Synflorix what’s new in preventing pneumococcal disease (feb 2012)
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Transcript of 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.
31
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