Inclusion Criteria:
1. Age ≥1 to ≤12 months at enrollment.
2. Born at ≥37 weeks gestation.
3. Parent and/or guardian able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process.
4. In good general health and without clinically significant medical history.
5. Parent and/or guardian able to provide informed consent.
6. Willing to have blood samples and data stored for future research.
7. Resides in or near Kalifabougou, Faladje, or Torodo, Mali, and available for the duration of the study.
Exclusion Criteria:
1. Body weight \<3.5 kg.
2. Behavioral, cognitive, or psychiatric disease in the parent and/or guardian that in the opinion of the investigator affects the ability of the parent and/or guardian to understand and comply with the study protocol.
3. Any fever (≥ 37.5°C, regardless of route) or acute illness within 7 days prior to randomization.
4. Clinically significant congenital anomaly or documented or suspected serious medical illness (e.g., history of epilepsy), serious congenital anomaly, or immediate life-threatening condition in the infant that may interfere with the ability to complete study requirements, as judged by the examining clinician.
5. Prior history of a suspected or actual acute life-threatening event.
6. Receipt of any blood products, monoclonal or polyclonal antibody/immunoglobulin (for example, hepatitis B immune globulin, intravenous immunoglobulin) or anticipated use during the study.
7. Any acute or chronic illnesses known in the mother during her pregnancy.
8. Parental study comprehension examination score of \<80% correct or per investigator discretion.
9. Hemoglobin, white blood cell (WBC), absolute neutrophil, or platelet count outside the local laboratory-defined limits of normal. (Participants may be included at the investigator's discretion for "not clinically significant" values.)
10. Alanine aminotransferase (ALT) or creatinine (Cr) level above the local laboratory-defined upper limit of normal. (Participants may be included at the investigator's discretion for "not clinically significant" values.)
11. Mother and/or infant infected with HIV.
12. Sickle cell disease by testing. (Note: Known sickle cell trait is NOT exclusionary.)
13. Evidence of clinically significant neurologic, cardiac, pulmonary, hepatic, endocrine, rheumatologic, autoimmune, hematological, oncologic, or renal disease by history, physical examination, and/or laboratory studies.
14. Receipt of any investigational product within the past 30 days.
15. Participation or planned participation in an interventional trial with an investigational product until the last required protocol visit. (Note: Past, current, or planned participation in observational studies is NOT exclusionary.)
16. History of a severe allergic reaction or anaphylaxis.
17. Salivary gland disorder diagnosed by a doctor (e.g., parotitis, sialadenitis, sialolithiasis, salivary gland tumors).
18. Pre-existing autoimmune or antibody-mediated diseases including but not limited to systemic lupus erythematosus or autoimmune thrombocytopenia.
19. Known immunodeficiency syndrome.
20. Known asplenia or functional asplenia.
21. Use of chronic (≥14 days) oral or IV corticosteroids (excluding topical or nasal) at immunosuppressive doses (i.e., prednisone \>10 mg/day) or immunosuppressive drugs within 30 days of day 0.
22. Previous receipt of the R21/Matrix-MTM vaccine.
23. Previous receipt of an investigational malaria vaccine or monoclonal antibody.
24. Clinical signs of malnutrition.
25. Other condition(s) that, in the opinion of the investigator, would jeopardize the safety or rights of an individual participating in the trial, interfere with the evaluation of the study objectives, or render the participant unable to comply with the protocol.
