Evaluation of Effectiveness of GSK Biologicals' Pneumococcal Conjugate Vaccine 1024850A Against Invasive Disease

Study Overview
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Brief Summary
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The aim of this study is to assess the effectiveness of GSK Biologicals' pneumococcal conjugate vaccine (GSK1024850A), administered according to different vaccination schedules, against invasive disease caused by S. pneumoniae or H. influenzae as well as vaccine impact on the occurrence of hospital-diagnosed pneumonia cases, tympanostomy tube placement and outpatient antimicrobial prescriptions. This study will also explore vaccine impact on occurrence of respiratory tract infections (RTIs), including acute otitis media (AOM) in a subset of children in Turku area.

Detailed Description
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The protocol posting has been updated with regards to the enrolment of subjects and outcome measures following Protocol amendment 2, 22 August 2011.

Official Title
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Evaluation of Effectiveness of GSK Biologicals' Pneumococcal Conjugate Vaccine 1024850A Against Invasive Disease

Conditions
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Infections, Streptococcal, Streptococcus Pneumoniae

Intervention / Treatment
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* Biological: Pneumococcal conjugate vaccine GSK1024850A
* Biological: GSK Biologicals' Engerix TM vaccine (Hepatitis B vaccine)
* Biological: GSK Biologicals' Havrix TM vaccine (Hepatitis A vaccine)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female between, and including, 6 weeks to 18 months of age at the time of the first vaccination. Written informed consent obtained from parent(s) or from the guardian(s) of the subject. Exclusion Criteria: Previous vaccination with any registered, non-registered or investigational pneumococcal vaccine other than the study vaccine, or planned use during the study period. If a child belongs to a high risk group for pneumococcal infections for which a licensed pneumococcal conjugate vaccine is made locally available, the subject can not be enrolled in the study and should be referred to the specific immunization program. Previous vaccination against Hepatitis B virus with any registered, non-registered or investigational vaccine, or planned use of such a vaccine other than the study vaccine during the study period. Previous vaccination against Hepatitis A virus with any registered, non-registered or investigational vaccine, or planned use of such a vaccine other than the study vaccine during the study period. Known severe hypersensitivity to any component of the study vaccines, including neomycin. Any medical condition that would contraindicate the initiation of routine immunization outside a clinical trial context.

Ages Eligible for Study
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Minimum Age: 6 Weeks
Maximum Age: 18 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 10Pn3+1-6W- 6M/043 Group<br>Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (NCT00861380 - EUDRACT 2008-005149-48) study, aged 6 weeks to 6 months at enrolment. Subjects received the Synflorix (called also 10Pn-PD-DiT, 10Pn or GSK1024850A) vaccine according to a 3-dose primary vaccination schedule with an interval of at least 4 weeks between doses, followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (3+1 Infant Schedule). The vaccine was administered intramuscularly in the thigh. | Biological: Pneumococcal conjugate vaccine GSK1024850A<br>* 2, 3 or 4 Intramuscular injections, depending on the age at the time of first vaccination<br>|
| Experimental: 10Pn2+1-6W-6M/043 Group<br>Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (NCT00861380 - EUDRACT 2008-005149-48) study, aged 6 weeks to 6 months at enrolment. Subjects received the Synflorix (called also 10Pn-PD-DiT, 10Pn or GSK1024850A) vaccine according to a 2-dose primary vaccination with an interval of at least 8 weeks, followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (2+1 Infant Schedule). The vaccine was administered intramuscularly in the thigh. | Biological: Pneumococcal conjugate vaccine GSK1024850A<br>* 2, 3 or 4 Intramuscular injections, depending on the age at the time of first vaccination<br>|
| Active Comparator: Ctrl-6W-6M/043 Group<br>Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (NCT00861380 - EUDRACT 2008-005149-48) study, aged 6 weeks to 6 months at enrolment. Subjects received the Engerix B vaccine (called also HBV vaccine) according to either a 3-dose primary vaccination schedule with an interval of at least 4 weeks between doses followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (3+1 Infant Schedule), or according to a 2-dose primary vaccination with an interval of at least 8 weeks followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (2+1 Infant Schedule). The vaccine was administered intramuscularly in the thigh. | Biological: GSK Biologicals' Engerix TM vaccine (Hepatitis B vaccine)<br>* 3 or 4 Intramuscular injections, depending on the age at the time of first vaccination. Control 3+1 and Control 2+1 groups, only for children < 12 months of age at the time of first study vaccination.<br>|
