Safety & Immunogenicity of Pneumococcal Vaccine 2189242A Co-administered With DTPa-HBV-IPV/Hib in Healthy Infants

Infections, Streptococcal Clinical Trial

Official title:

Safety, Reactogenicity & Immunogenicity of GSK Biologicals' Pneumococcal Vaccine 2189242A When Co-administered With DTPa-HBV-IPV/Hib Vaccine in Healthy Infants

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01204658
• Other study ID #: 113994
• Secondary ID: 2010-019730-27
• Status: Completed
• Phase: Phase 2
• Start date: September 27, 2010
• Est. completion date: October 1, 2012

Study information

• Verified date: May 2019
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will assess the safety, reactogenicity and immunogenicity of two formulations of GSK Biologicals' pneumococcal vaccine 2189242A given as a 3-dose primary vaccination course during the first 6 months of life followed by a booster dose at 12-15 months of age and co-administered with DTPa-HBV-IPV/Hib vaccine.

Description:

This study will assess the safety, reactogenicity, immunogenicity and persistence of two formulations of GSK Biologicals' pneumococcal vaccine 2189242A [high dose (HD) or low dose (LD)] given as a 3-dose primary vaccination course during the first 6 months of life followed by a booster dose at 12-15 months of age when co-administered with Infanrix hexa™ and compared to the vaccination with Synflorix™ and with Prevnar 13™ similarly co-administered with the Infanrix hexa™ vaccine.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 576
• Est. completion date: October 1, 2012
• Est. primary completion date: November 3, 2011
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 6 Weeks to 14 Weeks

Eligibility

Inclusion Criteria:

• Subjects who the investigator believes that their parent(s)/Legally Acceptable Representative(s) (LAR) can and will comply with the requirements of the protocol

• Male or female between, and including, 6 and 14 weeks (42-104 days) of age at the time of the first vaccination.

• Written informed consent obtained from the parents/LAR(s) of the subject.

• Healthy subjects as established by medical history and clinical examination before entering into the study.

• Born after a gestation period of 36 to 42 weeks inclusive.

Exclusion Criteria:

• Child in care.

• Use of any investigational or non-registered product other than the study vaccine(s) within 30 days preceding the first dose of study vaccine, or planned use during the study period.

• Chronic administration of immunosuppressants or other immune-modifying drugs since birth.

• Planned administration/administration of a vaccine not foreseen by the study protocol during the study period starting from 30 days before each dose and ending 30 days after each dose of vaccine(s), with the exception of licensed flu vaccines.

• Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational product.

• Previous vaccination against S. pneumoniae since birth.

• History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccine(s).

• Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination.

• A family history of congenital or hereditary immunodeficiency.

• Major congenital defects or any chronic illness.

• History of any neurologic disorders or seizures.

• Acute disease and/or fever at the time of enrolment.

• Fever is defined as temperature >= 38.0°C on rectal setting or >= 37.5°C on oral or axillary setting.

• Subjects with a minor illness without fever may be enrolled at the discretion of the investigator.

• Administration of immunoglobulins and/ or any blood products since birth or planned administration during the primary epoch and during the period starting three months before booster vaccination and ending one month after the booster vaccination.

Related Conditions & MeSH terms

• Infections, Streptococcal
• Streptococcal Infections

Intervention

Biological:
• Pneumococcal vaccine GSK 2189242A (LD formulation 1)
Intramuscular injection
• Pneumococcal vaccine GSK 2189242A (HD formulation 2)
Intramuscular injection
• Synflorix
Intramuscular injection
• Prevenar 13
Intramuscular injection
• Infanrix Hexa (DTPa-HBV-IPV/Hib)
Intramuscular injection

