Synflorix: A New Generation PCV

1

Pneumococcal Serotypes Surveillance so far

• 6 studies in children less than 5 years• All the isolates were from normally sterile sites

2

3

STP IBIS(1999)

SAPNA(2007)

ANSORP(2008)

PNEUMONET

(2008)Bangladesh1992-2007

PneumoADIPASIA 2009

India Sri lanka Nepal

n=101 n=4 n=26 N=56 n=18 n=137 n=71 n=162 n=4752, %14 08 03 01 02 09 02 15 11.6%6B 01 04 01 - 11.5%6 (22) (08) (08) (08)

23F 03 05 02 00 04 02 00 9.7%1 14 01 14 02 16 5 11 9.5%

19F 04 01 01 8.1%19 (11)

5 05 09 03 08 06 05 6.7%

9V (01) 01 3.1%18C (03) 01 01 05 01 NA 2.4%7F 04 02 - 08 03 16 2%4 06 - 1.6%

19A - 01 3/91 01 04 00 NA 2.6%

6A 05 3.5%

3 01 02 - - - 1.4%

0thers 24 02 09 24 00 26.4%

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 Antimicrob Chemother 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

JAN FEB MARCH AUG SEPT OCT – DEC’11 DEC – JAN ‘12

Identification of sentinel Drs / Pvt Lab for developing sentinel network in Mumbai , Delhi ,

Bangalore , Chennai

Sentinel network initiated in Kolkata , Coimbatore ,

Hyderabad , Ahmedabad

CRC Recruitment for

Chennai , Bangalore ,

Delhi

ASIP website launched e -CRF developed

JAN to NOV 2011 – Key developments

Serotyping and AST work initiated. Consolidation of study

data, presentation at 3rd IM

IM Meeting in GOA

Sept 2011

Pneumo season - Isolation + serotyping

PEDICON ASIP POSTER

ASIP – Year 2 ZONAL

CONSOLIDATION

16

February 2011 – ASIP website launched

http://www.asipindia.org

17

Sr. No.

Institutional Network

1 MGIMS, Wardha

2 SRMC, Chennai

3 AIMS, Cochin

4 KEM, Mumbai

5Safdarjung Hospital, Delhi

6 CNBC, Delhi

7St. John, Bangalore

8 CMC, Ludhiana

9 BVP, Pune

10 KEM, Pune

11 LTMMC, Mumbai

12Pushpagiri, Tiruvalla

Study Central Monitoring Laboratory, CMC, Vellore

Study Centres

19

Ahmedabad

Dr P.K. Assudani

Dr Sandip Trivedi

Dr. Pratima Shah

Dr. Raju Shah

Dr Azad H Jain

Dr. Deepika Jain

Dr Atul M Nayak

Dr K.P. Shah

Dr.Bharat Patel

Dr. Vinod V Patel

Dr. Mahesh Barot

Dr Rajiv Bhatla

Dr Naveen Thacker

Dr Jogesh Sachde

Dr Nitin Thakkar

Dr Nehal Vaidya

Mumbai

Dr. Y.K. Amdekar

Dr. Vijay N. Yewale

Dr. Mahesh A.Mohite

Dr. Indu Khosla

Dr. Praful R. Shanbhag

Pune

Dr. Ambrish Mishra

Dr. Rushikesh Damle

Dr. Mangalmurti Bhalerao

Delhi

Dr. Amarjeet Chitkara

Dr. P.S. Narang

Dr. Mukesh Agarwal

Dr Shyam Kukreja

Dr. Devender Gaba

Cochin

Dr. Grace Thomas

Dr. Suja Mathew

Dr. Varghese Cherian

Kolkata

Dr Jaydeep Choudhury

Dr. Rajen Bit

Dr. Arunaloke Bhattacharya

ChennaiDr S Balasubramaniam

Dr V V Varadarajan

BangaloreDr. Jagdish Chinnappa Dr. Srinivas G Kasi Dr. A. Nagesh Dr. R. Kishore Kumar Dr. Achamma Thomas

