Immunogenicity and Safety Study of GSK Biologicals' Candidate Malaria Vaccine Given at 6, 7.5 and 9 Months of Age in Co-administration With Measles, Rubella and Yellow Fever (YF) Vaccines Followed by a Booster of the Malaria Vaccine.

GlaxoSmithKline699 enrolled

Overview

The purpose of this study is to assess the immunogenicity, safety, and reactogenicity of the SB257049 candidate malaria vaccine when co-administered with Vitamin A, measles, rubella and yellow fever vaccines to children aged 6 months at the first vaccination.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

NONE

Enrollment

699

Conditions

Malaria Malaria Vaccines

Interventions

Vitamin ADIETARY_SUPPLEMENT

Oral administration of Vitamin A (1 dose)

Candidate Plasmodium falciparum malaria vaccineBIOLOGICAL

Intramuscular administration of SB257049 vaccine (4 doses)

MR-VacBIOLOGICAL

Subcutaneous injection of a combined measles and rubella vaccine (1 dose)

Eligibility

Sex: ALLMin age: 6 MonthsMax age: 6 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Subjects' parent(s)/Legally Acceptable Representative(s) (LAR\[s\]) who, in the opinion of the investigator, could and complied with the requirements of the protocol. * A male or female 6 months of age (from the day the child becomes 6 months of age until the day before the child achieved 7 months of age) at the time of the first vaccination. * Signed or thumb-printed informed consent obtained from the parent(s)/LAR(s) of the subject. Where parent(s)/LAR(s) were illiterate, the consent form was countersigned by an independent witness. * Healthy subjects as established by medical history and clinical examination before entering into the study. * Previously received three documented doses of diphtheria, tetanus, and whole-cell pertussis, hepatitis B vaccine (DTPwHepB), and a 3-dose course of oral polio vaccine and, if locally recommended, pneumococcal and rotavirus vaccines. Exclusion Criteria: * Child in care * Use of a drug or vaccine that is not approved for that indication other than the study vaccines within 30 days preceding the first dose of study vaccine, or planned use during the study period. * Any medical condition that in the judgment of the investigator would make intramuscular injection unsafe. * Chronic administration of immunosuppressants or other immune-modifying drugs within six months prior to the first vaccine dose. For corticosteroids, this meant prednisone≥ 0.5 mg/kg/day, or equivalent. Inhaled and topical steroids were allowed. * Planned administration/administration of a vaccine not foreseen by the study protocol in the period starting seven days before the first dose of SB257049 measles, rubella and YF vaccines and ending 42 days after the last dose of vaccines given at 9 months of age (Visit 4), with the exception of oral polio vaccine which could be given for unforeseen public health threat. * 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 vaccine/product. * Previous vaccination against measles, YF or rubella. * Previous administration of Vitamin A. * Moderate or severe malnutrition at screening defined as weight for age Z-score \< -2. * Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination. * Family history of congenital or hereditary immunodeficiency. * History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccine(s). See also Section 1.3. * Major congenital defects or serious chronic illness. * History of any neurological disorders or seizures. * Acute disease and/or fever at the time of enrolment. Fever was defined as temperature ≥ 37.5°C /99.5°F for oral, axillary or tympanic route, or ≥ 38.0°C /100.4°F on rectal route. The preferred route for recording temperature in this study was axillary. Subjects with a minor illness without fever might have been enrolled at the discretion of the investigator. * Administration of immunoglobulins and/or any blood products within the 3 months preceding the first dose of study vaccine or planned administration during the study period. * Same sex twin. * Maternal death. * Previous participation in any other malaria study.

Locations (2)

GSK Investigational Site

Kintampo, Ghana

GSK Investigational Site

Kumasi, Ghana

Outcomes

Primary Outcomes

Anti-Circumsporozoite (Anti-CS) Antibody Concentrations, One Month Post Dose 3 of SB257049 (Primary Analysis)

Concentrations were expressed as Geometric Mean Concentrations (GMCs) with the following unit of measure: Enzyme Linked Immunosorbent Assay (ELISA) units per milliliter (EU/mL). The 95% confidence intervals were calculated using the Analysis of Variance (ANOVA) model. The antibody response of anti-CS was assessed in the Coad Group and the RTS,S Group.

