A Study to Evaluate the Safety, Effectiveness and Impact of the GlaxoSmithKline Biologicals' Malaria Vaccine- RTS, S/AS01E in Young Children in Sub-Saharan Africa

Study Overview
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Brief Summary
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The RTS, S/AS01E vaccine has been developed for routine immunization of children living in malaria- endemic countries of sub-Saharan Africa. This study is intended as a post-implementation safety study (after vaccine implementation), with the primary objective to evaluate the safety of vaccine after its administration. In addition to the primary objective, the study will also evaluate the impact and effectiveness of the vaccine.

Detailed Description
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Active surveillance refers to prospective cohort monitoring of the AESI and other diseases during study follow-up visits at the community level as well outpatient and inpatient visits. Enhanced hospitalisation surveillance (EHS) is defined as case detection during hospitalisation through monitoring of medical records and registries for the study participants not enrolled in active surveillance. The study targets enrolling at least 45,000 children in active surveillance (AS), including 22,500 in the exposed clusters and 22,500 in the unexposed clusters for evaluation of the vaccine safety, effectiveness and impact. In the exposed clusters are included a minimum of 20,250 children vaccinated with RTS,S/AS01E for evaluation of the vaccine safety, and a minimum of 2,250 unvaccinated children for evaluation of effectiveness and impact assuming that 80% of the 22,500 study participants will receive three doses of RTS,S/AS01E, 10% will receive one or two doses and 10% will not have any dose. The Malaria Vaccine Implementation Programme (MVIP) is considering implementing the malaria vaccine in unexposed clusters as from 2023. This decision will directly impact the temporal (before/after) and concurrent (exposed versus unexposed clusters) comparisons. Based on this, the EHS recruitment will be stopped as from 01 January 2023 in sites that were not involved in the NCT02374450 study and study conclusion will be conducted in a timely manner for already enrolled subjects in those sites (EHS will stop in all sites in Malawi, Siaya and Nyando sites in Kenya and unexposed sites in Ghana).

Official Title
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A Prospective Study to Evaluate the Safety, Effectiveness and Impact of the RTS, S/AS01E Vaccine in Young Children in Sub-Saharan Africa

Conditions
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Malaria Vaccines, Malaria

Intervention / Treatment
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* Procedure: Whole blood sample


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Study participants' parent(s)/ LAR(s) who, in the opinion of the investigator, can and will comply with the requirements of the protocol. Written informed consent provided from either the parent(s) or LAR of the study participant. Study participant living in the HDSS or equivalent surveillance system area. For enrolment in the active surveillance - DTP group: children must be aged <18 months, identified at any administration of DTP/HepB/Hib (or at hospitalisation before 3rd dose of DTP/HepB/Hib in case of hospitalisation and vaccinated with at least one dose of DTP/HepB/Hib). (This group will include children from exposed and unexposed clusters.) OR For enrolment in the active surveillance - Catch-up group: children must be aged < 18 months, received at least one dose of DTP/HepB/Hib vaccine, whose age corresponds to the age after the 3rd dose of DTP/HepB/Hib vaccine and identified at administration of first dose of RTS,S/AS01E vaccine (This group will include children from exposed clusters only). OR For enrolment in the enhanced hospitalisation surveillance: children must be aged at least 6 weeks and < 5 years at the time of hospitalisation at any time during the study. (This group will include children from exposed and unexposed clusters.) Parent(s)/LARs of children meeting all eligibility criteria for active surveillance, not having completed the visits for DTP/HepB/Hib, and first identified during hospitalisation, must first be proposed enrolment in active surveillance (if recruitment is not completed). Children already enrolled in active surveillance will have hospitalisation monitored as part of the procedures related to the active surveillance and can therefore not be enrolled in enhanced hospitalisation surveillance. Exclusion Criteria: • Child in care

