Efficacy, Safety and Immunogenicity Study of GSK Biologicals' Candidate Malaria Vaccine (SB257049) Evaluating Schedules With or Without Fractional Doses, Early Dose 4 and Yearly Doses, in Children 5-17 Months of Age

Efficacy, Safety and Immunogenicity Study of GSK Biologicals' Candidate Malaria Vaccine (SB257049) Evaluating Schedules With or With-out Fractional Doses, Early Dose 4 and Yearly Doses, in Children 5-17 Months of Age

The study intends to establish proof of concept for a fractional dose schedule under conditions of natural exposure in children 5-17 months old at first vaccination. The study also aims to establish the role of third dose spacing in a fractional dose schedule, describe the effect of an earlier full fourth dose at Month 14 and describe the effect of multiple fractional or full yearly doses.

Study Overview

• Status: Completed
• Conditions: Malaria
• Intervention / Treatment: Biological: RTS,S/AS01E (Full dose); Biological: RTS,S/AS01E (1/5th dose); Biological: Rabies vaccine

Detailed Description

The current study intends to establish proof of concept (POC) for a fractional dose schedule under conditions of natural exposure. The study will be conducted in children 5-17 months old at first vaccination living in areas of mid to high malaria transmission, in line with the age group recommended by the World Health Organization (WHO) for the implementation of the RTS,S/AS01E vaccine. Results from this study will be critical in informing future possibilities for the development of vaccine-based strategies which, in combination with other interventions, may contribute to the malaria elimination agenda.

• Study Type: Interventional
• Enrollment (Actual): 1500
• Phase: Phase 2

Contacts and Locations

Study Locations

• Ghana
  • Kumasi, Ghana
    • GSK Investigational Site
• Kenya
  • Kisumu, Kenya, 40100
    • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 months to 1 year (Child)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Participants' parent(s)/LAR(s) who, in the opinion of the investigator, can and will comply with the requirements of the protocol (e.g. return for follow-up visits).
• Signed or thumb-printed and witnessed informed consent obtained from the parent(s)/LAR(s) of the participant prior to performance of any study specific procedure. Where parent(s)/LAR(s) are illiterate, the consent form will be countersigned by an independent witness.
• A male or female between, and including, five and 17 months of age at the time of the first vaccination.
• Healthy participants as established by medical history and clinical examination before entering into the study.
• Previously received three documented doses of diphtheria, tetanus, pertussis, hepatitis B vaccine (DTPHepB), and at least three doses of oral polio vaccine.

Exclusion Criteria:

• Child in care.
• Use of a drug or vaccine that is not approved for that indication (by one of the following regulatory authorities: Food and Drug Administration [FDA; USA] or European Union member state or WHO [with respect to prequalification]) other than the study vaccines during the period starting 30 days before the first dose of study vaccines (Day -29 to Day 0), or planned use during the study period.
• Any medical condition that in the judgment of the investigator would make intramuscular injection unsafe.
• Chronic administration (defined as more than 14 days in total) of immunosuppressants or other immune-modifying drugs during the period starting six months prior to the first vaccine dose. For corticosteroids, this will mean prednisone (0.5 mg/kg/day (for pediatric participants) or equivalent. Inhaled and topical steroids are allowed.
• Planned administration/administration of a vaccine not foreseen by the study protocol in the period starting seven days before each dose and ending seven days after each dose of vaccine administration.
• Concurrently participating in another clinical study, at any time during the study period, in which the participant has been or will be exposed to an investigational or a non-investigational vaccine/product (pharmaceutical product or device).
• Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination (no laboratory testing required).
• Family history of congenital or hereditary immunodeficiency.
• History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccines.
• History of anaphylaxis post-vaccination.
• History of any, or documented, serious adverse reaction to rabies vaccination.
• Contraindication to rabies vaccination (Rabipur is contraindicated in participants with history of a severe hypersensitivity to any of the ingredients in the vaccine. Note that the vaccine contains polygeline and residues of chicken proteins, and may contain traces of neomycin, chlortetracycline and amphotericin B).
• Major congenital defects.
• Serious chronic illness.
• Children with a past history of a neurological disorder or atypical febrile seizure (a febrile seizure is atypical if it meets one of the following criteria: not associated with fever; lasts > 5 minutes; focal (not generalized); followed by transient or persistent neurological abnormality; occurs in a child < 6 months of age).
• Acute disease and/or fever at the time of enrolment. Fever is defined as temperature ≥ 37.5°C/99.5°F for oral, axillary or tympanic route, or ≥ 38.0°C/100.4°F for rectal route.