Coimbatore

Dr K Neminathan

Dr Mallika Neminathan

Dr. Ishwarya

Dr. Poornima

Dr. Arunthathy

ASIP Sentinel Network

Anantapur- AP

Dr Gerardo

Dr Raghu

20

Sl. No. Local Labs

1Dr Neeraj Jain, Delhi

2Dr Shrikrishna. A. Joshi, Mumbai

3Dr.Anuradha Manoj, Kolkata

4Dr Brahmadathan, Coimbatore

5Dr Sangeetha Joshi, Bangalore

6

Dr. Manisha Shekhar, Ahmedabad

7Dr Urvesh U Shah, Ahmedabad

ASIP LOCAL LAB

21

InstitutionTotal

recruitments

Prospective/ Retrospective

S.pn H. inf

MGIMS, Wardha 190 - -

SRMC, Chennai 36 - -

AIMS, Cochin 40 1 -

KEM, Mumbai 26 4 -

Safdurjung Hosp, Delhi 14 14 -

CNBC, Delhi 38 - -

St. John, Bangalore 70 3 -

CMC, Ludhiana 6 2 1

BVP, Pune 14 4 -

KEM, Pune 42 2 -

LTMMC, Mumbai 10 4 -

Pushpagiri, Tiruvalla 68 2 -

Sentinel Network      

All regions 275 5  

Total 829 41 1

Update on Recruitment and +ve Cultures

(as on 23rd Nov 2011)

23

ASIP: Distribution of Serogroup/typePreliminary Results (n=35 out of 42), 2011

Serogroup / Serotype No. isolated

1 01

4 01

5 02

10 04

7F -

9V -

14 01

18C -

19F 03

23F 02

3 -

6 03

19A 01

Others 17

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

12Data on file: www.asipindia.org

Pneumonia kills 45 children an hour

…1095 children a day

…7,692 children a week

…33,300 children a month

DRAFT

Each year pneumonia kills over 400,000 children in

India~50,000 by Hib

~142,000 by pneumococcus

Hib Pneumo

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 19F Serotype 3

1.Poolman J, et al. Vaccine 2009;27: 3213-32222.Hammerschmidt et al. Infection and Immunity 2005;73(8):4653-673. Waite RD, Struthers JK, Dowson CG. Mol Microbiol 2001;42(5):1223-32

11Pn-PD post-primary

HAV post-primary

11Pn-PD post-booster

HAV post-booster

• 0.1 1.0 10.0

100.0

Antibody concentration (µg/mL)

Pat

ien

ts (

%)

100

90

80

70

60

50

40

30

20

10

0

Adapted from Prymula et al. Lancet 2006;367:740–748

Kieninger et al.,ICAAC 2008

(http://uploads.renegadedigital.com/Istanbul/

kieninger.pdf;)

11-valent Pn-PD in POET 13-valent-CRM

Serotype 3 ELISA immunogenicity: higher responses post-primary than post-

booster

Serotype 3 displays an atypical immunogenicity profile

PCV 10 vs PCV 13? Or PCV 12

Do 6B conjugates provide cross protection against 6A disease?

Decreases in 6A IPD after PCV7CRM introduction

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 Microbiol 2011;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 Dis 2008;198:1818-22