| Experimental: 10Pn7-11M/043 Group<br>Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (NCT00861380 - EUDRACT 2008-005149-48) study, aged 7 to 11 months at enrolment. Subjects received the Synflorix (called also 10Pn-PD-DiT, 10Pn or GSK1024850A) vaccine according to a 2-dose primary vaccination with an interval of at least 8 weeks followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (11-17M Schedule). The vaccine was administered intramuscularly in the thigh or in the deltoid region of upper arm, provided the muscle size was adequate. | Biological: Pneumococcal conjugate vaccine GSK1024850A<br>* 2, 3 or 4 Intramuscular injections, depending on the age at the time of first vaccination<br>|
| Active Comparator: Ctrl7-11M/043 Group<br>Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (NCT00861380 - EUDRACT 2008-005149-48) study, aged 7 to 11 months at enrolment. Subjects received the Engerix B (called also HBV) vaccine according to a 2-dose primary vaccination with an interval of at least 8 weeks followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (11-17M Schedule). The vaccine was administered intramuscularly in the thigh or in the deltoid region of upper arm, provided the muscle size was adequate. | Biological: GSK Biologicals' Engerix TM vaccine (Hepatitis B vaccine)<br>* 3 or 4 Intramuscular injections, depending on the age at the time of first vaccination. Control 3+1 and Control 2+1 groups, only for children < 12 months of age at the time of first study vaccination.<br>|
| Experimental: 10Pn12-18M/043 Group<br>Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (NCT00861380 - EUDRACT 2008-005149-48) study, aged 12 to 18 months at enrolment. Subjects received the Synflorix (called also 10Pn-PD-DiT, 10Pn or GSK1024850A) vaccine according to a 2-dose vaccination with an interval of at least and preferably 6 months between doses (12-18M Schedule). The vaccine was administered intramuscularly in the thigh or in the deltoid region of upper arm, provided the muscle size was adequate. | Biological: Pneumococcal conjugate vaccine GSK1024850A<br>* 2, 3 or 4 Intramuscular injections, depending on the age at the time of first vaccination<br>|
| Active Comparator: Ctrl12-18M/043 Group<br>Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (NCT00861380 - EUDRACT 2008-005149-48) study, aged 12 to 18 months at enrolment. Subjects received the Havrix (called also HAV) vaccine according to a 2-dose vaccination with an interval of at least and preferably 6 months between doses (12-18M Schedule). The vaccine was administered intramuscularly in the thigh or in the deltoid region of upper arm, provided the muscle size was adequate. | Biological: GSK Biologicals' Havrix TM vaccine (Hepatitis A vaccine)<br>* 2 Intramuscular injections. Control 3+1 and Control 2+1 groups, only for children >= 12 months of age at the time of first study vaccination.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Person Year Rate as Regards Subjects With Culture-confirmed IPD Due to Any of the 10 Pneumococcal Vaccine Serotypes. In Children Starting Vaccination Within 7 Months of Life and Assigned to a 3-dose Primary Vaccination Course | The PYAR (Person-Year Rate) as regards subjects with culture-confirmed invasive pneumococcal disease (IPD) due to any of the pneumococcal vaccine serotypes was tabulated (vaccine pneumococcal serotypes = serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F). PYAR was calculated as follows n (= number of subjects reported with a culture confirmed IPD) divided by T (= sum of follow-up period expressed in years) (per 1000) as well as the corresponding 95% confidence interval (CI), calculated as a 2-sided profile log-likelihood ratio 95% CI using a classical log linear Poisson regression with strata. | Period of follow-up was any time after the administration of first vaccine dose till the end of the blinded invasive disease (ID) Follow-up period (The blinded ID Follow-up period lasted at least 30 months) | 
| Person Year Rate as Regards Subjects With Culture-confirmed IPD Due to Any of the 10 Pneumococcal Vaccine Serotypes. In Children Starting Vaccination Within 7 Months of Life and Assigned to a 2-dose Primary Vaccination Course | The PYAR (Person-Year Rate) as regards subjects with culture-confirmed invasive pneumococcal disease (IPD) due to any of the pneumococcal vaccine serotypes was tabulated (vaccine pneumococcal serotypes = serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F). PYAR was calculated as follows n (= number of subjects reported with a culture confirmed IPD) divided by T (= sum of follow-up period expressed in years) (per 1000) as well as the corresponding 95% confidence interval (CI), calculated as a 2-sided profile log-likelihood ratio 95% CI using a classical log linear Poisson regression with strata. | Period of follow-up was any time after the administration of first vaccine dose till the