Post on 03-Jan-2016
FinOM Efficacy Trial of 7-Valent Pneumococcal Conjugate Vaccine
Terhi KilpiNational Public Health Institute (KTL)
Finland
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FinOM Study Group• Principal investigator• Study coordination• Bacteriology• Immunology• Otorhinolaryngology• Biostatistics
• Data management
• Virology• Study clinic personnel
• Senior adviser
• Juhani Eskola, Terhi Kilpi• Arto Palmu , Kari S Lankinen• Elja Herva, Maija Leinonen• Helena Käyhty, Heidi Åhman• Pekka Karma• Jukka Jokinen, Mika Lahdenkari, Jouko
Verho• Jaason Haapakoski, Esa Ruokokoski,
Marko Grönholm• Tapani Hovi• Wilhelm Bredenberg, Heljä Savolainen,
Ritva Syrjänen• P Helena Mäkelä
FinOM Vaccine Trial
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FinOM Vaccine Trial
• evaluated efficacy of two 7-valent pneumococcal (Pnc) conjugate vaccines for prevention of AOM due to vaccine serotypes in children less than 2 years of age
• clinical phase from December 1995 to March 1999• 2 497 children enrolled (55 % of the birth cohort) in
Tampere area
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Study design
• All children were randomized to receive PncCRM (Prevnar®, Prevenar®), PncOMPC, or control (HBV) vaccine at 2, 4, 6, and 12 mo
• Follow-up from 2 to 24 mo at the study clinic• All respiratory infections requiring medical attention
were evaluated and treated at the study clinic
FinOM Vaccine Trial
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Definition of AOM
• Symptoms– At least one of the following: fever, earache, irritability,
diarrhea, vomiting, acute otorrhea not caused by otitis externa, or other symptoms of respiratory infection
• Signs– A visually abnormal tympanic membrane (in regard of color,
position and/or mobility) suggesting middle ear effusion
FinOM Studies
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Acute Otitis Media (AOM)
• Myringotomy with aspiration performed in AOM with effusion
• Middle ear fluid (MEF) sample for bacterial culture, pneumococcal serotyping and pneumolysin PCR
• AOM episode defined to start at diagnosis and to last for 30 days
FinOM Studies
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Efficacy of PncCRM against AOM
• Primary– All AOM episodes due to vaccine serotypes
• Secondary– First and subsequent AOM episodes due to vaccine serotypes
• Other– All Pnc AOM episodes– All AOM episodes– Recurrent AOM
FinOM Vaccine Trial
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Efficacy of PncCRM against AOM
• Post Hoc– AOM episodes due to vaccine related serotypes (6A, 9N, 18B, 19A,
23A)– AOM episodes due to serotypes unrelated to vaccine types– AOM episodes due to individual serotypes
FinOM Vaccine Trial
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Disposition of subjects
PncCRM Control Total
Enrolled 831 831 1662
Excluded from PP analysis 20 10 30
Early temination of PP f-up 25 27 52
Withdrawn permanently 33 32 65
Completed as PP 786 794 1580
Completed ITT follow-up 798 799 1597
FinOM Vaccine Trial
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All AOM episodes due to vaccine serotypesFinOM Vaccine Trial
PncCRM Control Total
Number of episodes 107 250 357
Rate/person-year 0.09 0.21
Primary analysis
Vaccine efficacy: 57% (95% CI: 44% to 67%)
Per protocol follow-up from 6.5 to 24 months of age
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First and subsequent AOM episodes due to vaccine serotypes
PncCRM HBV Vaccine efficacy%
95 %lower CL
95 %upper CL
First
N 89 177
Rate* 0.08 0.17
52 39 63
Subsequent
N 18 73
Rate* 0.25 0.47
45 5 69
FinOM Vaccine Trial
Per protocol follow-up
Secondary analysis
*Per person-year
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Summary of efficacy results
EpisodesEndpointPncCRM HBV
Vaccine efficacy%
95 %lower CL
95 %upper CL
AOM due to vaccineserotypes 107 250 57 44 64
Pneumococcal AOM(culture+) 271 414 34 21 45
Pneumococcal AOM(culture and/or PCR+) 548 687 20 7 31
Any AOM 1251 1345 6 -4 16
