Malaria remains a major cause of pediatric deaths and morbidity in Africa. An affordable malaria vaccine, R21, is being deployed in Uganda and other African countries with high malaria transmission, but efficacy is incomplete and wanes rapidly, and R21 does not provide protection until infants complete the primary vaccination series, or ~9 months of age. The goal of this study is to see whether combining R21 vaccination with two novel perennial malaria chemoprevention regimens can enhance protection against malaria compared with R21 alone. This study will take place at Masafu General Hospital (MGH) in Busia District, a rural area in Southeastern Uganda bordering Lake Victoria.

Inclusion Criteria:

• Residency in Busia District, Uganda
• Provision of informed consent by the parent/guardian for her child
• Agreement to come to the study clinic for any febrile episode or other illness and avoid, where possible, medications given outside the study protocol

Exclusion Criteria:

• Intention of permanently moving outside Busia district during the study period
• Active medical problem requiring inpatient evaluation or chronic medical condition requiring frequent medical attention at the time of screening
• Evidence of sickle cell disease (Hemoglobin SS genotype)
• Biological mother known to be HIV positive

Clinical data will be recorded on case report forms, a study database will be updated monthly, and available (blinded) data will be shared with project investigators. Monthly reports will be generated for all investigators, including data summaries, number and type of assays performed, quality control checks, etc. To facilitate interpretation of the data, study protocols, data dictionaries, and documentation related to any of the data described above will be made publicly available. The same is true for any additional metadata used in the analyses resulting in publications including data on interventions. For parasite genomic and host immunologic data deposited in public repositories (e.g. GEO, IMMPORT), project, study, sample, experimental, and file level metadata will be provided using templates provided by GEO and SRA data repositories or IMMPORT.

All scientific data generated from this project will be made available as soon as possible, and no later than the time of publication or the end of the funding period, whichever comes first.