Locations

Country	Name	City	State
Czechia	GSK Investigational Site	Benesov
Czechia	GSK Investigational Site	Brno
Czechia	GSK Investigational Site	Decin
Czechia	GSK Investigational Site	Jindrichuv Hradec
Czechia	GSK Investigational Site	Kladno
Czechia	GSK Investigational Site	Liberec
Czechia	GSK Investigational Site	Nachod
Czechia	GSK Investigational Site	Ostrov
Czechia	GSK Investigational Site	Pardubice
Czechia	GSK Investigational Site	Praha 6
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Detmold	Nordrhein-Westfalen
Germany	GSK Investigational Site	Frankenthal	Rheinland-Pfalz
Germany	GSK Investigational Site	Schwäbisch-Hall	Baden-Wuerttemberg
Germany	GSK Investigational Site	Tuttlingen	Baden-Wuerttemberg
Poland	GSK Investigational Site	Debica
Poland	GSK Investigational Site	Krakow
Poland	GSK Investigational Site	Poznan
Poland	GSK Investigational Site	Siemianowice Slaskie
Poland	GSK Investigational Site	Warszawa
Poland	GSK Investigational Site	Wroclaw
Sweden	GSK Investigational Site	Örebro
Sweden	GSK Investigational Site	Östersund
Sweden	GSK Investigational Site	Umeå

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

Czechia,  Germany,  Poland,  Sweden, 

References & Publications (1)