end of the blinded invasive disease (ID) Follow-up period (The blinded ID Follow-up period lasted at least 30 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Person Year Rate in the Prevention of Culture-confirmed Invasive Disease (ID)- In Children Starting Vaccination Within 7 Months of Life and Assigned to a 3-dose Primary Vaccination Course (Till End of Blinded ID FU Period) | The PYAR (Person-Year Rate) was calculated as follows n (= number of subjects reported with a culture confirmed IPD) divided by T (= sum of follow-up period expressed in years) (per 1000) as well as the corresponding 95% confidence interval (CI), calculated as a 2-sided profile log- likelihood ratio 95% CI using a classical log linear Poisson regression with strata. | Period of follow-up was any time after the administration of first vaccine dose till the end of the blinded invasive disease (ID) Follow-up period (The blinded ID Follow-up period lasted at least 30 months) | 
| Person Year Rate in the Prevention of Culture-confirmed Invasive Disease (ID)- In Children Starting Vaccination Within 7 Months of Life and Assigned to a 2-dose Primary Vaccination Course (Till End of Blinded ID FU Period) | The PYAR (Person-Year Rate) was calculated as follows n (= number of subjects reported with a culture confirmed IPD) divided by T (= sum of follow-up period expressed in years) (per 1000) as well as the corresponding 95% confidence interval (CI), calculated as a 2-sided profile log- likelihood ratio 95% CI using a classical log linear Poisson regression with strata. | Period of follow-up was any time after the administration of first vaccine dose till the end of the blinded invasive disease (ID) Follow-up period (The blinded ID Follow-up period lasted at least 30 months) | 
| Person Year Rate in the Prevention of Culture-confirmed Invasive Disease (ID)- In Children Starting Vaccination in the 7-11 Months Schedule | The PYAR (Person-Year Rate) was calculated as follows n (= number of subjects reported with a culture confirmed IPD) divided by T (= sum of follow-up period expressed in years) (per 1000) as well as the corresponding 95% confidence interval (CI), calculated as a 2-sided profile log- likelihood ratio 95% CI using a classical log linear Poisson regression with strata. | Period of follow-up was any time after the administration of first vaccine dose till the end of the blinded invasive disease (ID) Follow-up period (The blinded ID Follow-up period lasted at least 30 months) | 
| Person Year Rate in the Prevention of Culture-confirmed Invasive Disease (ID)- In Children Starting Vaccination in the 12-18 Months Schedule (+ Indirect Effects on the Unvaccinated Population) | The PYAR (Person-Year Rate) was calculated as follows n (= number of subjects reported with a culture confirmed IPD) divided by T (= sum of follow-up period expressed in years) (per 1000) as well as the corresponding 95% confidence interval (CI), calculated as a 2-sided profile log- likelihood ratio 95% CI using a classical log linear Poisson regression with strata. | Period of follow-up was any time after the administration of first vaccine dose till the end of the blinded invasive disease (ID) Follow-up period (The blinded ID Follow-up period lasted at least 30 months) | 
| Person Year Rate in the Prevention of Probable Culture-confirmed Invasive Disease (ID)- In Children Starting Vaccination Within 7 Months of Life and Assigned to a 3-dose Primary Vaccination Course | The PYAR (Person-Year Rate) was calculated as follows n (= number of subjects reported with a probable or culture confirmed ID) divided by T (= sum of follow-up period expressed in years) (per 1000) as well as the corresponding 95% confidence interval (CI), calculated as a 2-sided profile log-likelihood ratio 95% CI using a classical log linear Poisson regression with strata. | Period of follow-up was any time after the administration of first vaccine dose till the end of the blinded invasive disease (ID) Follow-up period (The blinded ID Follow-up period lasted at least 30 months) | 
| Person Year Rate in the Prevention of Probable or Culture-confirmed Invasive Disease (ID)- In Children Starting Vaccination Within 7 Months of Life and Assigned to a 2-dose Primary Vaccination Course | The PYAR (Person-Year Rate) was calculated as follows n (= number of subjects reported with a probable or culture confirmed ID) divided by T (= sum of follow-up period expressed in years) (per 1000) as well as the corresponding 95% confidence interval (CI), calculated as a 2-sided profile log-likelihood ratio 95% CI using a classical log linear Poisson regression with strata. | Period of follow-up was any time after the administration of first vaccine dose till the end of the blinded invasive disease (ID) Follow-up period (The blinded ID Follow-up period lasted at least 30 months) | 