Recurrent AOM 123 149 16 -6 35
FinOM Vaccine Trial
Per protocol follow-up from 6.5 to 24 months of age
Acute Otitis Media
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Summary of efficacy results
EpisodesEndpointPncCRM HBV
Vaccine efficacy%
95 %lower CL
95 %upper CL
AOM due to vaccineserotypes 135 292 54 41 64
Pneumococcal AOM(culture+) 322 467 32 19 42
Pneumococcal AOM(culture and/or PCR+) 642 775 18 5 29
Any AOM 1474 1532 4 -7 14
Recurrent AOM 158 174 9 -12 27
FinOM Vaccine Trial
Intention to treat follow-up from 2 to 24 months of age
Acute Otitis Media
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Pneumococcal AOM episodes
EpisodesEndpointPncCRM HBV
Vaccine efficacy%
95 %lowerCL
95 %upper CL
Pneumococcal AOM(culture+) 271 414 34 21 45
Pneumococcal AOM(culture+ and/or PCR+) 548 687 20 7 31
Pneumococcal AOM(culture– and PCR+) 310 326 4 -15 19
FinOM Vaccine Trial
Per protocol follow-up from 6.5 to 24 months of age
Acute Otitis Media
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PCR counts* in MEF of Pnc Ply PCR positive AOM
0
100000
200000
300000
400000
500000
600000
PncCRM HBV PncCRM HBV
PCR counts
Pnc culture negative Pnc culture positive
* GM (95% CI)
FinOM Vaccine Trial
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Individual vaccine serotypes
EpisodesSerotypePncCRM HBV
Vaccine efficacy%
95 %lower CL
95 %upper CL
23F 33 82 59 35 75
19F 43 58 25 -14 51
6B 9 56 84 62 93
14 8 26 69 20 88
18C 7 17 58 -4 83
9V 5 11 54 -48 86
4 2 4 49 -176 91
FinOM Vaccine Trial
Per protocol follow-up
Acute Otitis Media
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Vaccine, vaccine-related and other serotypes
EpisodesSerotypesPncCRM HBV
Vaccine efficacy%
95 %lower CL
95 %upper CL
Vaccine 107 250 57 44 67
Vaccine-related 41 84 51 27 67
Other 125 95 -33 -80 1
Pnc AOM(culture+)
271 414 34 21 45
FinOM Vaccine Trial
Per protocol follow-up
Acute Otitis Media
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Vaccine-related serotypes
EpisodesSerotypePncCRM HBV
Vaccine efficacy%
95 %lower CL
95 %upper CL
6B 9 56 84 62 93
6A 19 45 57 24 76
19F 43 58 25 -14 51
19A 17 26 34 -26 65
FinOM Vaccine Trial
Per protocol follow-up
Acute Otitis Media
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PncCRM
• is efficacious against – culture-confirmed, vaccine serotype specific AOM
(VE: 57%)– culture-confirmed AOM due to vaccine-related
serotypes (VE: 51%)– culture-confirmed pneumococcal AOM (VE: 34%)
FinOM Vaccine Trial Conclusions
Extended follow-up
FinOM Vaccine Trial
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Objectives
• To assess long-term effects of PncCRM on– pneumococcal carriage– antibody persistence– surgery due to OM in the routine practice after
the Vaccine Trial
FinOM Follow-up Study
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Methods
• Single follow-up visit at the age of 4 to 5 years in spring 2001
• Collection of data– Parental interview– Pneumatic otoscopy– Medical records– Nasopharyngeal, blood and saliva samples
FinOM Follow-up Study
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Inclusion criteria
PncCRM Control Total %
Enrolled in the FinOMVaccine Trial 831 831 1662 100
Completed ITT follow-up 798 799 1597 96
Still living in the area 746 744 1490 90
Informed consent for the Follow-up Study 403 353 756 45
FinOM Follow-up Study
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0 10 20 30 40 50 60
1597
Study flow
Start of long-term follow-up
Children, N
FinOM Vaccine Trial and Follow-up Study
65 dropped out during the trial
1662
756
1490
107 moved out of Tampere Area
Age, months
Fully evaluated children= Analysis population 1
Eligible children= Analysis population 2
Complete tympanostomy dataavailable
Hospitaltympanostomy dataavailable
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Case ascertainment for tube placement
• Fully evaluated children (Analysis population 1)– Parental interview – Hospital records from Tampere University Hospital, three district