Time frame: At one month post Dose 3 of SB257049 (Month 4)

Anti-CS Antibody Concentrations, One Month Post Dose 3 of SB257049 (Study End Analysis)

Concentrations were expressed as GMCs with the following unit of measure: EU/mL. The 95% confidence intervals were calculated using the ANOVA model. The antibody response of anti-CS was assessed in the Coad Group and the RTS,S Group. The analysis was re-evaluated and performed on the Per-Protocol set for immunogenicity defined at study end.

Time frame: At one month post Dose 3 of SB257049 (Month 4)

Secondary Outcomes

Anti-CS Antibody Concentrations, Pre-vaccination and One Month Post Dose 3 of SB257049

Concentrations were expressed as Geometric Mean Concentrations (GMCs) with the following unit of measure: ELISA units per milliliter (EU/mL). The 95% CI for the GMC was obtained by exponential transformation (base 10) of the 95% CI for the mean of the log transformed concentrations. The antibody response of anti-CS was assessed in the Coad Group and the RTS,S Group.

Time frame: At Day 0 and one month post Dose 3 of SB257049 (Month 4)

Number of Seropositive Subjects for Anti-CS Antibodies, Pre-vaccination and One Month Post Dose 3 of SB257049

A subject seropositive for anti-CS antibody was a subject whose antibody concentration was greater than or equal (≥) to the cut-off value (anti-CS ≥ 1.9 ELISA unit per milliliter \[EU/mL\]). Seropositivity was assessed in the Coad Group and the RTS,S Group.

Time frame: At Day 0 and one month post Dose 3 of SB257049 (Month 4)

Data from ClinicalTrials.gov

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Intramuscular injection of a yellow fever (YF) vaccine (1 dose)

Anti-hepatitis B (Anti-HBs) Antibody Concentrations, Pre-vaccination and One Month Post-Dose 3 of SB257049

Concentrations were expressed as GMCs with the following unit of measure: milli-international unit per milliliter (mIU/mL). The antibody response of anti-HB was assessed in the Coad Group and the RTS,S Group.

Time frame: At Day 0 and one month post Dose 3 of SB257049 (Month 4)

Number of Seroprotected Subjects for Anti-HB Antibodies, Pre-vaccination and One Month Post-Dose 3 of SB257049

Seroprotection rate for anti-HBs antibody was defined as the percentage of subjects with antibody concentrations greater than or equal to an established cut-off value (anti-HBs ≥ 10 milli-international unit per milliliter \[mIU/mL\]). Seroprotection was assessed in the Coad Group and the RTS,S Group.

Time frame: At Day 0 and one month post-Dose 3 of SB257049 (Month 4)

Number of Seroconverted Subjects for Anti-Measles (Anti-Me) Antibodies, One Month Post-vaccination With the Combined Measles and Rubella (MeRu) Vaccine

Seroconversion was defined as number of subjects with an anti-Measles antibodies pre-vaccination concentration below 150 mIU/mL and a post-vaccination concentration ≥150 mIU/mL. Seroconversion was assessed in the Coad group and the Control group.

Time frame: At one month post-vaccination with the combined measles and rubella (MeRu) vaccine (Month 4)

Anti-Me Antibody Concentrations, Pre-vaccination and One Month Post-vaccination With the Combined Measles and Rubella Vaccine

Concentrations were expressed in GMCs with the following unit of measure: milli-international unit per milliliter (mIU/mL). The antibody response of anti-Me was assessed in the Coad Group and the Control Group.

Time frame: At pre-vaccination (Month 3) and one month post-vaccination with combined measles and rubella vaccine (Month 4)

Number of Seropositive Subjects for Anti-Me Antibodies, Pre-vaccination and One Month Post-vaccination With the Combined Measles and Rubella Vaccine

A subject seropositive for anti-CS antibody was a subject whose antibody concentration was greater than or equal (≥) to the cut-off value (anti-Me ≥ 150 mIU/mL). Seropositivity was assessed in the Coad Group and the Control Group.

Time frame: At pre-vaccination (Month 3) and one month post-vaccination with the combined measles and rubella vaccine (Month 4)

Number of Seroconverted Subjects for Anti-Rubella (Anti-Ru) Antibodies, One Month Post-vaccination With the Combined Measles and Rubella Vaccine

Seroconversion was defined as number of subjects with an anti-Ru pre-vaccination concentration less than (\<) 4 IU/mL and a post-vaccination concentration ≥ 4 IU/mL. Seroconversion was assessed in the Coad group and Control group.