| Person Year Rate in the Prevention of Probable or Culture-confirmed Invasive Disease (ID)- In Children Starting Vaccination in the 7-11 Months Schedule | The PYAR (Person-Year Rate) was calculated as follows n (= number of subjects reported with a probable or culture confirmed ID) divided by T (= sum of follow-up period expressed in years) (per 1000) as well as the corresponding 95% confidence interval (CI), calculated as a 2-sided profile log-likelihood ratio 95% CI using a classical log linear Poisson regression with strata. | Period of follow-up was any time after the administration of first vaccine dose till the end of the blinded invasive disease (ID) Follow-up period (The blinded ID Follow-up period lasted at least 30 months) | 
| Person Year Rate in the Prevention of Probable or Culture-confirmed Invasive Disease (ID)- In Children Starting Vaccination in the 12-18 Months Schedule (+ Indirect Effects on the Unvaccinated Population) | The PYAR (Person-Year Rate) was calculated as follows n (= number of subjects reported with a probable or culture confirmed ID) divided by T (= sum of follow-up period expressed in years) (per 1000) as well as the corresponding 95% confidence interval (CI), calculated as a 2-sided profile log-likelihood ratio 95% CI using a classical log linear Poisson regression with strata. Data were not collected regarding indirect effects. | Period of follow-up was any time after the administration of first vaccine dose till the end of the blinded invasive disease (ID) Follow-up period (The blinded ID Follow-up period lasted at least 30 months) | 
| Person Year Rate in Reducing Hospital-diagnosed Pneumonia- In Children Starting Vaccination Within 7 Months of Life and Assigned to a 3-dose Primary Vaccination Course | PYAR was calculated: n (=number of subjects with hospital-diagnosed pneumonia) divided by T (=sum of follow-up (FU) period expressed in years) (per 1000) with 95% CI (2-sided profile log-likelihood ratio 95% CI-classical log linear Poisson regression with strata). FU period considered as period between Dose 1 administration and cut-off date of 31 December 2011. Hospital-diagnosed pneumonia (HDP) cases identified based on hospital discharge diagnosis using international Classification of Disease (ICD)-10 diagnosis codes: J10.0 (Influenza with HDP, other influenza virus identified), J11.0 (Influenza with HDP, virus not identified), J12 (Viral HDP, not elsewhere classified), J13 (HDP due to Sp.), J14 (for HDP due to Hi.), J15 (all HDP, not elsewhere classified), J16 (HDP due to other infectious organisms, not elsewhere classified), J17 (HDP in diseases classified elsewhere), J18 (HDP organism unspecified), J85.1 (Abscess of lung with HDP), and J86 (Pyothorax including empyema). | Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) - FU mean time=24 months | 
| Person Year Rate in Reducing Hospital-diagnosed Pneumonia - In Children Starting Vaccination Within 7 Months of Life and Assigned to a 2-dose Primary Vaccination Course | PYAR was calculated: n (= number of subjects with hospital-diagnosed pneumonia) divided by T (= sum of follow-up (FU) period expressed in years) (per 1000) with 95% CI (2-sided profile log-likelihood ratio 95% CI-classical log linear Poisson regression with strata). FU period considered as period between Dose 1 administration and cut-off date of 31 December 2011. Hospital-diagnosed pneumonia (HDP) cases identified based on hospital discharge diagnosis using international Classification of Disease (ICD)-10 diagnosis codes: J10.0 (Influenza with HDP, other influenza virus identified), J11.0 (Influenza with HDP, virus not identified), J12 (Viral HDP, not elsewhere classified), J13 (HDP due to Sp.), J14 (for HDP due to Hi.), J15 (all HDP, not elsewhere classified), J16 (HDP due to other infectious organisms, not elsewhere classified), J17 (HDP in diseases classified elsewhere), J18 (HDP organism unspecified), J85.1 (Abscess of lung with HDP), and J86 (Pyothorax including empyema). | Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) - FU mean time=24 months | 
| Person Year Rate in Reducing Hospital-diagnosed Pneumonia- In Children Starting Vaccination in the 7-11 Months Schedule | PYAR was calculated: n (= number of subjects with hospital-diagnosed pneumonia) divided by T (= sum of follow-up (FU) period expressed in years) (per 1000) with 95% CI (2-sided profile log-likelihood ratio 95% CI-classical log linear Poisson regression with strata). FU period considered as period between Dose 1 administration and cut-off date of 31 December 2011. Hospital-diagnosed pneumonia (HDP) cases identified based on hospital discharge diagnosis using international Classification of Disease (ICD)-10 diagnosis codes: J10.0 (Influenza with HDP, other influenza virus identified), J11.0 (Influenza with HDP, virus not identified), J12 (Viral HDP, not elsewhere classified), J13 (HDP due to Sp.), J14 (for HDP due to Hi.), J15 (all HDP, not elsewhere classified), J16 (HDP due to other infectious organisms, not elsewhere classified), J17 (HDP in diseases classified elsewhere), J18 (HDP organism unspecified), J85.1 (Abscess of lung with HDP), and J86 (Pyothorax including empyema). | Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) - FU mean time=27 months | 
