Synflorix revisited - April 2012

PNEUMOCOCCAL DISEASE BURDEN & VACCINATION

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



4

Description of PCV vaccines 4, 6B, 9V, 14, 18C, 19F, 23F

PCV 13 (Prevenar13) 4, 6B, 9V, 14, 18C, 19F, 23F, 1, 5, 7F

CRM197 Diphtheria carrier protein

CRM197 Diphtheria carrier protein

PCV 7 (Prevenar)

3, 6A, 19A

NTHi protein D

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

NTHi protein DTT DT

PCV 10 (Synflorix)

1000 XAOM

MeningitisStrep Pneumoniae in developing countries

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 & IndiaPneumonia & IndiaPneumonia 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

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, March 2011

We are missing the target(Millennium Development Goal 4)

9

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.

Overview



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 )

16

17

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

Burden of Disease –Pneumonet Data Age group (months)

Clinical Pneumonia No. of cases

Incidence rates per 1,00,000

pop.

X-ray Pneumonia No. of cases

Incidence rates per

1,00,000 pop.

1 to 6 393 4,800.88 145 1,771.32

6 to 12 499 3,826.69 214 1,641.10

12 to 24 627 2,752.78 318 1,396.15

24 to 36 384 1,708.95 175 778.82

36 to 60 468 1,017.17 254 552.05

Overall 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

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 20

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

Indian Data – A brief Synopsis

Study Total numberof Isolates

Top 3 Isolates

IBIS – 1999 307 6, 1, 19

SAPNA 4 1, 6 B

Pneumonet * 17 6 A, 5, 1/ 3/ 14

ASIP * 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 1998-2011

PCV 10 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

http://portal.saude.gov.br/portal/saude/profissional/visualizar_texto.cfm?idtxt=37811

Overview



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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.

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

NTHi in AOM

Overview



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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 ?

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 Kenya

1. 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 13Korea 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” group

1. 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 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

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.

NEW GENERATION PNEUMOCOCCAL VACCINE

Health & Medicine

Synflorix revisited - April 2012