Participants with a minor illness (such as mild diarrhea, mild upper respiratory infection) without fever may, be enrolled at the discretion of the investigator.

• Administration of immunoglobulins and/or any blood products during the period starting three months before the first dose of study vaccine or planned administration during the study period.
• Moderate or severe malnutrition at screening defined as weight for age or weight for height Z-score < -2.
• Hemoglobin concentration < 8 g/dl at screening.
• Same sex twins (to avoid misidentification).
• Maternal death.
• Prior receipt of an investigational malaria vaccine.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: R012-20 Group; Participants will receive a full dose of RTS,S/AS01E at Month 0, Month 1, Month 2 and at Month 20.	Biological: RTS,S/AS01E (Full dose); Participants will receive intramuscular injection of RTS,S/AS01E (full dose: 0.5 ml).
Experimental: R012-14-mD Group; Participants will receive a full dose of RTS,S/AS01E at Month 0, Month 1, Month 2 and yearly full doses at Month 14, Month 26 and Month 38.	Biological: RTS,S/AS01E (Full dose); Participants will receive intramuscular injection of RTS,S/AS01E (full dose: 0.5 ml).
Experimental: Fx012-14-mFxD Group; Participants will receive a full dose of RTS,S/AS01E at Month 0 and Month 1, and RTS,S/AS01E 1/5th dose at Month 2 and yearly fractional doses at Month 14, Month 26 and Month 38.	Biological: RTS,S/AS01E (Full dose); Participants will receive intramuscular injection of RTS,S/AS01E (full dose: 0.5 ml).; Biological: RTS,S/AS01E (1/5th dose); Participants will receive intramuscular injection of RTS,S/AS01E (1/5th dose: 0.1 ml).
Experimental: Fx017-mFxD Group; Participants will receive a full dose of RTS,S/AS01E at Month 0 and Month 1, and RTS,S/AS01E 1/5th dose at Month 7 and yearly fractional doses at Month 20 and Month 32.	Biological: RTS,S/AS01E (Full dose); Participants will receive intramuscular injection of RTS,S/AS01E (full dose: 0.5 ml).; Biological: RTS,S/AS01E (1/5th dose); Participants will receive intramuscular injection of RTS,S/AS01E (1/5th dose: 0.1 ml).
Experimental: Control Group; Participants will receive rabies vaccine at Month 0, Month 1 and Month 2.	Biological: Rabies vaccine; Participants will receive intramuscular injection of rabies vaccine (0.1 ml).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Clinical Malaria Meeting the Primary Case Definition	The primary case definition is: Plasmodium (P.) falciparum asexual parasitemia greater than (>)5000 parasites/microliters (μl) and presence of fever (axillary temperature greater than or equal to [≥]37.5°C) at the time of presentation and occurring in a child who is unwell and brought for treatment to a healthcare facility. The incidence is expressed as a person year rate for each group (n/T), representing the number of events (n) reported over the risk period, which was counted in days and expressed as person years at risk (T). The objective of this endpoint was to demonstrate the superiority of a Fx012-14-mFxD Group compared to a standard schedule of RTS,S/AS01E with three full doses (R012-20+R012-14 Group) in terms of vaccine efficacy. This analysis was reported for the R012-20+R012-14 Group (Pooled group) because the interventional strategy (1st dose at Month 0, 2nd dose at Month 1, 3rd dose at Month 2) was the same for both the R012-20 group and the R012-14 group until Month 14.	From Month 2.5 to Month 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Clinical Malaria Meeting the Primary and Secondary Case Definitions of the Fx012-14-mFxD Group Versus the R012-20 Group	The primary case definition is P. falciparum asexual parasitemia > 5000 μl and presence of fever (axillary temperature ≥ 37.5°C) at the time of presentation and occurring in a child who is unwell and brought for treatment to a healthcare facility. The secondary case definition is P. falciparum asexual parasitemia > 0 and presence of fever (axillary temperature ≥ 37.5°C) at the time of presentation or history of fever within 24 hours of presentation and occurring in a child who is unwell and brought for treatment to a healthcare facility. The incidence of clinical malaria for primary and secondary case definition is expressed as n/T, representing the n reported over the risk period, which was counted in days and expressed as T.	From Month 0 to Month 50