Ages Eligible for Study
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Maximum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active surveillance (DTP sub-Group)<br>Children enrolled in the active surveillance (AS), <18 months of age who were identified at any administration of DTP/HepB/Hib (usually given at 6, 10 and 14 weeks of age) or at hospitalisation before administration of 3rd dose of DTP/HepB/Hib and vaccinated with at least one dose of DTP/HepB/Hib; including both RTS,S/AS01E vaccinated and unvaccinated children (from exposed or unexposed clusters), living in the HDSS area are eligible for enrolment in the DTP sub-group of active surveillance. | Procedure: Whole blood sample<br>* Whole blood samples will be collected from all enrolled children hospitalised and suspected of having an AESI or meningitis.<br>|
| Active surveillance (Catch-up sub-Group)<br>Children enrolled in the active surveillance (AS), <18 months of age who were identified at 1st RTS,S/AS01E dose administration and who either received all DTP/HepB/Hib doses before study start or received at least one dose of DTP/HepB/Hib and are older than the age corresponding to the 3rd DTP/HepB/Hib dose at study start; including only RTS,S/AS01E vaccinated children from exposed clusters who could not be recruited at the time of DTP/HepB/Hib administration because the study had not yet started, living in the HDSS area are eligible for enrolment in the Catch-up sub-group of active surveillance. | Procedure: Whole blood sample<br>* Whole blood samples will be collected from all enrolled children hospitalised and suspected of having an AESI or meningitis.<br>|
| Enhanced Hospitalisation Surveillance Group<br>Children at least 6 weeks and <5 years of age, within the study areas in both exposed and unexposed clusters, not already enrolled in the active surveillance (because parents/ Legally Acceptable Representative (LARs) declined enrolment in active surveillance or because recruitment had been completed) or not eligible for active surveillance at the time of hospitalisation, living in the HDSS area are eligible for enrolment in the Enhanced Hospital Surveillance (EHS) group. | Procedure: Whole blood sample<br>* Whole blood samples will be collected from all enrolled children hospitalised and suspected of having an AESI or meningitis.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence rates of adverse events of special interest (AESI) | AESI are predefined list of adverse events that have historically been associated with vaccines other than RTS,S/AS01E, or may hypothetically be associated with RTS,S/AS01E due to the fact that this vaccine has components which are new compared to current widely used vaccines. The incidence rate will be calculated by dividing the number of study participants reporting at least one event over the follow-up period by the total person-time. The person-time for an event of interest will be calculated as the time between the reference date (date of first RTS,S/AS01E vaccination for the vaccinated study participants and virtual vaccination corresponding to the week before first visit for the unvaccinated study participants) and the end of the at-risk period or the earliest of the followings: Date of first diagnosis of event of interest, Date of end of study period, Date when child reaches 5 years, Date of last contact or Date of death. | During the entire study period (From Day 0 up to Month 62) | 
| Incidence rates of aetiology-confirmed meningitis | Incidence rate of aetiology confirmed meningitis is analyzed with an at-risk period of 12 months. At the site level, a suspected meningitis case based on clinical symptoms and/or signs is defined as: A child with sudden onset of fever (> 38.0°C rectal or 37.5°C axillary) and one or more of the following signs: neck stiffness, altered consciousness with no other alternative diagnosis, or other meningeal sign such as bulging fontanelle in children under one year of age. If a Cerebrospinal fluid (CSF) sample is available and any known aetiologic agent (bacterial or not) has been identified, it is defined as an aetiology confirmed meningitis. The incidence rate will be calculated by dividing the number of study participants reporting at least one event over the follow-up period by the total person-time. | During the entire study period (From Day 0 up to Month 62) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence rate of probable meningitis (final classification) | At the site level, a suspected probable meningitis case based on clinical symptoms and/or signs is defined by the below characteristics: CSF sample is available, no bacterial agent has been identified in the CSF, but some abnormalities in the CSF have been detected (such as turbid macroscopic aspect, positive Gram, positive antigen test, pleiocytosis, abnormal glucose or protein levels) or positive blood culture to a bacterial agent. The incidence rate will be calculated by dividing the number of study participants reporting at least one event over the follow-up period by the total person-time. | During the entire study period (From Day 0 up to Month 62) | 