Prymula R, Szenborn L, Silfverdal SA, Wysocki J, Albrecht P, Traskine M, Gardev A, Song Y, Borys D. Safety, reactogenicity and immunogenicity of two investigational pneumococcal protein-based vaccines: Results from a randomized phase II study in infants. Vaccine. 2017 Aug 16;35(35 Pt B):4603-4611. doi: 10.1016/j.vaccine.2017.07.008. Epub 2017 Jul 17. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Subjects With Any and Grade 3 Solicited General Symptoms and With Solicited General Symptoms Related to Vaccination - Primary Phase of the Study	Assessed solicited general symptoms were Drowsiness, Irritability, Loss of appetite (Loss Appet.) and Fever (rectal temperature higher than or equal to [>=] 38 degrees Celsius [°C]). Any = Occurrence of the specified solicited general symptom, regardless of intensity and relationship to vaccination. Related = Occurrence of the specified symptom assessed by the investigators as causally related to vaccination. Grade 3 (G3) Drowsiness = Drowsiness that prevented normal activity. G3 Irritability = Crying that could not be comforted/prevented normal activity. G3 Loss of appetite = Subject did not eat at all. G3 Fever = Rectal temperature higher than (>) 40.0°C. Primary results correspond to results for occurrences of G3 fever symptoms assessed by the investigators as related to vaccination (Related G3 fever).	Within the 7-day (Days 0-6) periods post vaccination, after each dose (D) of the 3-dose primary vaccination course
Primary	Percentage of Subjects Reporting Fever > 40.0°C With Causal Relationship to Vaccination After Each Primary Vaccination Dose and Across Doses in 10PP-LD/Infanrix Hexa Group and in Synflorix/Infanrix Hexa Group	Grade 3 fever was defined as fever by rectal measurement > 40.0°C. Related was defined as causal relationship to vaccination. This endpoint was assessed after each primary vaccination dose and across doses and in subjects in the 10PP-LD/Infanrix hexa (or 10PP-LD) and Synflorix/Infanrix hexa (or 10PN) groups only.	During the 7-day (Days 0-6) post-vaccination period following each primary vaccination dose and across doses
Primary	Percentage of Subjects Reporting Fever > 40° C With Causal Relationship to Vaccination After Each Primary Vaccination Dose and Across Doses in the 10PP-HD/Infanrix Hexa Group and in the Synflorix/Infanrix Hexa Group	Grade 3 fever was defined as fever by rectal measurement >40.0°C. Related was defined as causal relationship to vaccination. This endpoint was assessed after each primary vaccination dose and across doses and in subjects in the 10PP-HD/Infanrix hexa (or 10PP-HD) and Synflorix/Infanrix hexa (or 10PN) groups only.	During the 7-day (Days 0-6) post-vaccination period following each primary vaccination dose and across doses
Secondary	Antibody Concentrations Against Pneumococcal Pneumolysin Toxoid (dPly) and Pneumococcal Histidine Triad Protein D (PhtD) Proteins - Primary Phase of the Study	Antibody concentrations against dPly and PhtD (anti-dPly and anti-PhtD, respectively) were measured by enzyme-linked immunosorbent assay (ELISA), expressed as geometric mean concentrations (GMCs), in ELISA Units per milliliter (EL.U/mL). Cut-offs for seropositivity were concentrations higher than or equal to (=)12 EL.U/mL for anti-dPly antibodies and = 17 EL.U/mL for anti-PhtD antibodies. This outcome concerns results for the Primary Phase of the study.	At Month 3, e. g. one month post-Dose 3 of pneumococcal vaccine (10PP, Synflorix™ or Prevnar 13™)
Secondary	Antibody Concentrations Against Pneumococcal Pneumolysin Toxoid (dPly) and Pneumococcal Histidine Triad Protein D (PhtD) Proteins - Booster Phase of the Study	Antibody concentrations against dPly and PhtD (anti-dPly and anti-PhtD, respectively) were measured by enzyme-linked immunosorbent assay (ELISA), expressed as geometric mean concentrations (GMCs), in ELISA Units per milliliter (EL.U/mL). Cut-offs for seropositivity were concentrations higher than or equal to (=)12 EL.U/mL for anti-dPly antibodies and = 17 EL.U/mL for anti-PhtD antibodies. This outcome concerns results for the Booster Phase of the study.	At Months 10 and 11, e.g. prior to and at one month post booster vaccination with pneumococcal vaccine (10PP, Synflorix™ or Prevnar 13™)
Secondary	Antibody Concentrations Against Protein D (Anti-PD) - Primary Phase of the Study	Antibody concentrations were measured by enzyme-linked immunosorbent assay (ELISA), expressed as geometric mean concentrations (GMCs), in ELISA Units per milliliter (EL.U/mL). The seropositivity cut-off of the assay was a concentration of anti-PD antibodies = 100 EL.U/mL. This outcome concerns results for the Primary Phase of the study.	At Month 3, e. g. one month post-Dose 3 of pneumococcal vaccine (10PP, Synflorix™ or Prevnar 13™)