| Person Year Rate in Reducing Hospital-diagnosed Pneumonia - In Children Starting Vaccination in the 12-18 Months Schedule (+ Indirect Effects on the Unvaccinated Population) | PYAR was calculated: n (= number of subjects with hospital-diagnosed pneumonia) divided by T (= sum of follow-up (FU) period expressed in years) (per 1000) with 95% CI (2-sided profile log-likelihood ratio 95% CI-classical log linear Poisson regression with strata). FU period considered as period between Dose 1 administration and cut-off date of 31 December 2011. Hospital-diagnosed pneumonia (HDP) cases identified based on hospital discharge diagnosis using international Classification of Disease (ICD)-10 diagnosis codes: J10.0 (Influenza with HDP, other influenza virus identified), J11.0 (Influenza with HDP, virus not identified), J12 (Viral HDP, not elsewhere classified), J13 (HDP due to Sp.), J14 (for HDP due to Hi.), J15 (all HDP, not elsewhere classified), J16 (HDP due to other infectious organisms, not elsewhere classified), J17 (HDP in diseases classified elsewhere), J18 (HDP organism unspecified), J85.1 (Abscess of lung with HDP), and J86 (Pyothorax including empyema). | Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) - FU mean time=27 months | 
| Person Year Rate in Reducing Hospital-diagnosed Pneumonia With Chest X-ray (CXR) Reading According to WHO Criteria- In Children Starting Vaccination Within 7 Months of Life and Assigned to a 3-dose Primary Vaccination Course | PYAR was calculated: n (= number of subjects with hospital-diagnosed pneumonia [HDP]) divided by T (= sum of follow-up (FU) period expressed in years) (per 1000) with 95% CI (2-sided profile log-likelihood ratio 95% CI-classical log linear Poisson regression with strata for non-consolidated HDP and without strata for consolidated HDP). FU period considered as period between Dose 1 administration and cut-off date of 31 December 2011. CXR HDP was defined as a HDP case with the presence of abnormal pulmonary infiltrates on the CXR as per independent review panel judgement using WHO methodology. Abnormal pulmonary infiltrates could be either with (Consolidated HDP) or without (Non-consolidated HDP) alveolar consolidation/pleural effusion. New cases of HDP and CXR HDP were based on a 30-day rule, i.e. a new episode was considered if at least a 30-day interval elapsed from the onset of the previous episode. | Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) - FU mean time=24 months | 
| Person Year Rate in Reducing Hospital-diagnosed Pneumonia With CXR Reading According to WHO Criteria - In Children Starting Vaccination Within 7 Months of Life and Assigned to a 2-dose Primary Vaccination Course | PYAR was calculated: n (= number of subjects with hospital-diagnosed pneumonia [HDP]) divided by T (= sum of follow-up (FU) period expressed in years) (per 1000) with 95% CI (2-sided profile log-likelihood ratio 95% CI-classical log linear Poisson regression with strata for non-consolidated HDP and without strata for consolidated HDP). FU period considered as period between Dose 1 administration and cut-off date of 31 December 2011. CXR HDP was defined as a HDP case with the presence of abnormal pulmonary infiltrates on the CXR as per independent review panel judgement using WHO methodology. Abnormal pulmonary infiltrates could be either with (Consolidated HDP) or without (Non-consolidated HDP) alveolar consolidation/pleural effusion. New cases of HDP and CXR HDP were based on a 30-day rule, i.e. a new episode was considered if at least a 30-day interval elapsed from the onset of the previous episode. | Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) - FU mean time=24 months | 
| Person Year Rate in Reducing Hospital-diagnosed Pneumonia With CXR Reading According to WHO Criteria - In Children Starting Vaccination in the 7-11 Months Schedule | PYAR was calculated: n (= number of subjects with hospital-diagnosed pneumonia [HDP]) divided by T (= sum of follow-up (FU) period expressed in years) (per 1000) with 95% CI (2-sided profile log-likelihood ratio 95% CI-classical log linear Poisson regression with strata for non-consolidated HDP and without strata for consolidated HDP). FU period considered as period between Dose 1 administration and cut-off date of 31 December 2011. CXR HDP was defined as a HDP case with the presence of abnormal pulmonary infiltrates on the CXR as per independent review panel judgement using WHO methodology. Abnormal pulmonary infiltrates could be either with (Consolidated HDP) or without (Non-consolidated HDP) alveolar consolidation/pleural effusion. New cases of HDP and CXR HDP were based on a 30-day rule, i.e. a new episode was considered if at least a 30-day interval elapsed from the onset of the previous episode. | Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) - FU mean time=27 months | 
