to 57.4)

Note: Results cannot be quantitatively compared due to differences in study population, epidemiology of AOM, case-ascertainment , etc.

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Synflorix Only new generation PCV offer dual Pathogen Protection against S. Pneumoniae and

NTHi in AOM

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 %

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

4, 6B, 9V, 14, 18C, 19F, 23F

4, 6B, 9V, 14, 23F, 18C, 19F 1, 5, 7F

Prevenar13 4, 6B, 9V, 14, 18C, 19F, 23F, 1, 5, 7F

CRM197 Diphtheria carrier protein

CRM197 Diphtheria carrier protein

Prevenar

Synflorix

NTHi protein D

3, 6A, 19A

35

Synflorix designed to potentially:

• protect against most prevelent 10 pneumococcal serotypes

• minimize risk of interference with co-administered vaccines

• provide protection against NTHi disease

Design of Synflorix

Why use a carrier protein derived from H. influenzae?

S.pneumoniae

protein D[carrier protein]

Non-TypeableH. influenzae

Polysaccharides(10 serotypes*)

* 2 polysaccharides conjugated on tetanus and diphtheria toxoid respectively

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

Summary : What about Serotype 3, 6A and 19A?

Is there any difference between these 2 Vaccines ?

Clinical Otitis Media and Pneumonia Study (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

Argentina: 17

centres

N=14.000 subjects

Colombia: 3

centres

N= 3.000 subjects

Panama: 7

centres

N= 7.000

subjects

Synflorix : Only new generation PCV with Proven Efficacy Against Clinical Pneumonia

^ 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

Synflorix™Vaccine efficacy (%) ,[95% CIs] , p-value

C-CAPAlveolar consolidation on

Chest X-ray analyzed acc to WHO definition

Per-protocol (ATP) 25.7 [8.4;39.6]

Intent-to-treat (TVC) 23.4 [8.8;35.7]

Synflorix IPD Effectiveness II:Pneumococcal Meningitis in Brazil, in <2 yr olds 1998-2011

Synflorix™ introduction March-June 2010. UMV, 3+1 schedule

~48% reduction any Pn.

meningitis Jun11 vs Jun10

Cumulative number of Pneumococcal meningitis cases in children <2 years of age by month of occurrence, Brazil, 2007-10

Brazil National Pneumococcal menigitis reporting. MoH - SAUDE : http://portal.saude.gov.br/portal/saude/profissional/visualizar_texto.cfm?idtxt=37811 accessed 21Nov2011

2011

2010

2009

Synflorix in Various Countries NIPs

National Immunization Programs Regional Imm.

Programs

High Risk Populations

Finland Brazil New Zealand Sweden (5 regions)

Bosnia & 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,

Trinidad & Tobago, BarbadosCyprus, Albania

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

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

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

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

45

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.

NEW GENERATION PNEUMOCOCCAL VACCINE