Time frame: At one month post-vaccination with combined measles and rubella vaccine (Month 4)

Anti-Ru Antibody Concentrations, Pre-vaccination and One Month Post-vaccination With the Combined Measles and Rubella Vaccine

Concentrations were expressed as GMCs with the following unit of measure: International unit per milliliter (IU/mL). The antibody response of anti-Ru was assessed in the Coad Group and Control Group.

Time frame: At pre-vaccination (Month 3) and one month post-vaccination with combined measles and rubella vaccine (Month 4)

Number of Seropositive Subjects for Anti-Ru Antibodies, Pre-vaccination and One Month Post-vaccination With the Combined Measles and Rubella Vaccine

A subject seropositive for anti-Ru antibody was a subject whose antibody concentration was greater than or equal (≥) to the cut-off value (anti-Ru ≥ 4 IU/mL). Seropositivity was assessed in the Coad Group and Control Group.

Time frame: At pre-vaccination (Month 3) and one month post-vaccination with combined measles and rubella vaccine (Month 4)

Number of Seropositive Subjects for Anti-Yellow Fever (Anti-YF) Antibodies, at One Month Post-vaccination With the YF Vaccine

Seropositivity was defined as number of subjects with anti-YF titers greater than or equal to (≥) 10 End point Dilution 50 (ED50). Seropositivity was assessed in the Coad group and Control group.

Time frame: At one month post-vaccination with the YF vaccine (Month 4)

Anti-YF Antibody Titers One Month Post-vaccination With the YF Vaccine

Titers were expressed as Geometric Mean Titres (GMTs). The antibody response of anti-YF was assessed in the Coad Group and Control Group.

Time frame: At one month post-vaccination with the YF vaccine (Month 4)

Number of Subjects With Any and Grade 3 Solicited Local Symptoms for Coad Group and RTS,S Group After Administration of Vitamin A and Study Vaccines at 6 Months of Age

Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = subject crying when limb was moved /spontaneously painful. Grade 3 redness/swelling = redness/swelling spreading beyond 20 millimeters (mm) at injection site.

Time frame: During a 7-day follow-up period (day of administration and 6 subsequent days) after administration of Vitamin A and SB257049 dose 1 (Day 0)

Number of Subjects With Any, Grade 3, Related, Grade 3 and Related Solicited General Symptoms for the Coad Group and RTS,S Group After Administration of Vitamin A and Study Vaccines at 6 Months of Age

Assessed solicited general symptoms were drowsiness, irritability/fussiness, loss of appetite, measles/rubella-like rash and fever. Any = occurrence of the symptom regardless of intensity grade. Any Fever = temperature greater than or equal to (≥) 37.5° C (axillary route). Grade 3 drowsiness= symptom that prevented normal activity; Grade 3 Irritability/Fussiness = Crying that couldn't be comforted/prevented normal activity; Grade 3 Loss of appetite = not eating at all; Grade 3 Measles /rubella rash = \>150 lesions; Grade 3 fever= temperature grater than (\>) 39°C; Related = symptom assessed by the investigator as causally related to the vaccination.

Time frame: During a 7-day follow-up period (day of administration and 6 subsequent days) after administration of Vitamin A and SB257049 dose 1 (Day 0)

Number of Subjects With Any, Grade 3, Related, Grade 3 and Related Solicited General Symptoms for the Control Group After Administration of Vitamin A at 6 Months of Age

Time frame: During a 7-day follow-up period (day of administration and 6 subsequent days) after administration of Vitamin A (Day 0)

Number of Subjects With Any and Grade 3 Solicited Local Symptoms for Coad Group and RTS,S Group After Dose of Study Vaccines Administered at 7.5 Months of Age

Time frame: During a 7-day follow-up period (day of administration and 6 subsequent days) after administration of SB257049 dose 2 (Month 1.5)

Number of Subjects With Any, Grade 3, Related, Grade 3 and Related Solicited General Symptoms for the Coad Group and RTS,S Group After Dose of Study Vaccines Administered at 7.5 Months of Age

