This is an observational case-control study to assess the effectiveness of the R21/Matrix-M vaccine against severe malaria, clinical malaria (in high transmission perennial areas), and to assess if the R21 vaccine recipients are at an increased risk of deaths (all-cause). Clinical malaria, severe malaria and death (all-cause) cases will be enrolled in study. For each case (severe or death) 4 controls matched for age and neighborhood will be enrolled whereas for clinical malaria case, 1 matched control will be enrolled.

1. Proportion of vaccinated and unvaccinated children amongst Severe Malaria Cases caused by P. falciparum.
2. Proportion of vaccinated and unvaccinated children amongst Clinical Malaria Cases in high-transmission perennial areas caused by P. falciparum.
3. Proportion of vaccinated and unvaccinated children in cases of death (all cause)
4. Exploratory effectiveness endpoint: Proportion of vaccinated and unvaccinated children in the hospitalized clinical and severe malaria cases.

The study will be conducted at multiple centers with the appropriate research infrastructure to carry out safety and/or effectiveness research across different countries where the R21/Matrix-M vaccine is (or will be) approved and deployed for vaccination with subsequent population uptake.

The cases will be enrolled from hospitals/clinics and the matched controls will be recruited from the community by visiting the neighborhood.

Children eligible for receiving R21/Matrix-M vaccine, residing in the geographical area where the vaccine has been deployed will be considered as either cases or controls if they meet the eligibility criteria. All participants will be screened for eligibility after obtaining informed written consent from parents/legal guardians/ caregivers.

Surveillance and detection of cases: Cases qualifying the case definitions of clinical or severe malaria, cases will be recruited from the hospitals, clinics or the sub-sites.

For deaths, cases will be recruited from the hospital or the community. Cause of death will be ascertained from hospital or available medical records as well as discussions with family or healthcare professionals who may have been involved.

Identification of controls: Four controls for each case will be recruited by study physician or field staff from community for severe malaria and death cases. For clinical malaria cases in high-transmission perennial areas, case: control ratio will be 1:1. Controls will be matched for age and neighborhood. Controls should be residing in the same neighborhood as the respective case, but not from the same house. Living controls will be enrolled against the death cases. Vaccination status will be confirmed from the vaccination/immunization cards, hospital/clinic records, home based registers, or national immunization database. History from the parents/ guardians/ caregivers will be considered in case of non-vaccination. Field staff may visit the homes of controls and (if required) cases for collection of the required data.

Inclusion Criteria:

For Cases- A male or female child eligible to have received R21/Matrix-M Vaccine based on age. 2 Parent/legal guardian/ caregiver of the child willing to provide the written informed consent for their child's participation in the study.

3 Parent/legal guardian/ caregiver willing to comply with the study requirements and share or allow access to the data regarding the vaccination status and medical records with the study personnel.

4 Resident of the R21/Matrix-M vaccine implementation area and brought to the study hospital /clinic or sub-site with clinical complaints. 5 Child meeting the respective case definition (Severe Malaria, Clinical Malaria or Death due to any cause).

For Controls- A male or female child eligible to have received R21/Matrix-M Vaccine based on age. The matched control should have a date of birth within 60 days of that of the case.

2. Parent/legal guardian/ caregiver of the child willing to provide the informed consent for their child's participation in the study.

3. Parent/ legal guardian/ caregiver willing to comply with the study requirements and share or allow access to the data regarding the vaccination status and medical records with the study personnel 4. Resident of the R21/Matrix-M vaccine implementation area and who would have sought treatment at the same hospital if they had developed symptoms. Resident will be defined as child and/or child's parents/ guardian/caregiver eating and sleeping in a household in the location for most days of the week from past 6 months. The matched control should be residing in the same neighborhood as the respective case, but not from the same household.

Exclusion Criteria:

For Cases-

1. Parent/legal guardian/ caregiver not consenting to let the child participate or not permitting to access the data related to vaccination or other medical records.
2. Child not meeting the respective case definition (Severe Malaria, Clinical Malaria or Death due to any cause).
3. Received one or more doses of RTS,S/AS01 vaccine in the past.

For Controls-

1. Parent/legal guardian/ caregiver not consenting to let the child participate or not permitting to access the data related to vaccination or other medical records.
2. Child meeting any of the case definitions (Severe Malaria, Clinical Malaria).
3. Child having history suggestive of clinical malaria in past 30 days (applicable for clinical malaria and severe malaria case-control studies only).
4. Received one or more doses of RTS,S/AS01 vaccine/s in the past.

The study population will comprise children aged 5 months and above who live in R21-Malaria vaccine implementation areas in Uganda, Burkina Faso, Nigeria, Cote d'ivoire and who were eligible to have received R21-malaria vaccine based on their date of birth and age