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

IPD

cas

es p

er 1

00,0

00

3.3

4

1.91.6

2.1

4.9

1.10.8

0.4

1 1.1

0.46

0

1

2

3

4

5

6

Pre-PCV7

Post-PCV7

Belgium

4 , 0–5y

2002/3 vs

. 2008

Denmark5 , 0

–2y

2000/7 vs

. 2008

Engla

nd6 , 0–2y

2003/6 vs

. 2006/9

Norway

7 , 0–5y

2004/5 vs

. 2008

Australia

8 , 0–2y

2002/4 vs

. 2007

USA10 , 0

–5y

1999 vs. 2

003/6

0

20

40

60

80

100

Synflorix Post-primaryPCV7 Post-primary

PCV7 Post-booster

DiT-001/0072-3-4 mo

& 12>18 mo

DiT-011/0172-4-6 mo

& 11>18 mo

DiT-0362-4-6 mo

& 11>18 mo

DiT-012/0182-4-6 mo

& 12>18 mo

DiT-012/0186-10-14 wks& 12>18 mo

DTPa-combo DTPw-combo

Synflorix Post-booster

Ser

oty

pe

6A

OP

A,

% >

8

Synflorix anti-6A functional activity (OPA) appears similar to PCV7CRM

Schuerman, et al. ISPPD-7 Tel Aviv, 14–18 March 2010 (Abstract 475) ;

PCV 10 vs PCV 13? Or PCV 11

SY

N-2

010

-051

Vaccine efficacy or effectiveness against 19A invasive disease

1. 14 v PS: US indirect cohort analysis (1993) (with 19F but not 19A)1

2. 7vCRM: US post-marketing surveillance (assessment 2nd year after launch)2

3. 7vCRM: US CDC case-control3

4. 7vCRM & 9vCRM: meta-analysis of 4 efficacy studies in US, Gambia, South Africa4

5. 7vCRM: Quebec post-marketing surveillance5

6. 7vCRM: Finland: FinOM6

7. 7vOMP: Finland: FinOM6

Vac

cine

effi

cacy

or

effe

ctiv

enes

s ag

ains

t 19A

IPD

AOM

-80

-60

-40

-20

0

20

40

60

80

1 2 3 4 6 7

Adapted from Hausdorff et al BMC 20101. Butler 1995; 2. Whitney NEJM 2003; Whitney Lancet 2006; 4. Klugman 2008; 5. Deceunick ESPID 2009; 6. Eskola NEJM 2001

5

Every time it has been examined, the efficacy/effectiveness point estimate against 19A has been positive

PCV7-CRM: Prevenar™/Prevnar™ is a trademark of Pfizer/Wyeth

Synflorix elicits higher functional activity (OPA) against vaccine-related serotype 19A than PCV7

18Schuerman, et al. ISPPD-7 Tel Aviv,14–18 March 2010 (Abstract 475)

0

20

40

60

80

100

DiT-001/0072-3-4 mo

& 12>18 mo

DiT-011/0172-4-6 mo

& 11>18 mo

DiT-0362-4-6 mo

& 11>18 mo

DiT-012/0182-4-6 mo

& 12>18 mo

DiT-012/0186-10-14 wks& 12>18 mo

PCV7 Post-primaryPCV7 Post-booster

Synflorix Post-primarySynflorix Post-booster

DTPa-combo DTPw-combo

Ser

oty

pe

19A

OP

A, %

≥8

SY

N-2

010

-051

Pneumococcal 19F polysaccharide conjugation to the carrier proteins

19F structure in Synflorix™19F structure in Pfizer vaccines

Reductive amination

Native 19F structure

Cyalinilation

Different conjugation chemistries used for the two vaccines

Kim et al. Anal . Biochemistry 2005

PCV 10 vs PCV 13? Or PCV 10 ½

Cross-sectional surveys in South IndiaPrevalence and sequelae of otitis media

20

Prevalence rate of CSOM was found to be 6% in children 2-10 yrs

Acute suppurative otitis media: 1.5%Otitis Media with Effusion: 6%

Chronic suppurative otitis media: 1.4%Eustachian tubal block: 4%

S. pneumoniae and H. influenzae account for up to 80% of bacterial AOM cases in children16

211. Broides et al., Clinl Infects Dis 2009;49:1641–7; 2. Eskola J, et al. N Engl J Med 2001;344:4039; 3. Gehanno P, et al. Pediatr Infect Dis J 2001;20:5703; 4.Prymula R, et al. Lancet 2006;367:7408; 5. Del Catillo F, et al. Pediatr Infect Dis J 1996;15:5413; 6.Rosenblut A, et al. Pediatr Infect Dis J 2001;20:5017; 7. Guevara et al., Pediatr Infect Dis J 2008;27: 12–6; 8. Suzuki A, et al. Pediatr Infect Dis J 2005;24:6557; 9.Block SL, et al. Pediatr Infect Dis J 2004;23:8293; 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 Pediatr Otorhinolaryngol 2010;74:572–77 .