Assessed solicited general symptoms were drowsiness, irritability/fussiness, loss of appetite, measles/rubella-like rash and fever. Any = occurrence of the symptom regardless of intensity grade. Any Fever = temperature greater than or equal to (≥) 37.5° C (axillary route). Grade 3 drowsiness= symptom that prevented normal activity; Grade 3 Irritability/Fussiness = Crying that couldn't be comforted/prevented normal activity; Grade 3 Loss of appetite = not eating at all; Grade 3 Measles /rubella rash = \>150 lesions; Grade 3 Fever= temperature grater than (\>) 39°C; Related = symptom assessed by the investigator as causally related to the vaccination.

Time frame: During a 7-day follow-up period (day of administration and 6 subsequent days) after administration of SB257049 dose 2 (Month 1.5)

Number of Subjects With Solicited General Symptoms for the Control Group, After Visit at 7.5 Months of Age

Solicited symptoms were not analyzed for the Control Group after visit at Month 1.5 because no vaccination was administered at that visit.

Time frame: After visit at Month 1.5

Number of Subjects With Any and Grade 3 Solicited Local Symptoms for All Groups, After Dose of Study Vaccines Administered at 9 Months of Age

Time frame: During a 14-day follow-up period (day of administration and 13 subsequent days) after administration of SB257049 dose 3 in Coad (and MeRu+YF) and RTS,S Groups and after MeRu+YF vaccines in Control Group (Month 3)

Number of Subjects With Any, Grade 3, Related, Grade 3 and Related Solicited General Symptoms for All Groups, After Dose of Study Vaccines Administered at 9 Months of Age

Assessed solicited general symptoms were drowsiness, irritability/fussiness, loss of appetite, measles/rubella-like rash and fever. Any = occurrence of the symptom regardless of intensity grade. Any Fever = temperature greater than or equal to (≥) 37.5° C (axillary route). Grade 3 drowsiness= symptom that prevented normal activity; Grade 3 Irritability/Fussiness = Crying that couldn't be comforted/prevented normal activity; Grade 3 Loss of appetite = not eating at all; Grade 3 Measles /rubella rash = \>150 lesions; Grade 3 Fever= temperature grater than (\>) 39°C; Related = symptom assessed by the investigator as causally related to the vaccination.

Number of Subjects With Unsolicited Adverse Events (AEs) for All Groups, After Administration of Vitamin A and Study Vaccines at 6 Months of Age

An unsolicited adverse event is any adverse event (i.e. any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with use of a medicinal product, whether or not considered related to the medicinal product) reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms.

Time frame: Within 30-day (Days 0-29) period after dose 1 of SB257049 and Vitamin A- Coad and RTS,S Groups, and 30-day period after Vitamin A administration - Control Group

Number of Subjects With Unsolicited AEs for the Coad Group and RTS,S Group, After Dose of Study Vaccines at 7.5 Months of Age

Time frame: Within 30-day (Day of vaccination and 29 subsequent days) period after dose 2 of SB257049 administered at Month 1.5 - Coad and RTS,S Groups

Number of Subjects With Unsolicited AEs for the Control Group, at Visit at 7.5 Months of Age

Time frame: During the 30-day period (Day of the visit and 29 subsequent days) after the visit at Month 1.5

Number of Subjects With Unsolicited AEs for All Study Groups, After Dose of Study Vaccines Administered at 9 Months of Age

Time frame: Within 42-day (vaccination day and 41 subsequent days) period after dose 3 of SB257049 in Coad (+MeRu+YF vaccines) and RTS,S groups, and 42-day period after MeRU+YF vaccination in Control group, administered at Month 3

Number of Subjects With Serious Adverse Events (SAEs): All, Fatal and Related, for All Study Groups, Following Each Administration at Day 0, Month1.5 and Month 3

SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.

Time frame: During 30-Days period (Day of vaccination and 29 subsequent days) following each administration at Day 0, Month1.5 and Month 3 for Coad and RTS,S groups and at Day 0 and Month 3 in the Control Group.

Number of Subjects With Any SAEs for All Study Groups, From Day 0 Until Month 4.5

SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.

Time frame: From Day 0 up to Month 4.5

Number of Subjects With Potential Immune-Mediated Disease (pIMDs) for All Study Groups From Day 0 Until Month 4.5

pIMDs are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurological disorders of interest which may or may not have an autoimmune etiology.