| Incidence rates of clinically suspected meningitis (final classification) | At the site level, a clinically suspected meningitis case based on clinical symptoms and/or signs is defined by the below characteristics: If a CSF sample is available and all examinations are normal at first line laboratory level, or if no CSF sample is available and no alternative diagnosis. The incidence rate will be calculated by dividing the number of study participants reporting at least one event over the follow-up period by the total person-time. | During the entire study period (From Day 0 up to Month 62) | 
| Number of meningitis cases identified at site level (first line laboratory) | At the site level, a suspected meningitis case based on clinical symptoms and/or signs is defined as: A child with sudden onset of fever (> 38.0°C rectal or 37.5°C axillary) and one or more of the following signs: neck stiffness, altered consciousness with no other alternative diagnosis, or other meningeal sign such as bulging fontanelle in children under one year of age. | During the entire study period (From Day 0 up to Month 62) | 
| Incidence rates of cerebral malaria (diagnosed by Rapid Diagnostic Test [RDT] and/or microscopy) | Cerebral malaria is defined as: Severe Plasmodium falciparum malaria with impaired consciousness (Glasgow coma score < 11 in children ≥ 2 years of age or Blantyre coma score < 3 in children < 2 years of age); 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). Suspected malaria cases routinely tested using RDT will have a blood smear for reading by microscopy in parallel, in order to measure sensitivity and specificity. This is done for all suspected cases presenting at primary health care facilities one day per month during the first year of the study. The incidence rate will be calculated by dividing the number of study participants reporting at least one event over the follow-up period by the total person-time. | During the entire study period (From Day 0 up to Month 62) | 
| Incidence rates of cases of hospitalisations (including those attributed to an AESI, other AE, meningitis or malaria). | Hospitalisation is defined as: A study participant requiring overnight stay in hospital/inpatient facility. Hospitalisation for malaria (including P. falciparum) is defined as: A hospitalized study participant with malaria (including P. falciparum malaria) and for whom malaria is the primary cause of hospitalisation. The incidence rate will be calculated by dividing the number of study participants reporting at least one event over the follow-up period by the total person-time. | During the study period (From Day 0 up to Month 62) | 
| Incidence rates of febrile convulsions 7-days following each dose of RTS,S/AS01E vaccine | Febrile convulsion is defined as: Generalized seizures with measured fever ≥ 37.5 °C (axillary) or reported history of fever. The risk of febrile convulsions is assessed using SCSS (self-controlled case-series) analysis. The frequency (with 95% CI) of febrile convulsion within 7 days post vaccination is reported in all study participants from the exposed clusters. The incidence rate will be calculated by dividing the number of study participants reporting at least one event over the follow-up period by the total person-time. | During the 7-day (Days 0-6) period following each dose of RTS,S/AS01E vaccine | 
| Incidence rates of febrile convulsions 1-month following each dose of RTS,S/AS01E vaccine | Febrile convulsion is defined as: Generalized seizures with measured fever ≥ 37.5 °C (axillary) or reported history of fever. The risk of febrile convulsions is assessed using SCSS (self-controlled case-series) analysis. The frequency (with 95% CI) of febrile convulsion within 30 days post vaccination is reported in all study participants from the exposed clusters. The incidence rate will be calculated by dividing the number of study participants reporting at least one event over the follow-up period by the total person-time. | During the 1-month period (Days 0-29) following each dose of RTS,S/AS01E | 
| Incidence rates of abscess at injection site used as surveillance quality indicator | Abscess at injection used as positive control site is defined as a localised material collection in subcutaneous tissue, fat, fascia/muscle at immunisation site confirmed in spontaneous/ surgical material drainage from the mass/by presence of palpable fluctuance. The abscess is classified as: infectious aetiology, sterile abscess or not determined. Abscesses of infectious aetiology may be accompanied by fever/regional lymphadenopathy. Sterile abscesses are not accompanied by fever/region lymphadenopathy. The incidence rate will be calculated by dividing the number of study participants reporting at least one event over the follow-up period by the total person-time. | During the 7-day period (Days 0-6) following each vaccination | 