| Person Year Rate in Reducing Hospital-diagnosed Pneumonia With CXR Reading According to WHO Criteria - In Children Starting Vaccination in the 12-18 Months Schedule | PYAR was calculated: n (= number of subjects with hospital-diagnosed pneumonia [HDP]) divided by T (= sum of follow-up (FU) period expressed in years) (per 1000) with 95% CI (2-sided profile log-likelihood ratio 95% CI-classical log linear Poisson regression with strata for non-consolidated HDP and without strata for consolidated HDP). FU period considered as period between Dose 1 administration and cut-off date of 31 December 2011. CXR HDP was defined as a HDP case with the presence of abnormal pulmonary infiltrates on the CXR as per independent review panel judgement using WHO methodology. Abnormal pulmonary infiltrates could be either with (Consolidated HDP) or without (Non-consolidated HDP) alveolar consolidation/pleural effusion. New cases of HDP and CXR HDP were based on a 30-day rule, i.e. a new episode was considered if at least a 30-day interval elapsed from the onset of the previous episode. | Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) - FU mean time=27 months | 
| Person Year Rate in Prevention of All Tympanostomy Tube Placements- In Children Starting Vaccination Within 7 Months of Life and Assigned to a 3-dose Primary Vaccination Course | PYAR was calculated: n (= number of subjects with tympanostomy tube placement[TTP]) divided by T (= sum of follow-up (FU) period expressed in years) (per 1000) with 95% CI (2-sided profile log-likelihood ratio 95% CI-classical log linear Poisson regression with strata). FU period considered as period between Dose 1 administration and cut-off date of 31 December 2011. A TTP episode was defined as a TTP episode classified under the DCA 20 code in the Finnish National Institute of Health and Welfare (THL) and Social Insurance Institution of Finland (KELA) registers, using the Nordic Centre for Classifications in Health Care (NOMESCO) Classification of Surgical Procedures (NCSP), version 1.12 from January 2008, and could refer to either an unilateral or a bilateral TTP procedure. New episodes of TTP defined according to a 30-day rule meaning that a new episode was considered if at least 30-day interval elapsed from the onset of the previous episode. | Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) - FU mean time=24 months | 
| Person Year Rate in Prevention of All Tympanostomy Tube Placements - In Children Starting Vaccination Within 7 Months of Life and Assigned to a 2-dose Primary Vaccination Course | PYAR was calculated: n (= number of subjects with tympanostomy tube placement[TTP]) divided by T (= sum of follow-up (FU) period expressed in years) (per 1000) with 95% CI (2-sided profile log-likelihood ratio 95% CI-classical log linear Poisson regression with strata). FU period considered as period between Dose 1 administration and cut-off date of 31 December 2011. A TTP episode was defined as a TTP episode classified under the DCA 20 code in the Finnish National Institute of Health and Welfare (THL) and Social Insurance Institution of Finland (KELA) registers, using the Nordic Centre for Classifications in Health Care (NOMESCO) Classification of Surgical Procedures (NCSP), version 1.12 from January 2008, and could refer to either an unilateral or a bilateral TTP procedure. New episodes of TTP defined according to a 30-day rule meaning that a new episode was considered if at least 30-day interval elapsed from the onset of the previous episode. | Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) - FU mean time=24 months | 
| Person Year Rate in Prevention of All Tympanostomy Tube Placements - In Children Starting Vaccination in the 7-11 Months Schedule | PYAR was calculated: n (= number of subjects with tympanostomy tube placement[TTP]) divided by T (= sum of follow-up (FU) period expressed in years) (per 1000) with 95% CI (2-sided profile log-likelihood ratio 95% CI-classical log linear Poisson regression with strata). FU period considered as period between Dose 1 administration and cut-off date of 31 December 2011. A TTP episode was defined as a TTP episode classified under the DCA 20 code in the Finnish National Institute of Health and Welfare (THL) and Social Insurance Institution of Finland (KELA) registers, using the Nordic Centre for Classifications in Health Care (NOMESCO) Classification of Surgical Procedures (NCSP), version 1.12 from January 2008, and could refer to either an unilateral or a bilateral TTP procedure. New episodes of TTP defined according to a 30-day rule meaning that a new episode was considered if at least 30-day interval elapsed from the onset of the previous episode. | Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) - FU mean time=27 months | 
| Person Year Rate in Prevention of All Tympanostomy Tube Placements - In Children Starting Vaccination in the 12-18 Months Schedule (+ Indirect Effects on the Unvaccinated Population) | PYAR was calculated: n (= number of subjects with tympanostomy tube placement[TTP]) divided by T (= sum of follow-up (FU) period expressed in years) (per 1000) with 95% CI (2-sided profile log-likelihood ratio 95% CI-classical log linear Poisson regression with strata). FU period considered as period between Dose 1 administration and cut-off date of 31 December 2011. A TTP episode was defined as a TTP episode classified under the DCA 20 code in the Finnish National Institute of Health and Welfare (THL) and Social Insurance Institution of Finland (KELA) registers, using the Nordic Centre for Classifications in Health Care (NOMESCO) Classification of Surgical Procedures (NCSP), version 1.12 from January 2008, and could refer to either an unilateral or a bilateral TTP procedure. New episodes of TTP defined according to a 30-day rule meaning that a new episode was considered if at least 30-day interval elapsed from the onset of the previous episode. | Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) - FU mean time=27 months | 