% of culture confirmed cases0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Israel 00-01 (1)

Finland (2)

France 87-97 (3)

Czech & Slovak 00-02 (4)

Spain 89-95 (5)

Chile (6)

Costa Rica 99-04 (7)

Costa Rica 02-07 (10)

Mexico 08 (11)

Columbia 08 (12)

US pre-PCV7 92-98 (9)

US Post-PCV7 00-03 (9)

US Post-PCV7 006-08 (13)

Japan 03 (8)

Thailand 07-08 (14)

Australia Post-PCV7 08-09 (15)

Spn

Spn + Hi

Hi

Mcat

S. pyog

Others

AOM caused by S. pneumoniae and H. influenzae are clinically indistinguishable (Liebowitz PIDJ 2004)

NTHi in lower respiratory tract diseaseBronchoalveolar lavage studies (non-CF patients)

Country Author, Reference, Year Cases % NTHi

France Le Bourgeois, Chest, 2002 Recurrent wheezing 50%

US Saito, Ped Pulm, 2006 Recurrent wheezing 26%

Spain Romero, ERS, 2009 Persistent bacterial bronchitis 28%

Belgium De Schutter, ESPID, 2009 Refractory bronchopneumonia,Recurrent bronchopneumonia,Persistent X-ray abnormalitiesPersistent wheezing

43%

UK Marguet, Am J Resp, 1999 Chronic cough 43%

Davidson, ERS, 2010 Persistent respiratory symptoms 30%

Australia Hare, J Ped, 2010 Bronchiectasis 47%

Greece Mammas, ERS, 2010 Protracted purulent bronchitis 61%

22GSK Internal literature review, M. Van dyke; Hausdorff & Dagan Vaccine 2008

In contrast, likely minor role for NTHi in consolidated alveolar pneumonias

RAN

DO

MIS

ATIO

N 1

:1

Dose 1

±3 months

Dose 2

±4 months

Dose 3

±5 months

Booster

±15–18 months

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)

DTPa-HBV-IPV/Hib: Infanrix hexa™ and HAV: Havrix™ are trademarks of the GlaxoSmithKline group of companies

+ Infarix Hexa in both groups

Adapted from Prymula, et al. Lancet 2006; 367: 740–48

Key endpoints: 1. AOM due to

Vaccine typesAny pneumococcusNTHi

2. Nasopharyngeal carriage due to pneumococcus and NTHi

24–27 months follow-up

.

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)

AOM Efficacy Trial Results

*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.

24

PCV 10 vs PCV 10 ½ ?Or

2 (pathogens) vs 1 (pathogen)

Synflorix has undergone an extensive clinical development programme

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 J 2009; 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].

30 clinical studies completed by August 2011

6,730 infants; 5,098 toddlers; ~26,000 doses of PHiD-CV administered

Immunogenicity profile documented

for 10 vaccine serotypes, cross-reactive serotypes 6A and 19A, and

protein D1–5,7–12

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

Multiple immunization schedules1–14

Vaccine interchangeability at booster age1

Catch-up schedules in older children not primed at younger age15

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

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)*

Andrade A, et al. WSPID 2011, Melbourne, Australia, Abstract 670.

*PHiD-CV is not currently indicated for the prevention of pneumococcal pneumonia in Brazil.