| Incidence rates of cases with foot positional deformation used as surveillance quality indicators | Foot positional deformation as a birth defect used as a negative control is defined as: metatarsus adductus characterised by medial deviation of forefoot while hindfoot remains in normal position, forming a C shape/concavity of the medial aspect of foot or positional calcaneovalgus feet characterised by foot hyperdorsiflexion with forefoot abduction which often results in forefoot resting on the anterior surface of lower leg or clubfoot characterised by foot being excessively plantar flexed with forefoot swung medially and sole facing inward. The incidence rate will be calculated by dividing the number of study participants reporting at least one event over the follow-up period by the total person-time. | During the entire study period (From Day 0 up to month 62) | 
| Incidence rates of other AEs leading to hospitalisation | AEs leading to hospitalisation are all reported cases by the physician not due to an AESI or meningitis, or to any malaria or to severe malaria (including cerebral malaria). The incidence rate will be calculated by dividing the number of study participants reporting at least one event over the follow-up period by the total person-time. | During the entire study period (From Day 0 up to month 62) | 
| Incidence rates of malaria episodes diagnosed by RDT and/or microscopy | Any malaria is uncomplicated malaria (i.e. Plasmodium parasitaemia >0 detected by microscopy and/or RDT, presence of fever (≥37.5°C) reported by parent(s)/LARs or recorded at time of presentation and without severity signs or vital organ dysfunction) and severe malaria (SM) (i.e. P. falciparum parasitaemia >0 detected by microscopy and/or RDT, one/more of the following: impaired consciousness, prostration, multiple convulsions, acidosis, hypoglycemia, severe malarial anemia, renal impairment, jaundice, pulmonary oedema, significant bleeding, shock, hyperparasitemia). Severe vivax malaria is SM but with no parasite density thresholds. Cerebral malaria is SM with impaired consciousness with the exclusion of other treatable causes of coma. The incidence rate will be calculated by dividing the number of subjects reporting at least one event over the follow-up period by the total person-time. | During the entire study period (From Day 0 up to Month 62) | 
| Incidence rates of anaemia cases at hospital entry among hospitalised children | This outcome measure is assessed for children included only in active surveillance. Anaemia is defined as: All anaemia: haemoglobin <11 (grams per decilitre) g/dL. Severe anaemia: haemoglobin <7g/dL. The incidence rate will be calculated by dividing the number of study participants reporting at least one event over the follow-up period by the total person-time. | During the entire study period (From Day 0 up to Month 62) | 
| Incidence rates of hospitalisation cases | Hospitalisation is defined as: All causes and hospitalisations for any malaria (including P. falciparum malaria), severe malaria (including P. falciparum malaria) and cerebral malaria. A hospitalised study participant with malaria (including P. falciparum malaria) and for whom malaria is the primary cause of hospitalisation. This outcome measure is assessed for children included only in active surveillance. The incidence rate will be calculated by dividing the number of study participants reporting at least one event over the follow-up period by the total person-time. | During the entire study period (From Day 0 up to month 62) | 
| Mortality rates | Death is defined as: Malaria attributed death (including P. falciparum malaria) defined as a fatality for which malaria (including P. falciparum malaria) is listed as a contributing cause of death, based on either verbal autopsy using the INDEPTH Standard Verbal Autopsy Questionnaire for children, who died at home or medical judgment/medical records for children who died at a primary health care facility or hospital. Deaths attributed to an AE defined as a fatality for which an AE is listed as a contributing cause of death, based on either verbal autopsy using the INDEPTH Standard Verbal Autopsy Questionnaire for children, who died at home or medical judgment/medical records for children who died at a primary health care facility or hospital. The incidence rate (mortality rate) will be calculated by dividing the number of study participants reporting at least one event over the follow-up period by the total person-time. | During the entire study period (From Day 0 up to month 62) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Malaria, Plasmodium falciparum, Vaccine effectiveness, Sub-Saharan Africa, Active surveillance