# Presentation: 884371

## FinOM Efficacy Trial of 7-Valent Pneumococcal Conjugate Vaccine

- Terhi Kilpi
- National Public Health Institute (KTL)
- Finland

## 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

## 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

## 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

## 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

## 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

**Notes:**
Symptoms
At least one of the following symptoms or signs of acute infection: 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

## 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

## 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

## Disposition of subjects

- FinOM Vaccine Trial

## All AOM episodes due to vaccine serotypes

- FinOM Vaccine Trial

**Primary analysis**

- Vaccine efficacy:** 57% (95% CI: 44% to 67%)**

- Per protocol follow-up from 6.5 to 24 months of age

## First and subsequent AOM episodes due to vaccine serotypes

- FinOM Vaccine Trial

- Per protocol follow-up

**Secondary analysis**

- *Per person-year

## Summary of efficacy results

- FinOM Vaccine Trial

- Per protocol follow-up from 6.5 to 24 months of age

- Acute Otitis Media

## Summary of efficacy results

- FinOM Vaccine Trial

- Intention to treat follow-up from 2 to 24 months of age

- Acute Otitis Media

## Pneumococcal AOM episodes

- FinOM Vaccine Trial

- Per protocol follow-up from 6.5 to 24 months of age

- Acute Otitis Media

## PCR counts* in MEF of Pnc Ply PCR positive AOM

- PCR counts

**Pnc culture negative**

**Pnc culture positive**

- * GM (95% CI)

- FinOM Vaccine Trial

## Individual vaccine serotypes

- FinOM Vaccine Trial

- Per protocol follow-up

- Acute Otitis Media

## Vaccine, vaccine-related and other serotypes

- FinOM Vaccine Trial

- Per protocol follow-up

- Acute Otitis Media

## Vaccine-related serotypes

- FinOM Vaccine Trial

- Per protocol follow-up

- Acute Otitis Media

## 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

## 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

## 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

## Inclusion criteria

- FinOM Follow-up Study

## Study flow

**Study flow**

- Start of long-term follow-up

**Children, N**

- FinOM Vaccine Trial and Follow-up Study

**Age, months**

**Fully evaluated children**
**= Analysis population 1**

**Eligible children**
**= Analysis population 2**

**Hospital**
**tympanostomy data**
**available**

## 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

## 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

## 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

## Incidence of tube placement

**Incidence of tube placement**

- *

- * National hospital discharge register and national sick insurance reimbursement
- 	database

- / 100 person-years

- *

- Age, years

## Study flow

**Study flow**

- Start of long-term follow-up

**Children, N**

- FinOM Vaccine Trial and Follow-up Study

**Age, months**

**Fully evaluated children**
**= Analysis population 1**

**Eligible children**
**= Analysis population 2**

## Tympanostomy tube placement in fully evaluated children*

- FinOM Vaccine Trial and Follow-up Study

- Intention to treat follow-up

- *Per 100 person-years

- *Analysis population 1

## Tympanostomy tube placement in all eligible children*

- Intention to treat follow-up

- *Per 100 person-years

- FinOM Vaccine Trial and Follow-up Study

- *Analysis population 2

## Cumulative hazard of tympanostomy tube placement

**Cumulative hazard of tympanostomy tube placement**

- Start of long-term follow-up

- Cumulative hazard

- FinOM Vaccine Trial and Follow-up Study

**Fully evaluated**
**children**

- HBV

- PncCRM

## Cumulative hazard of tympanostomy tube placement

**Cumulative hazard of tympanostomy tube placement**

- Start of long-term follow-up

- Cumulative hazard

- FinOM Vaccine Trial and Follow-up Study

**All eligible**
**children**

- HBV

- PncCRM

## Kinetics of anti-23F

**Kinetics of anti-23F**

- Start of long-term follow-up

- g/ml

- FinOM Vaccine Trial and Follow-up Study

- HBV

- PncCRM

## Kinetics of anti-19F

**Kinetics of anti-19F**

- Start of long-term follow-up

- g/ml

- FinOM Vaccine Trial and Follow-up Study

- PncCRM

- HBV

## Kinetics of anti-6B

**Kinetics of anti-6B**

- Start of long-term follow-up

- g/ml

- FinOM Vaccine Trial and Follow-up Study

- PncCRM

- HBV

## Long-term effect on otitis media and carriage 

- FinOM Follow-up Study

- P=0.05

## PncCRM 

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

- FinOM Follow-up Study

- Conclusions

## Thank you