FinOM Efficacy Trial of 7-Valent Pneumococcal Conjugate Vaccine

Terhi Kilpi National Public Health Institute (KTL) Finland

FinOM Vaccine Trial

FinOM Study Group
• • • • • •
Principal investigator Study coordination Bacteriology Immunology Otorhinolaryngology Biostatistics

• 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 2 Grönholm

• Data management • Virology • Study clinic personnel • Senior adviser

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 3

FinOM Vaccine Trial

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 4 treated at the study clinic

FinOM Studies

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) 5 suggesting middle ear effusion

FinOM Studies

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

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FinOM Vaccine Trial

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
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FinOM Vaccine Trial

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

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FinOM Vaccine Trial

Disposition of subjects
PncCRM Enrolled Excluded fromPP analysis Early tem ination of PP f-up W ithdraw perm n anently Com pleted as PP Com pleted ITT follow -up 831 20 25 33 786 798 Control 831 10 27 32 794 799 Total 1662 30 52 65 1580 1597
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FinOM Vaccine Trial

Primary analysis

All AOM episodes due to vaccine serotypes

protocol follow-up from 6.5 to 24 months of age
PncCRM Num of episodes ber Rate/person-year 107 0.09 Control 250 0.21 Total 357

Vaccine efficacy: 57% (95% CI: 44% to 67%)
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FinOM Vaccine Trial

Secondary analysis

First and subsequent AOM episodes due to vaccine serotypes
Per protocol follow-up
PncCRM First N Rate* Subsequent N Rate*
*Per person-year

HBV

Vaccine efficacy %

95 % low CL er

95 % upper CL

89 0.08 18 0.25

177 0.17 73 0.47

52

39

63

45

5

69
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FinOM Vaccine Trial

Acute Otitis Media

Summary of efficacy results
Endpoint Episodes PncCRM HBV 250 414 687 1345
149

rotocol follow-up from 6.5 to 24 months of age
Vaccine efficacy % 57 34 20 6
16

95 % low CL er 44 21 7 -4
-6

95 % upper CL 64 45 31 16
35 12

AOM due to vaccine 107 serotypes Pneum ococcal AOM 271 (culture+ ) Pneum ococcal AOM 548 (culture and/or PCR+ ) Any AOM 1251
Recurrent AOM 123

FinOM Vaccine Trial

Acute Otitis Media

Summary of efficacy results
Endpoint Episodes PncCRM HBV 292 467 775 1532
174

ion to treat follow-up from 2 to 24 months of age
Vaccine efficacy % 54 32 18 4
9

95 % low CL er 41 19 5 -7
-12

95 % upper CL 64 42 29 14
27 13

AOM due to vaccine 135 serotypes Pneum ococcal AOM 322 (culture+ ) Pneum ococcal AOM 642 (culture and/or PCR+ ) Any AOM 1474
Recurrent AOM 158

FinOM Vaccine Trial

Acute Otitis Media

Pneumococcal AOM episodes
Endpoint Pneum ococcal AOM (culture+ ) Pneum ococcal AOM (culture+and/or PCR+ ) Pneum ococcal AOM (culture– and PCR+ ) Episodes PncCRM HBV 271 548
310

rotocol follow-up from 6.5 to 24 months of age
Vaccine efficacy % 34 20
4

95 % 95 % low er upper CL CL 21 7
-15

414 687
326

45 31
19

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FinOM Vaccine Trial

PCR counts* in MEF of Pnc Ply PCR positive AOM
* GM (95% CI)

PCR counts
600000 500000 400000 300000 200000 100000 0 PncCRM HBV PncCRM

HBV
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Pnc culture negative

Pnc culture positive

FinOM Vaccine Trial

Acute Otitis Media

Individual vaccine serotypes
Per protocol follow-up
Serotype 23F 19F 6B 14 18C 9V 4 Episodes PncCRM HBV 33 82 43 58 9 56 8 26 7 17 5 11 2 4 Vaccine efficacy % 59 25 84 69 58 54 49 95 % low CL er 35 -14 62 20 -4 -48 -176 95 % upper CL 75 51 93 88 83 86 91
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FinOM Vaccine Trial

Acute Otitis Media

Vaccine, vaccine-related and other serotypes
Per protocol follow-up
Serotypes Vaccine Vaccine-related Other Pnc AOM (culture+) Episodes PncCRM HBV 107 41 125 271 250 84 95 414 Vaccine efficacy % 57 51 -33 34 95 % low CL er 44 27 -80 21 95 % upper CL 67 67 1 45
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FinOM Vaccine Trial