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 effectiveness against IPD – Brazil

• Recent surveillance data from Brazil has shown that PHiD-CV has reduced the incidence of meningitis

PHiD-CV introduced March-June 2010. UMV, 3+1 schedule

~48% reduction any pneumococcal meningitis Jun11 vs. Jun10

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

Brazil National Pneumococcal meningitis reporting. MoH - SAUDE : http://portal.saude.gov.br/portal/saude/profissional/visualizar_texto.cfm?idtxt=37811 accessed 21 Nov 2011

0

50

100

150

200

250

300

350

400

Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec

Month

Cu

mu

lati

ve

ca

se

s

2007 2008 2009 2010 2011

Cu

mu

lati

ve

ca

se

s

Month

0

200

400

600

800

1000

1200

1400

Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec

2007 2008 2009 2010 2011

Interim Analysis: COMPAS study

Clinical Otitis Media & PneumoniA Study

Dr. Shailesh MEHTAClinical R & D and Medical affairs, South Asia

COMPAS design summary

• COMPAS is the most comprehensive Synflorix study to date and was designed to:

– Assess the public health value of Synflorix

– Confirm and quantify impact of Synflorix against pneumonia

– Assess the impact of Synflorix against acute otitis media

Sáez-Llorens X, et al. ESPID 2011, The Hague, The Netherlands, Abstract 1412

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

Study design relative to CAP surveillanceRa

ndom

isatio

n 1:

1

Control Group N=~12,000

SynflorixTM Group N=~12,000

Double Blind randomized Controlled Multi center study in Argentina (3), Colombia, Panama

+ DTPa-HBV-IPV/Hib

(HBV) + DTPa-IPV/Hib

+ DTPa-IPV/Hib

(HAV) + DTPa-IPV/Hib

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

~2 ~4 ~6Age (Months) 15-18

3-Dose primary BoosterVaccine

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

CAP Suspected CAP (X-ray request)

Independent Data Monitoring Committee (IDMC) of experts overviewed ethical, safety aspects

1. Tregnaghi et al., XIV SLIPE, May 2011; 2.Tregnaghi et al., 29 th ESPID, June 2011; 3 . Saez-Llorenz et al., 29th ESPID, June 2011; 4. 10PN-PD-DIT-028; NCT00466947

CAP definitions in COMPAS

Non-consolidated(CXR-NAC-CAP)

Consolidated (CXR-AC-CAP)

Alveolar consolidationNon-consolidationNo pneumoniaNon-interpretable

Normal (no pneumonia) or

non-interpretable

Any abnormality on chest x-ray (CXR-CAP)

X-ray readers panel

Any abnormality on chest x-ray (CXR-CAP)

Suspected CAP (S-CAP)

Clinical suspicion of CAP or child with ARI

Case definitionX-ray request Suspected CAP

(S-CAP)

Primary endpointlikely bacterial CAP

(B-CAP)CXR-NAC-CAP

with CRP < 40 g/mL

Lab resultsCRP value g/mL

CXR-NAC-CAPwith CRP ≥ 40 g/mL

CXR-NAC-CAPwith CRP ≥ 40 g/mL

Primary endpointlikely bacterial CAP

(B-CAP)

Consolidated (CXR-AC-CAP)

Sáez-Llorens X. et al. ESPID 2011; The Hague, The Netherlands. abstract 1412

COMPAS timeline

20122007 2008 2009 2010 2011

Interim analysis B-CAP

Nov 2010 – Jan 2011 ≥ 535 B-CAP ATP cases

Enrolment Jun 2007 – Dec 2008

Observation periodObservation period

End-of-study results Spring 2012

ConclusiveInitiate final analysis

Pneumonia aetiology is difficult to establish and can be caused by both viruses and bacteria1

– Limitations of microbiological diagnostic methods make exact aetiology difficult to establish3

– Viral pneumonia may suppress immune responses, and result in bacterial pneumonia super-infections4

 Aetiology of pneumonia in 99 hospitalised children <5 years old in Switzerland2

1. UNICEF, 2006. Pneumonia: the forgotten killer of children; 2. Cevey-Macherel et al. Eur J Pediatr 2009; 168: 1429–36; 3. Brown. Respirology 2009;14:1068–71; 4. Warr & Jakab. Inflammation 1983; 7: 93–104

Bacterial only (single or multiple bacteria)

19%

Viral only (single or multiple)

34%

Mixedviral/bacterial infec-

tion 33%

Unknown14%

Samples from blood culture and

nasopharyngeal aspirates

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

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

Per-protocol (ATP) Intent-to-treat (TVC)