Incidence of Clinical Malaria Meeting the Primary and Secondary Case Definitions of the Fx012-14-mFxD Group Versus the R012-14-mD Group	The primary case definition is P. falciparum asexual parasitemia > 5000 μl and presence of fever (axillary temperature ≥ 37.5°C) at the time of presentation and occurring in a child who is unwell and brought for treatment to a healthcare facility. The secondary case definition is P. falciparum asexual parasitemia > 0 and presence of fever (axillary temperature ≥ 37.5°C) at the time of presentation or history of fever within 24 hours of presentation and occurring in a child who is unwell and brought for treatment to a healthcare facility. The incidence of clinical malaria for primary and secondary case definition is expressed as n/T, representing the n reported over the risk period, which was counted in days and expressed as T.	From Month 0 to Month 50
The Prevalence of P. Falciparum Infections Defined by Positive Blood Slide at Each Cross-sectional Survey	Prevalence of P. falciparum infections of each RTS,S/AS01E schedule at cross-sectional visits. As specified in the statistical analysis plan, a graphical presentation of the prevalence over time was analyzed for this outcome measure and only the percentage values were reported to depict the prevalence of P. falciparum infections.	Monthly from Month 0 to Month 20 and every 3 months thereafter until Study End (Month 50)
Incidence of P. Falciparum Infections Defined by Positive Blood Slide	The incidence of P. falciparum infections is expressed as n/T, representing the n reported over the risk period, which was counted in days and expressed as T. Assessment of vaccine efficacy (VE) against first or only episodes of incident P. falciparum infections defined by positive blood slide over the entire study period (Month 0 to Month 50) was not done after the Month 21 Interim analysis since it was assumed that almost all children would have already contracted malaria at least once.	Month 0 to Month 14
Number of Seropositive Participants for Anti-circumsporozoite (Anti-CS) Antibodies	A seropositive participant is defined as a participant with antibody concentrations ≥ 0.5 ELISA units per milliliter (EU/mL).	Before Dose 1, one month post-Dose 2, before and one month post-Dose 3, before and one month after Dose 4, before and one month after each yearly dose and at Study End (Month 50)
Number of Seropositive Participants for Anti-hepatitis B (Anti-HB) Antibodies	A seropositive participant is defined as a participant with antibody concentrations ≥ 10 milli-international units per milliliter (mIU/mL).	Before Dose 1, one month post-Dose 2, before and one month post-Dose 3, before and one month after Dose 4, before and one month after each yearly dose and at Study End (Month 50)
Antibody Concentrations for Anti-CS	The antibody concentrations were calculated as geometric mean concentrations (GMCs) and expressed as EU/mL.	Before Dose 1, one month post-Dose 2, before and one month post-Dose 3, before and one month after Dose 4, before and one month after each yearly dose and at Study End (Month 50)
Antibody Concentrations for Anti-HB	The antibody concentrations were calculated as GMCs and expressed as mlU/mL.	Before Dose 1, one month post-Dose 2, before and one month post-Dose 3, before and one month after Dose 4, before and one month after each yearly dose and at Study End (Month 50)
Number of Participants With Any, Fatal and Related Serious Adverse Events (SAEs)	SAEs assessed included any untoward medical occurrences that resulted in death, were life-threatening, required hospitalization or prolongation of hospitalization or resulted in disability/incapacity. Related SAEs= Any SAE related to investigational vaccine or related to study participation or to a GSK concomitant medication/vaccine as assessed by the investigator. Fatal SAEs= Any SAEs leading to death.	From Day 0 to Month 50
Number of Participants With Any Adverse Events (AEs) and SAEs Leading to Withdrawal From Further Vaccination	An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. SAEs include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.	From Day 0 to Month 50
Number of Participants With Cerebral Malaria and Severe Malaria	Cerebral malaria is defined as Severe P. falciparum malaria with coma (Blantyre coma score less than [<] 3); and if malaria with seizure: coma persisting for > 30 min after the seizure. Other treatable causes of coma should be excluded before diagnosing cerebral malaria (e.g. hypoglycaemia, bacterial meningitis). Severe malaria is defined as P. falciparum parasitemia > 0 detected by microscopy and/or rapid diagnostic test (RDT) and one or more of the following, occurring in the absence of an identified alternative cause: Impaired consciousness, Prostration, Multiple convulsions, Acidosis, Hypoglycemia, Severe malarial anemia, Renal impairment, Jaundice, Pulmonary edema, Significant bleeding: including recurrent or prolonged bleeding from the nose, gums or venipuncture sites, hematemesis or melaena, Shock, Hyperparasitemia.	From Day 0 to Month 50
