synflorix: a new generation pcv 1. pneumococcal serotypes surveillance so far 6 studies in children...
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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
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