Secondary	Antibody Concentrations Against Protein D (Anti-PD) - Booster Phase of the Study	Antibody concentrations were measured by enzyme-linked immunosorbent assay (ELISA), expressed as geometric mean concentrations (GMCs), in ELISA Units per milliliter (EL.U/mL). The seropositivity cut-off of the assay was a concentration of anti-PD antibodies = 100 EL.U/mL. This outcome concerns results for the Booster Phase of the study.	At Months 10 and 11, e.g. prior to and at one month post booster vaccination with pneumococcal vaccine (10PP, Synflorix™ or Prevnar 13™)
Secondary	Antibody Concentrations Against Pneumococcal Serotypes - Primary Phase of the Study	Antibodies assessed for this outcome measure were those against the vaccine/cross-reactive pneumococcal serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F (ANTI-1, -3, -4, -5, -6A, -6B, -7F, -9V, -14, -18C, -19A, -19F and -23F). Antibody concentrations were measured by 22F enzyme-linked immunosorbent assay (ELISA), expressed as geometric mean concentrations (GMCs), in micrograms per milliliter (µg/mL). The seropositivity cut-off of the assay was an antibody concentration = 0.05 µg/mL. This outcome concerns results for the Primary Phase of the study.	At Month 3, e. g. one month post-Dose 3 of pneumococcal vaccine (10PP, Synflorix™ or Prevnar 13™)
Secondary	Antibody Concentrations Against Pneumococcal Serotypes - Booster Phase of the Study	Antibodies assessed for this outcome measure were those against the vaccine/cross-reactive pneumococcal serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F (ANTI-1, -3, -4, -5, -6A, -6B, -7F, -9V, -14, -18C, -19A, -19F and -23F). Antibody concentrations were measured by 22F enzyme-linked immunosorbent assay (ELISA), expressed as geometric mean concentrations (GMCs), in micrograms per milliliter (µg/mL). The seropositivity cut-off of the assay was an antibody concentration higher than or equal to (=) 0.05 µg/mL. This outcome concerns results for the Booster Phase of the study.	At Months 10 and 11, e.g. prior to and at one month post booster vaccination with pneumococcal vaccine (10PP, Synflorix™ or Prevnar 13™)
Secondary	Titers for Opsonophagocytic Activity Against Pneumococcal Serotypes - Primary Phase of the Study	Titers for opsonophagocytic activity assessed for this outcome measure were those for opsonophagocytic activity against the vaccine/cross-reactive pneumococcal serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F (OPA-1, -3, -4, -5, -6A, -6B, -7F, -9V, -14, -18C, -19A, -19F and -23F). The Seropositivity cut-off of the assay was a titer for opsonophagocytic activity higher than or equal to (=) 8, except for the OPA-19A for which the titer was = to the serotype-specific Lower Limit of Quantification (=143). This outcome concerns results for the Primary Phase of the study.	At Month 3, e. g. one month post-Dose 3 of pneumococcal vaccine (10PP, Synflorix™ or Prevnar 13™)
Secondary	Titers for Opsonophagocytic Activity Against Pneumococcal Serotypes - Booster Phase of the Study	Titers for opsonophagocytic activity assessed for this outcome measure were those for opsonophagocytic activity against the vaccine/cross-reactive pneumococcal serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F (OPA-1, -3, -4, -5, -6A, -6B, -7F, -9V, -14, -18C, -19A, -19F and -23F). The Seropositivity cut-off of the assay was a titer for opsonophagocytic activity higher than or equal to (=) 8, except for the OPA-19A for which the titer was = to the serotype-specific Lower Limit of Quantification (=143). This outcome concerns results for the Booster Phase of the study.	At Months 10 and 11, e.g. prior to and at one month post booster vaccination with pneumococcal vaccine (10PP, Synflorix™ or Prevnar 13™)
Secondary	Concentrations of Antibodies Inhibiting Pneumococcal Pneumolysin Toxoid Haemolysis Activity - Primary Phase of the Study	Analysis of the concentrations of antibodies inhibiting pneumococcal pneumolysin toxoid haemolysis activity (anti-Ply) was not performed as no assay was validated to perform this analysis. This outcome concerns results for the Primary Phase of the study.	At Month 3, e. g. one month post-Dose 3 of pneumococcal vaccine (10PP, Synflorix™ or Prevnar 13™)
Secondary	Concentrations of Antibodies Inhibiting Pneumococcal Pneumolysin Toxoid Haemolysis Activity - Booster Phase of the Study	Analysis of the concentrations of antibodies inhibiting pneumococcal pneumolysin toxoid haemolysis activity (anti-Ply) was not performed as no assay was validated to perform this analysis. This outcome concerns results for the Booster Phase of the study.	At Months 10 and 11, e.g. prior to and at one month post booster vaccination with pneumococcal vaccine (10PP, Synflorix™ or Prevnar 13™)
