FinOM Efficacy Trial of 7-Valent Pneumococcal Conjugate Vaccine Terhi Kilpi National Public Health...

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


Acute Otitis Media

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Summary of efficacy results


Vaccine efficacy%

95 %lower CL

95 %upper CL

AOM due to vaccineserotypes 135 292 54 41 64


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


Vaccine efficacy%

95 %lowerCL

95 %upper CL


Pneumococcal AOM(culture+ and/or PCR+) 548 687 20 7 31

Pneumococcal AOM(culture– and PCR+) 310 326 4 -15 19

FinOM Vaccine Trial


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


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


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


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


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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


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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


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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


Children, N


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


39% (4 61)


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


4% (-19 23)

2 years to 4-5 years N=746 N=744


44% (19 62)

Intention to treat follow-up

*Per 100 person-years


*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


Cumulative hazard


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


Cumulative hazard


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


g/ml


HBV

PncCRM

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0,01

0,1

1

10

0 10 20 30 40 50 60

Kinetics of anti-19F


g/ml


PncCRM

HBV

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0,01

0,1

1

10

0 10 20 30 40 50 60

Kinetics of anti-6B


g/ml


PncCRM

HBV

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Long-term effect on otitis media and carriage


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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Thank you

FinOM Efficacy Trial of 7-Valent Pneumococcal Conjugate Vaccine Terhi Kilpi National Public Health...

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