Time frame: From Day 0 up to Month 4.5

Number of Subjects With Meningitis for All Study Groups From Day 0 Until Month 4.5

Meningitis is an adverse event of specific interest (AESI). An AESI is defined as an AE including autoimmune diseases and other mediated inflammatory disorders. It was assessed by the investigator as specific to the treatment administration.

Time frame: From Day 0 up to Month 4.5

Number of Subjects With Seizures for All Groups, Post-vaccination for Vaccines Administered at 6, 7.5 or 9 Months of Age

Seizure is an adverse event of specific interest (AESI). An AESI is defined as an AE including autoimmune diseases and other mediated inflammatory disorders. It is assessed by the investigator as specific to the treatment administration.

Time frame: Within 30 days post-vaccination for vaccine doses administered at Day 0, Month 1.5 or 42 days post-vaccination (doses given at Month 3 [Coad & Control Groups] or Month 4.5 [RTS,S Group]) vaccination period from Day 0 until Month 4.5

Number of Subjects With Generalized Convulsive Seizure for All Study Groups, After Vaccines Administered at Day 0 and Month 1.5 (Coad and RTS,S Groups) and After Vaccines Administered at Month 3 (All Groups)

Generalized convulsive seizure is an adverse event of specific interest (AESI). An AESI is defined as an AE including autoimmune diseases and other mediated inflammatory disorders. It is assessed by the investigator as specific to the treatment administration.

Time frame: Within 7 days after vaccines administered at Day 0 and Month 1.5 for the Coad and RTS,S groups and 14 days after vaccines administered at Month 3 for all groups

Number of Subjects With Unsolicited AEs for the Coad Group and RTS,S Group, After the Booster Dose of Study Vaccine Administered at 27 Months of Age

Time frame: During the 30-day period (Day of vaccination and 29 subsequent days) after booster dose administered at Month 21

Number of Subjects With Unsolicited AEs for the Control Group, After Dose of Study Vaccine Administered at 10.5, 11.5, 12.5 and 30 Months of Age

Time frame: During the 30-Day Period (Day of vaccination and 29 subsequent days) after primary doses of study vaccine administered at Month 4.5, Month 5.5, Month 6.5 (across primary doses), and after booster dose administered at Month 24

Number of Subjects With SAEs for All Study Groups From Day 0 Until Study End

SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.

Time frame: During the entire study period (From Day 0 until Month 33 for Coad and RTS,S Groups and Month 36 for the Control Group)

Number of Subjects With pIMDs for All Study Groups From Day 0 Until Study End

pIMDs are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurological disorders of interest which may or may not have an autoimmune etiology.

Time frame: During the entire study period (From Day 0 until Month 33 for Coad and RTS,S Groups and Month 36 for the Control Group)

Number of Subjects With Meningitis for All Study Groups From Day 0 Until Study End

Meningitis is an adverse event of specific interest (AESI). An AESI is defined as an AE including autoimmune diseases and other mediated inflammatory disorders. It is assessed by the investigator as specific to the treatment administration.

Time frame: During the entire study period (From Day 0 until Month 33 for Coad and RTS,S Groups and Month 36 for the Control Group)

Number of Subjects With Seizures for Vaccines Doses Administered at 6, 7.5, 27 Months of Age for Coad and RTS,S Groups; and at 9 Months of Age for Coad Group or 10.5 Months of Age for RTS,S Group

Seizure is an adverse event of specific interest (AESI). An AESI is defined as an AE including autoimmune diseases and other mediated inflammatory disorders. It was assessed by the investigator as specific to the treatment administration. Results are presented across all doses for Coad and RTS,S Groups.

Time frame: Within 30 days post-vaccination (doses given at Day 0, Month 1.5, Month 21) & 42 days post-vaccination (dose given at Month 3 [Coad Group] or Month 4.5 [RTS,S Group])

Number of Subjects With Seizures for Vaccines Doses Administered at 10.5, 11.5, 12.5, 30 and 9 Months of Age for Control Group

Time frame: Within 30 days post-vaccination (doses given at Month 4.5, Month 5.5, Month 6.5, Month 24) & 42 days post-vaccination (dose given at Month 3)