| Person Year Rate in Prevention of All Antimicrobial Prescriptions- In Children Starting Vaccination Within 7 Months of Life and Assigned to a 3-dose Primary Vaccination Course | PYAR was calculated: n (= number of subjects with antimicrobial prescriptions (APs)) divided by T (= sum of follow-up (FU) period expressed in years) (per 1000) with 95% CI (2-sided profile log-likelihood ratio 95% CI-classical log linear Poisson regression with strata). FU period considered as period between Dose 1 administration and cut-off date of 31 December 2011. An APs episode was an episode of APs to an infant/child falling under following Anatomic Therapeutic Chemical [ATC] codes: J01 (APs) and following codes for AP usually recommended for otitis media (OM) and respiratory tract infections (RTI). For OM and RTI category corresponds to following definition: APs for antibacterial usually recommended for OM and RTI (ATC codes: J01CA04, J01CR02, J01CE02, J01DC02, J01DC04, J01EE02, J01FA09 and J01FA10). New episodes of APs were analyzed according to a 2-day rule meaning new episode considered if at least 2 day interval elapsed from the onset of the previous episode. | Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) - FU mean time=24 months | 
| Person Year Rate in Prevention of All Antimicrobial Prescriptions - In Children Starting Vaccination Within 7 Months of Life and Assigned to a 2-dose Primary Vaccination Course | PYAR was calculated: n (= number of subjects with antimicrobial prescriptions (APs)) divided by T (= sum of follow-up (FU) period expressed in years) (per 1000) with 95% CI (2-sided profile log-likelihood ratio 95% CI-classical log linear Poisson regression with strata). FU period considered as period between Dose 1 administration and cut-off date of 31 December 2011. An APs episode was an episode of APs to an infant/child falling under following Anatomic Therapeutic Chemical [ATC] codes: J01 (APs) and following codes for AP usually recommended for otitis media (OM) and respiratory tract infections (RTI). For OM and RTI category corresponds to following definition: APs for antibacterial usually recommended for OM and RTI (ATC codes: J01CA04, J01CR02, J01CE02, J01DC02, J01DC04, J01EE02, J01FA09 and J01FA10). New episodes of APs were analyzed according to a 2-day rule meaning new episode considered if at least 2 day interval elapsed from the onset of the previous episode. | Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) - FU mean time=24 months | 
| Person Year Rate in Prevention of All Antimicrobial Prescriptions - In Children Starting Vaccination in the 7-11 Months Schedule | PYAR was calculated: n (= number of subjects with antimicrobial prescriptions (APs)) divided by T (= sum of follow-up (FU) period expressed in years) (per 1000) with 95% CI (2-sided profile log-likelihood ratio 95% CI-classical log linear Poisson regression with strata). FU period considered as period between Dose 1 administration and cut-off date of 31 December 2011. An APs episode was an episode of APs to an infant/child falling under following Anatomic Therapeutic Chemical [ATC] codes: J01 (APs) and following codes for AP usually recommended for otitis media (OM) and respiratory tract infections (RTI). For OM and RTI category corresponds to following definition: APs for antibacterial usually recommended for OM and RTI (ATC codes: J01CA04, J01CR02, J01CE02, J01DC02, J01DC04, J01EE02, J01FA09 and J01FA10). New episodes of APs were analyzed according to a 2-day rule meaning new episode considered if at least 2 day interval elapsed from the onset of the previous episode. | Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) - FU mean time=27 months | 
| Person Year Rate in Prevention of All Antimicrobial Prescriptions - In Children Starting Vaccination in the 12-18 Months Schedule (+ Indirect Effects on the Unvaccinated Population) | PYAR was calculated: n (= number of subjects with antimicrobial prescriptions (APs)) divided by T (= sum of follow-up (FU) period expressed in years) (per 1000) with 95% CI (2-sided profile log-likelihood ratio 95% CI-classical log linear Poisson regression with strata). FU period considered as period between Dose 1 administration and cut-off date of 31 December 2011. An APs episode was an episode of APs to an infant/child falling under following Anatomic Therapeutic Chemical [ATC] codes: J01 (APs) and following codes for AP usually recommended for otitis media (OM) and respiratory tract infections (RTI). For OM and RTI category corresponds to following definition: APs for antibacterial usually recommended for OM and RTI (ATC codes: J01CA04, J01CR02, J01CE02, J01DC02, J01DC04, J01EE02, J01FA09 and J01FA10). New episodes of APs were analyzed according to a 2-day rule meaning new episode considered if at least 2 day interval elapsed from the onset of the previous episode. | Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) - FU mean time=27 months | 