Number of Participants With Potential Immune Mediated Diseases (pIMDs)	Potential immune-mediated diseases (pIMDs) are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune etiology.	From Day 0 to Month 50
Number of Participants With Meningitis	Meningitis is an adverse event of specific interest (AESI). An AESI is defined as an AE including autoimmune diseases and other mediated inflammatory disorders.	From Day 0 to Month 50
Number of Participants With Seizures	Seizure is an adverse event of specific interest (AESI). An AESI is defined as an AE including autoimmune diseases and other mediated inflammatory disorders.	During the 30-day (Day 0 to Day 29) follow-up period after any dose of study vaccine
Number of Participants With Generalized Convulsive Seizures	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.	During the 7-day (Day 0 to Day 6) follow-up period after any dose of study vaccine
Number of Participants With Any Unsolicited AEs	An unsolicited AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with use of a medicinal product, whether or not considered related to the medicinal product.	During the 30-day (Day 0 to Day 29) follow-up period following the 1st 3 doses and post dose 4, 5 and 6 of study vaccine
Number of Participants With Grade 4 Hematology and Biochemical Toxicities Before Dose 3	The assessed parameters (alanine aminotransferase [ALT], creatinine, haemoglobin, white blood cells [WBC], platelets) were summarized according to DAIDS, 2004 (Division of AIDS). Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, life-threatening or disabling. Data are presented for those participants who experienced Grade 4 toxicities. Grade 4 hematological toxicities included ALT: > 10.0 x ULN (Upper limit of normal), creatine: > 6.0 x ULN or requires dialysis, WBC: < 1.0 x 103 per microliter, platelets: < 25 x 103/μl and clinical signs of bleeding, and hemoglobin: < 5.0 grams/deciliter and clinical signs of heart failure.	Before Dose 3 (at Month 2)
Number of Participants With Grade 4 Hematology and Biochemical Toxicities at 7 Days Post-Dose 3	The assessed parameters (ALT, creatinine, haemoglobin, WBC, platelets) were summarized according to DAIDS, 2004 (Division of AIDS). Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, life-threatening or disabling. Data are presented for those participants who experienced Grade 4 toxicities. Grade 4 hematological toxicities included ALT: > 10.0 x ULN, creatine: > 6.0 x ULN or requires dialysis, WBC: < 1.0 x 103 per microliter, platelets: < 25 x 103/μl and clinical signs of bleeding, and hemoglobin: < 5.0 grams/deciliter and clinical signs of heart failure.	At 7 days post-Dose 3
Number of Participants With Grade 4 Hematology and Biochemical Toxicities at 30 Days Post-Dose 3	The assessed parameters (ALT, creatinine, haemoglobin, WBC, platelets) were summarized according to DAIDS, 2004 (Division of AIDS). Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, life-threatening or disabling. Data are presented for those participants who experienced Grade 4 toxicities. Grade 4 hematological toxicities included ALT: > 10.0 x ULN, creatine: > 6.0 x ULN or requires dialysis, WBC: < 1.0 x 103 per microliter, platelets: < 25 x 103/μl and clinical signs of bleeding, and hemoglobin: < 5.0 grams/deciliter and clinical signs of heart failure.	At 30 days post-Dose 3
Number of Participants With Any Solicited Local Symptoms	Assessed solicited local AEs are: redness, pain and swelling. Any = occurrence of the adverse event regardless of intensity grade. Any redness and swelling = adverse event reported with a surface diameter > 0 millimeters.	During the 4-day (Day 0 to Day 3) follow-up period after Dose 3, Dose 4, Dose 5 and Dose 6 of study vaccination
Number of Participants With Any Solicited General Symptoms	Assessed solicited general AEs are: drowsiness, irritability/fussiness and loss of appetite. Any = occurrence of the adverse event regardless of intensity grade or relation to study vaccination.	During the 4-day (Day 0 to Day 3) follow-up period after Dose 3, Dose 4, Dose 5 and Dose 6 of study vaccination