Acute Otitis Media

Vaccine-related serotypes
Per protocol follow-up
Serotype 6B 6A 19F 19A Episodes PncCRM HBV 9 19 43 17 56 45 58 26 Vaccine efficacy % 84 57 25 34 95 % low CL er 62 24 -14 -26 95 % upper CL 93 76 51 65

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FinOM Vaccine Trial

Conclusions

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%)
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FinOM Vaccine Trial

Extended follow-up

FinOM Follow-up Study

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

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FinOM Follow-up Study

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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FinOM Follow-up Study

Inclusion criteria
PncCRM Enrolled in the FinOM Vaccine Trial Com pleted ITT follow -up Still living in the area Inform consent for ed the Follow Study -up 831 798 746 403 Control 831 799 744 353 Total 1662 1597 1490 756 % 100 96 90 45
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OM Vaccine Trial and Follow-up Study

Study flow
Children, N 65 dropped out during the trial

1662 1597

107 moved out of Tampere Area

1490

Hospital Eligible children tympanostomy data = Analysis population 2 available 756

Fully evaluated children Complete tympanostomy data = Analysis population 1 available
0 10 20 30 40 50 60

Age, months
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Start of long-term follow-up

FinOM Follow-up Study

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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FinOM Studies

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

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FinOM Studies

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%
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Incidence of tube placement
/ 100 person-years
14 12 10 8 6 4 2 0 <2 2-4

FinOM control group * * Finland overall

Age, years

nal hospital discharge register and national sick insurance reimburse 28 ase

OM Vaccine Trial and Follow-up Study

Study flow
Children, N 65 dropped out during the trial

1662 1597

107 moved out of Tampere Area

1490

Eligible children = Analysis population 2
756

Fully evaluated children = Analysis population 1
0 10 20 30 40 50 60

Age, months
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Start of long-term follow-up

OM Vaccine Trial and Follow-up Study

Tympanostomy tube placement in fully evaluated children*
PncCRM N= 403 2 months to 2 years % with events Rate of events* 2 years to 4-5 years % with events Rate of events*
*Analysis population 1

ntention to treat follow-up
HBV N= 353 23.8 14.8 13.0 5.7 Vaccine efficacy 95%CI

20.3 12.9 8.2 3.5

12%

(-17− 34)

39%

(4− 61)
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*Per 100 person-years

nOM Vaccine Trial and Follow-up Study

Tympanostomy tube placement in all eligible children*
HBV N= 831 19.3 12.7 N= 744 9.5 4.1 Vaccine efficacy

ntention to treat follow-up
PncCRM 2 months to 2 years % with events Rate of events* 2 years to 4-5 years % with events Rate of events*
*Analysis population 2

95%CI

N= 831 18.4 12.0 N= 746 6.2 2.4

4%

(-19− 23)

44%

(19− 62)

*Per 100 person-years 31

OM Vaccine Trial and Follow-up Study

Cumulative hazard of tympanostomy tube placement
Cumulative 0,45 hazard 0,40
0,35 0,30 0,25 0,20 0,15 0,10 0,05 0,00 0 10 20 30 40 50 60 70 Age,months

HBV PncCRM

Fully evaluated children

Start of long-term follow-up

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OM Vaccine Trial and Follow-up Study

Cumulative hazard of tympanostomy tube placement
Cumulative 0,40 hazard
0,35 0,30 0,25 0,20 0,15 0,10 0,05 0,00 0 10 20 30 40 50 60 70 Age,months

HBV PncCRM

All eligible children

Start of long-term follow-up

33

OM Vaccine Trial and Follow-up Study

Kinetics of anti-23F
µg/ml
10

1

PncCRM HBV

0,1

0,01 0 10 20 30 40 50 60
34

Start of long-term follow-up

OM Vaccine Trial and Follow-up Study

Kinetics of anti-19F
µg/ml
10

PncCRM
1

HBV

0,1

0,01 0 10 20 30 40 50 60
35

Start of long-term follow-up

OM Vaccine Trial and Follow-up Study

Kinetics of anti-6B
µg/ml
10

PncCRM
1

HBV
0,1

0,01 0 10 20 30 40 50 60
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Start of long-term follow-up

FinOM Follow-up Study

Long-term effect on otitis media and carriage
PncCRM N 403 Children w AOM after 24 m of age,% ith o Diagnosed w OM at the Follow visit,% ith -up Vaccine type Pnc carriage, % 67.3 11.4 8.5 HBV N 353 72.7 12.5 13.6
P=0.05

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FinOM Follow-up Study

Conclusions

PncCRM

• PncCRM reduces tube placement due to
OM • Vaccine efficacy against OM persists for several years

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Thank you

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