hospitals (78%)– Medical records from private physician offices for verification
(22%)
• Eligible children (Analysis population 2)– Hospital records from Tampere University Hospital, three district
hospitals
FinOM Follow-up Study
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Tube placement during the Vaccine Trial
• Included in the study services• Close follow-up in the study clinics, active treatment
strategy, specific criteria for referral in the SOP• Tampere University Hospital• Free of charge• Within 4 to 8 weeks of referral
FinOM Studies
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Tube placement after the Vaccine Trial
• Public hospitals– Nominal charge– Waiting time 3 to 4 months– 78%
• Private medical centers and hospitals– Charge 10 x public sector charge– No waiting time– 22%
FinOM Studies
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0
2
4
6
8
10
12
14
<2 2 - 4
FinOM control groupFinland overall
Incidence of tube placement
*
* National hospital discharge register and national sick insurance reimbursement database
/ 100 person-years
*
Age, years
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0 10 20 30 40 50 60
1597
Study flow
Start of long-term follow-up
Children, N
FinOM Vaccine Trial and Follow-up Study
65 dropped out during the trial
1662
756
1490
107 moved out of Tampere Area
Age, months
Fully evaluated children= Analysis population 1
Eligible children= Analysis population 2
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Tympanostomy tube placement in fully evaluated children*
PncCRMN=403
HBVN=353
Vaccineefficacy 95% CI
2 months to 2 years
% with events 20.3 23.8Rate of events* 12.9 14.8
12% (-17 34)
2 years to 4-5 years
% with events 8.2 13.0Rate of events* 3.5 5.7
39% (4 61)
FinOM Vaccine Trial and Follow-up Study
Intention to treat follow-up
*Per 100 person-years*Analysis population 1
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Tympanostomy tube placement in all eligible children*
PncCRM HBV Vaccineefficacy 95% CI
2 months to 2 years N=831 N=831
% with events 18.4 19.3Rate of events* 12.0 12.7
4% (-19 23)
2 years to 4-5 years N=746 N=744
% with events 6.2 9.5Rate of events* 2.4 4.1
44% (19 62)
Intention to treat follow-up
*Per 100 person-years
FinOM Vaccine Trial and Follow-up Study
*Analysis population 2
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0,00
0,05
0,10
0,15
0,20
0,25
0,30
0,35
0,40
0,45
0 10 20 30 40 50 60 70
Age,months
Cumulative hazard of tympanostomy tube placement
Start of long-term follow-up
Cumulative hazard
FinOM Vaccine Trial and Follow-up Study
Fully evaluatedchildren
HBV
PncCRM
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0,00
0,05
0,10
0,15
0,20
0,25
0,30
0,35
0,40
0 10 20 30 40 50 60 70
Age,months
Cumulative hazard of tympanostomy tube placement
Start of long-term follow-up
Cumulative hazard
FinOM Vaccine Trial and Follow-up Study
All eligiblechildren
HBV
PncCRM
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0,01
0,1
1
10
0 10 20 30 40 50 60
Kinetics of anti-23F
Start of long-term follow-up
g/ml
FinOM Vaccine Trial and Follow-up Study
HBV
PncCRM
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0,01
0,1
1
10
0 10 20 30 40 50 60
Kinetics of anti-19F
Start of long-term follow-up
g/ml
FinOM Vaccine Trial and Follow-up Study
PncCRM
HBV
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0,01
0,1
1
10
0 10 20 30 40 50 60
Kinetics of anti-6B
Start of long-term follow-up
g/ml
FinOM Vaccine Trial and Follow-up Study
PncCRM
HBV
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Long-term effect on otitis media and carriage
FinOM Follow-up Study
PncCRMN 403
HBVN 353
Children with AOM after 24 mo of age,% 67.3 72.7
Diagnosed with OM at the Follow-up visit,% 11.4 12.5
Vaccine type Pnc carriage, % 8.5 13.6 P=0.05
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PncCRM
• PncCRM reduces tube placement due to OM• Vaccine efficacy against OM persists for several years
FinOM Follow-up Study Conclusions
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