Collaborators and Investigators

• Sponsor: GlaxoSmithKline
• Investigators: Study Director: GSK Clinical Trials, GlaxoSmithKline

Publications and helpful links

General Publications

• Samuels AM, Ansong D, Kariuki SK, Adjei S, Bollaerts A, Ockenhouse C, Westercamp N, Lee CK, Schuerman L, Bii DK, Osei-Tutu L, Oneko M, Lievens M, Attobrah Sarfo MA, Atieno C, Morelle D, Bakari A, Sang T, Jongert E, Kotoh-Mortty MF, Otieno K, Roman F, Buabeng PBY, Ntiamoah Y, Ofori-Anyinam O, Agbenyega T; RTS,S study group. Efficacy of RTS,S/AS01E malaria vaccine administered according to different full, fractional, and delayed third or early fourth dose regimens in children aged 5-17 months in Ghana and Kenya: an open-label, phase 2b, randomised controlled trial. Lancet Infect Dis. 2022 Sep;22(9):1329-1342. doi: 10.1016/S1473-3099(22)00273-0. Epub 2022 Jun 23. Erratum In: Lancet Infect Dis. 2022 Sep 9;:
• Westercamp N, Osei-Tutu L, Schuerman L, Kariuki SK, Bollaerts A, Lee CK, Samuels AM, Ockenhouse C, Bii DK, Adjei S, Oneko M, Lievens M, Attobrah Sarfo MA, Atieno C, Bakari A, Sang T, Kotoh-Mortty MF, Otieno K, Roman F, Buabeng PBY, Ntiamoah Y, Ansong D, Agbenyega T, Ofori-Anyinam O. Could less be more? Accounting for fractional-dose regimens and different number of vaccine doses when measuring the impact of the RTS, S/AS01E malaria vaccine. J Infect Dis. 2024 Mar 4:jiae075. doi: 10.1093/infdis/jiae075. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Actual): September 28, 2017
• Primary Completion (Actual): November 4, 2019
• Study Completion (Actual): November 14, 2022

Study Registration Dates

• First Submitted: September 7, 2017
• First Submitted That Met QC Criteria: September 7, 2017
• First Posted (Actual): September 8, 2017

Study Record Updates

• Last Update Posted (Actual): May 21, 2024
• Last Update Submitted That Met QC Criteria: May 16, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: safety; Malaria; infants; immunogenicity; malaria vaccine; RTS,S/AS01; falciparum, efficacy
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Mosquito-Borne Diseases; Malaria
• Other Study ID Numbers: 204889; 2016-000290-20 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
• IPD Sharing Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints, key secondary endpoints and safety data of the study
• IPD Sharing Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No