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

Infections, Streptococcal Clinical Trial

— FinIP  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00861380
• Other study ID #: 111442
• Secondary ID: 2008-005149-48
• Status: Completed
• Phase: Phase 3
• Start date: May 4, 2009
• Est. completion date: October 5, 2013

Study information

• Verified date: November 2020
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 41188
• Est. completion date: October 5, 2013
• Est. primary completion date: January 31, 2012
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 6 Weeks to 18 Months

Eligibility

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.

Related Conditions & MeSH terms

• Infections, Streptococcal
• Pneumonia
• Streptococcal Infections
• Streptococcus Pneumoniae

Intervention

Biological:
• Pneumococcal conjugate vaccine GSK1024850A
2, 3 or 4 Intramuscular injections, depending on the age at the time of first vaccination
• GSK Biologicals' Engerix TM vaccine (Hepatitis B vaccine)
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.
• GSK Biologicals' Havrix TM vaccine (Hepatitis A vaccine)
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.

Locations

Country	Name	City	State
Finland	GSK Investigational Site	Helsinki

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Country where clinical trial is conducted

Finland, 

References & Publications (7)

Kilpi TM, Jokinen J, Puumalainen T, Nieminen H, Ruokokoski E, Rinta-Kokko H, Traskine M, Lommel P, Moreira M, Ruiz-Guinazu J, Borys D, Schuerman L, Palmu AA. Effectiveness of pneumococcal Haemophilus influenzae protein D conjugate vaccine against pneumonia in children: A cluster-randomised trial. Vaccine. 2018 Sep 18;36(39):5891-5901. doi: 10.1016/j.vaccine.2018.08.020. Epub 2018 Aug 23. — View Citation

Nieminen H, Rinta-Kokko H, Jokinen J, Puumalainen T, Moreira M, Borys D, Schuerman L, Palmu AA. Effectiveness of the 10-valent pneumococcal conjugate vaccine among girls, boys, preterm and low-birth-weight infants - Results from a randomized, double-blind vaccine trial. Vaccine. 2019 Jun 19;37(28):3715-3721. doi: 10.1016/j.vaccine.2019.05.033. Epub 2019 May 20. — View Citation

Palmu AA, Jokinen J, Borys D, Nieminen H, Ruokokoski E, Siira L, Puumalainen T, Lommel P, Hezareh M, Moreira M, Schuerman L, Kilpi TM. Effectiveness of the ten-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against invasive pneumococcal disease: a cluster randomised trial. Lancet. 2013 Jan 19;381(9862):214-22. doi: 10.1016/S0140-6736(12)61854-6. Epub 2012 Nov 16. Erratum in: Lancet. 2013 May 18;381(9879):1720. Erratum in: Lancet. 2015 May 30;385(9983):2152. — View Citation

Palmu AA, Jokinen J, Nieminen H, Rinta-Kokko H, Ruokokoski E, Puumalainen T, Borys D, Lommel P, Traskine M, Moreira M, Schuerman L, Kilpi TM. Effect of pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) on outpatient antimicrobial purchases: a double-blind, cluster randomised phase 3-4 trial. Lancet Infect Dis. 2014 Mar;14(3):205-12. doi: 10.1016/S1473-3099(13)70338-4. Epub 2013 Nov 26. — View Citation

Palmu AA, Jokinen J, Nieminen H, Rinta-Kokko H, Ruokokoski E, Puumalainen T, Moreira M, Schuerman L, Borys D, Kilpi TM. Vaccine-preventable disease incidence of pneumococcal conjugate vaccine in the Finnish invasive pneumococcal disease vaccine trial. Vaccine. 2018 Mar 27;36(14):1816-1822. doi: 10.1016/j.vaccine.2018.02.088. — View Citation

Palmu AA, Jokinen J, Nieminen H, Rinta-Kokko H, Ruokokoski E, Puumalainen T, Traskine M, Moreira M, Borys D, Schuerman L, Kilpi TM. Effectiveness of the Ten-valent Pneumococcal Conjugate Vaccine Against Tympanostomy Tube Placements in a Cluster-randomized Trial. Pediatr Infect Dis J. 2015 Nov;34(11):1230-5. doi: 10.1097/INF.0000000000000857. — View Citation

Palmu AA, Jokinen J, Nieminen H, Syrjänen R, Ruokokoski E, Puumalainen T, Moreira M, Schuerman L, Borys D, Kilpi TM. Vaccine effectiveness of the pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against clinically suspected invasive pneumococcal disease: a cluster-randomised trial. Lancet Respir Med. 2014 Sep;2(9):717-27. doi: 10.1016/S2213-2600(14)70139-0. Epub 2014 Aug 7. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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)
Secondary	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)