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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.