Secondary	Concentrations of Antibodies Against Diphtheria (Anti-D) and Tetanus (Anti-T) - Primary Phase of the Study	Antibody concentrations will be expressed as geometric mean concentrations (GMCs) in International Units per milliliter (IU/mL). The seroprotection cut-off of the assay was an antibody concentration higher than or equal to (=) 0.1 IU/mL. This outcome concerns results for the Primary Phase of the study.	At Month 3, e. g. one month post-Dose 3 of pneumococcal vaccine (10PP, Synflorix™ or Prevnar 13™)
Secondary	Concentrations of Antibodies Against Diphtheria (Anti-D) and Tetanus (Anti-T) - Booster Phase of the Study	Antibody concentrations will be expressed as geometric mean concentrations (GMCs) in International Units per milliliter (IU/mL). The seroprotection cut-off of the assay was an antibody concentration higher than or equal to (=) 0.1 IU/mL. This outcome concerns results for the Booster Phase of the study.	At Months 10 and 11, e.g. prior to and at one month post booster vaccination with pneumococcal vaccine (10PP, Synflorix™ or Prevnar 13™)
Secondary	Concentrations of Antibodies Against Pertussis Toxoid (Anti-PT), Filamentous Haemagglutinin (Anti-FHA), Pertactin (Anti-PRN) - Primary Phase of the Study	Antibody concentrations will be measured by enzyme-linked immunosorbent assay (ELISA), expressed as geometric mean concentrations (GMCs) in Elisa Units per milliliter (EL.U/mL). The seropositivity cut-off of the assay was an antibody concentration higher than or equal to (=) 5 EL.U/mL. This outcome concerns results for the primary Phase of the study.	At Month 3, e. g. one month post-Dose 3 of pneumococcal vaccine (10PP, Synflorix™ or Prevnar 13™)
Secondary	Concentrations of Antibodies Against Pertussis Toxoid (Anti-PT), Filamentous Haemagglutinin (Anti-FHA), Pertactin (Anti-PRN) - Booster Phase of the Study	Antibody concentrations will be measured by enzyme-linked immunosorbent assay (ELISA), expressed as geometric mean concentrations (GMCs) in Elisa Units per milliliter (EL.U/mL). The seropositivity cut-off of the assay was an antibody concentration higher than or equal to (=) 5 EL.U/mL. This outcome concerns results for the Booster Phase of the study.	At Months 10 and 11, e.g. prior to and at one month post booster vaccination with pneumococcal vaccine (10PP, Synflorix™ or Prevnar 13™)
Secondary	Concentrations of Antibodies Against Hepatitis B (Anti-HBs) - Primary Phase of the Study	Antibody concentrations will be expressed as geometric mean concentrations (GMCs) in milli-International Units per milliliter (mIU/mL). The seroprotection cut-off of the assay was an antibody concentration higher than or equal to (=) 10 mIU/mL. This outcome concerns results for the Primary Phase of the study. Note that the percentage of subjects with concentration =10 mIU/mL was over-estimated due to the use of in-house assay overestimating concentrations between 10-100 mIU/mL. Accordingly GMCs were also overestimated.	At Month 3, e. g. one month post-Dose 3 of pneumococcal vaccine (10PP, Synflorix™ or Prevnar 13™)
Secondary	Concentrations of Antibodies Against Hepatitis B (Anti-HBs) - Booster Phase of the Study	Antibody concentrations will be expressed as geometric mean concentrations (GMCs) in milli-International Units per milliliter (mIU/mL). The seroprotection cut-off of the assay was an antibody concentration higher than or equal to (=) 10 mIU/mL. This outcome concerns results for the Booster Phase of the study. * A decrease in the specificity of the anti-HB Enzyme-Linked ImmunoSorbent Assay (ELISA) assay had been observed in some studies for low levels of antibody (10-100 mIU/mL). The table shows updated results following partial or complete reanalysis. The retest has been performed in using Food and Drug Administration (FDA)-approved ChemiLuminescence ImmunoAssay (CLIA) commercial assay Centaur™.	At Months 10 and 11, e.g. prior to and at one month post booster vaccination with pneumococcal vaccine (10PP, Synflorix™ or Prevnar 13™)
Secondary	Concentrations of Antibodies Against Polyribosyl Ribitol Phosphate (Anti-PRP) - Primary Phase of the Study	Antibody concentrations will be expressed as geometric mean concentrations (GMCs) in microgram per milliliter (µg/mL). The seroprotection cut-off of the assay was an antibody concentration higher than or equal to (=) 0.15 µg/mL or 1 µg/mL. This outcome concerns results for the Primary Phase of the study.	At Month 3, e. g. one month post-Dose 3 of pneumococcal vaccine (10PP, Synflorix™ or Prevnar 13™)
Secondary	Concentrations of Antibodies Against Polyribosyl Ribitol Phosphate (Anti-PRP) - Booster Phase of the Study	Antibody concentrations will be expressed as geometric mean concentrations (GMCs) in microgram per milliliter (µg/mL). The seroprotection cut-off of the assay was an antibody concentration higher than or equal to (=) 0.15 µg/mL or 1 µg/mL. This outcome concerns results for the Booster Phase of the study.	At Months 10 and 11, e.g. prior to and at one month post booster vaccination with pneumococcal vaccine (10PP, Synflorix™ or Prevnar 13™)