B-CAP Likely Bacterial CAP

Crx-CAP + NCrx-CAP & CRP ≥ 40 µg/ml

22.0 [7.7;34.2]p=0.0020^

18.2 [5.5;29.1]p=0.0031

C-CAPAlveolar consolidation on Chest X-ray analyzed

acc to WHO definition25.7 [8.4;39.6] 23.4 [8.8;35.7]

CxrC-CAP Confirmed CAP

by any abnormality on Chest X-ray 13.3 [3.4;22.1] 10.5 [1.8;18.4]

S-CAPAll Suspected clinical CAP

6.7 [0.7;12.3] 7.3 [2.1;12.3]

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

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

Endpoint for ITT cohort Efficacy % (95% CI)

Synflorix™N=11.875

ControlN=11.863

# of cases/ averted

B-CAP Likely Bacterial CAP

Crx-CAP + NCrx-CAP & CRP ≥ 40 µg/ml

18.2%[5.5;29.1] 341 414 73

C-CAPAlveolar consolidation on Chest X-ray

analyzed acc to WHO definition

23.4% [8.8;35.7] 223 289 66

CrxC-CAP Confirmed CAP

by any abnormality on Chest X-ray

10.5% [1.8;18.4] 854 947 93

S-CAPAll Suspected clinical CAP

7.3%[2.1;12.3] 2455 2616 161

1. Tregnaghi et al., 29th ESPID, The Hague, June 2011; 2.10PN-PD-DIT-028; NCT00466947

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

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

December 2004PCV-7

(including catch up for ≤ 5 years of age)

June 2009PHiD-CV

(transition in July–August 2008, no catch-up)

December 2010PCV-13

(transition in January 2011, no catch-up)

High-risk & indigenous children

3+1 schedule(2, 4, 6 + 12 mo)

Universal mass vaccination programme

2+1 schedule (2, 4 + 12 months)

HIGH VACCINATION COVERAGE (~97% of children vaccinated)

October 2002PCV-7

(including catch up for ≤ 5 years of age)

Quebec

Institut national de santé publique du Québec, Programme de surveillance du Pneumocoque, RAPPORT 2009http://209.171.32.187/gouvqc/communiques/GPQF/Decembre2010/10/c4447.html.

Primary vaccine PCV-7 PHiD-CV PCV-7 PCV-7

Booster vaccine PCV-7 PHiD-CV PCV-7 PHiD-CV

• A recent effectiveness study examined the rates of IPD in children immunised with PCV-7 or PHiD-CV

Jun 2007-Jun 2008 Jun 2009-Jun 20100

10203040506070

64.1

37.1

Birth cohort (6–18 months)

PCV effectiveness against IPD – Quebec

Aug 2007-Jan 2008 Aug 2008-Jan 20090

10

20

30

40

50

60

54.0

23.9

Birth cohort (13–28 months)

p < 0.05 p = 0.02

De Wals P, et al. ESPID 2011; The Hague, The Netherlands. Abstract P763.

• 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

IPD

ra

te/1

00

,00

00

p

ers

on

ye

ars

42% reduction 56% reduction

PCV effectiveness against IPD – Quebec

Birth cohort

Observation period

Vaccine for primary series

and booster

IPD cases IPDrate per 100 000 person-years

PCV-7 types

Additional PHiD-CV

types

19 A Other types

All types

Aug 2007-Jan 2008

13-28 mos PCV-7PCV-7

0 5 12 9 26 54.0

Aug 2008-Jan 2009

13-28 mos PCV-7PHiD-CV

0 0 8 4 12 23.9

Jun 2007-Jun 2008

6-18 mos PCV-7PCV-7

1 3 16 15 35 64.1

Jun 2009-Jun 2010

6-18 mos PHiD-CVPHiD-CV

2 0 10 9 21 37.1

De Wals P, et al. ESPID 2011; The Hague, The Netherlands. Abstract P763.

Thank you