| Number of Subjects Classified by Antimicrobial Susceptiblity of IPD Isolates in Children Starting Vaccination Within 7 Months of Life and Assigned to a 2 or 3-dose Primary Vaccination Course | Antimicrobial susceptibility classification of IPD isolates reported during IPD follow-up with percentages for each serotype for the following categories: S= susceptible; I = intermediate ; R = resistant; N = not available. | Period of follow-up was any time after the administration of first vaccine dose till the end date of the follow-up (31 December 2011) - mean FU time=24 months | 
| Number of Subjects With Lower Respiratory Tract Infections (LRTIs) (in a Subset of Subjects in Turku Area) | Analysis of this outcome was performed in the Turku area. The number of subjects reporting at least one LRTI any time after the administration of the first vaccine dose was tabulated. | From the administration of the first vaccine dose till the end of the blinded invasive disease (ID) Follow-up period (at least 30 months) | 
| Number of Subjects With Upper Respiratory Tract Infections (URTIs) (in a Subset of Subjects in Turku Area) | Analysis of this outcome was performed in the Turku area. The number of subjects reporting at least one URTI any time after the administration of the first vaccine dose was tabulated. | From the administration of the first vaccine dose till the end of the blinded invasive disease (ID) Follow-up period (at least 30 months) | 
| Number of Subjects With SAEs Reported During the Blinded Invasive Disease Phase, of the Study | An event is defined as 'serious' when it meets one of the pre-defined outcomes described below: results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation; results in disability/incapacity, or is a congenital anomaly/birth defect in the offspring of a study subject. Medical or scientific judgement should be exercised in deciding whether reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalisation but may jeopardize the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These should also be considered serious. | For Month 0 till the end of the blinded ID Follow-Up, (at least 30 months from study start) | 
| Number of Subjects Enrolled and Vaccinated in the 10PN-PD-DIT-043 and 10PN-PD-DIT-053 Study With Post-study SAEs Reported Via Passive Surveillance- Subjects Enrolled Aged 6 Weeks to 6 Months and 7 to 18 Months | An event is defined as 'serious' when it meets one of the pre-defined outcomes described below: results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation; results in disability/incapacity, or is a congenital anomaly/birth defect in the offspring of a study subject. Medical or scientific judgement should be exercised in deciding whether reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalisation but may jeopardize the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These should also be considered serious. | From the end of the blinded ID Follow-Up period(at least 30 months from study start) up to the end of 18-month period after study unblinding | 
| Culture-confirmed Invasive Disease (ID) Person Year Rate - In Children Starting Vaccination Within 7 Months of Life and Assigned to a 3-dose Primary Vaccination Course Till End of LT FU Period | The PYAR (Person-Year Rate) was calculated as follows n (= number of subjects reported with a culture confirmed IPD) divided by T (= sum of follow-up period expressed in years) (per 1000) as well as the corresponding 95% confidence interval (CI), calculated as a 2-sided profile log-likelihood ratio 95% CI using a classical log linear Poisson regression with strata. | Period of follow-up was any time after the administration of first vaccine dose till the end of the long-term Follow-up period (The Follow-up period lasted at least 77 months) | 
| Culture-confirmed Invasive Disease (ID) Person Year Rate - In Children Starting Vaccination Within 7 Months of Life and Assigned to a 2-dose Primary Vaccination Course Till End of LT FU Period | The PYAR (Person-Year Rate) was calculated as follows n (= number of subjects reported with a culture confirmed IPD) divided by T (= sum of follow-up period expressed in years) (per 1000) as well as the corresponding 95% confidence interval (CI), calculated as a 2-sided profile log-likelihood ratio 95% CI using a classical log linear Poisson regression with strata. | Period of follow-up was any time after the administration of first vaccine dose till the end of the long-term Follow-up period (The Follow-up period lasted at least 77 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pneumococcal conjugate vaccine, Invasive disease, Respiratory tract infections, Haemophilus influenzae, Streptococcus pneumoniae, Acute otitis media, Pneumonia