Secondary	Titers of Antibodies Against Poliovirus Types 1, 2 and 3 (Anti-1, Anti-2 and Anti-3) - Primary Phase of the Study	Antibody titers will be measured by virus microneutralization test, expressed as geometric mean titers (GMTs). The cut-off of the assay for anti-1, anti-2 and anti-3 antibody was a titer higher than or equal to (=) 8. This outcome concerns results for the Primary Phase of the study.	At Month 3, e. g. one month post-Dose 3 of pneumococcal vaccine (10PP, Synflorix™ or Prevnar 13™)
Secondary	Titers of Antibodies Against Poliovirus Types 1, 2 and 3 (Anti-1, Anti-2 and Anti-3) - Booster Phase of the Study	Antibody titers will be measured by virus microneutralization test, expressed as geometric mean titers (GMTs). The cut-off of the assay for anti-1, anti-2 and anti-3 antibody was a titer higher than or equal to (=) 8. This outcome concerns results for the Booster Phase of the study.	At Months 10 and 11, e.g. prior to and at one month post booster vaccination with pneumococcal vaccine (10PP, Synflorix™ or Prevnar 13™)
Secondary	Number of Subjects With Any and Grade 3 Solicited Local Symptoms - Primary Phase of the Study	Assessed local symptoms were pain, redness and swelling at injection site. Any = Occurrence of the specified solicited local symptom, regardless of intensity. Grade 3 Pain = Crying when limb was moved/spontaneously painful. Grade 3 Redness/Swelling = Redness/swelling at injection site larger than (>) 30 millimeters (mm).	Within the 7-day (Days 0-6) periods post vaccination, after each dose (D) of the 3-dose primary vaccination course
Secondary	Number of Subjects With Any and Grade 3 Solicited Local Symptoms - Booster Phase of the Study	Assessed local symptoms were pain, redness and swelling at injection site. Any = Occurrence of the specified solicited local symptom, regardless of intensity. Grade 3 Pain = Crying when limb was moved/spontaneously painful. Grade 3 Redness/Swelling = Redness/swelling at injection site larger than (>) 30 millimeters (mm).	Within the 7-day (Days 0-6) period after booster vaccination
Secondary	Number of Subjects With Any, Grade 3 Solicited General Symptoms and Solicited General Symptoms With Relationship to Vaccination - Booster Phase of the Study	Assessed solicited general symptoms were Drowsiness, Irritability, Loss of appetite (Loss Appet.) and Fever (rectal temperature higher than [=] 38 degrees Celsius [°C]). Any = Occurrence of the specified solicited general symptom, regardless of intensity and relationship to vaccination. Related = Occurrence of the specified symptom assessed by the investigator as causally related to vaccination. Grade 3 Drowsiness = Drowsiness that prevented normal activity. Grade 3 Irritability = Crying that could not be comforted/prevented normal activity. Grade 3 Loss of appetite = Subject did not eat at all. Grade 3 Fever = Axillary temperature higher than (>) 40.0°C.	Within the 7-day (Days 0-6) period post vaccination after booster vaccination
Secondary	Number of Subjects With Unsolicited Adverse Events (AEs) - Primary Phase of the Study	An unsolicited AE was defined as any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For the marketed products administered in the study, this also included failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse of the product. Any = Occurrence of an unsolicited AE, regardless of intensity or relationship to vaccination.	Within the 31-day (Days 0-30) period post primary vaccination, across doses
Secondary	Number of Subjects With Unsolicited Adverse Events (AEs) - Booster Phase of the Study	An unsolicited AE was defined as any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For the marketed products administered in the study, this also included failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse of the product. Any = Occurrence of an unsolicited AE, regardless of intensity or relationship to vaccination.	Within the 31-day (Days 0-30) period post booster vaccination
Secondary	Number of Subjects With Serious Adverse Events (SAEs)	An SAE was defined as any medical occurrence that resulted in death, was life-threatening, required hospitalization or prolongation of hospitalization, resulted in disability/incapacity in a subject. AE(s) considered as SAE(s) also included invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that did not result in hospitalization, as per the medical or scientific judgement of the physician. Any = Occurrence of an SAE, regardless of relationship to vaccination.	During the entire study period (Months 0-11)