This is a Phase 1, individually randomized, double-blind, dose escalating study designed to evaluate the safety, tolerability, and immunogenicity of Pfs230D1 conjugate vaccines, R21 nanoparticle vaccine, or their combination conjugate vaccines, formulated on Matrix-M in healthy African adults aged 18 to 50 years.

240 healthy adults (18-50 years of age) will be enrolled from Mali, Africa in a staggered manner by increasing Pfs230D1 dosing.

Participants will be randomized by cohorts as (detailed below) to one of the study arms to receive single antigen (Pfs230D1 or R21) or combination (Pfs230D1 + R21) with 50 μg of Matrix-M, all administered as an IM injection on a 1, 29, 57-day schedule. Participants will be followed for safety for 6 months post last dose with continued assessment for clinical malaria cases and immunogenicity up until 12 months post last dose.

Cohort 1 (n=120); 1:1:1:1:1:1

• Arm 1a (n=20): 6μg Pfs230D1-CRM197 + 5μg of R21 in 50μg Matrix-M
• Arm 1b (n=20): 6μg Pfs230D1-CRM197 + 10μg of R21 in 50μg Matrix-M
• Arm 1c (n=20): 12μg Pfs230D1-CRM197 + 5μg of R21 in 50μg Matrix-M
• Arm 1d (n=20): 12μg Pfs230D1-CRM197 + 10μg of R21 in 50μg Matrix-M
• Arm 1e (n=20): 5μg of R21 in 50μg Matrix-M
• Arm 1f (n=20): 10μg of R21 in 50μg Matrix-M

Followed by Cohort 2 (n=80); 1:1:1:1

• Arm 2a (n=20): 20μg Pfs230D1-CRM197 + 5μg of R21 in 50μg Matrix-M
• Arm 2b (n=20): 20μg Pfs230D1-CRM197 + 10μg of R21 in 50μg Matrix-M
• Arm 2c (n=20): 20μg Pfs230D1-CRM197 in 50μg Matrix-M
• Arm 2d (n=20): 20μg Pfs230D1-EPA + 5μg of R21 in 50μg Matrix-M

Followed by Cohort 3 (n=40); 1:1

• Arm 3a (n=20): 40μg Pfs230D1-CRM197 + 5μg of R21 in 50μg Matrix-M
• Arm 3b (n=20): 40μg Pfs230D1-CRM197 + 10μg of R21 in 50μg Matrix-M

Inclusion Criteria:

1. Age: 18 to 50 years old.
2. Provides written informed consent.
3. Able to understand and comply with planned study procedures and be available for the duration of the trial.
4. In good general health and without clinically significant medical history in the opinion of the investigator.
5. Females of childbearing potential must be willing to use reliable contraception from 21 days prior to Study Day 1 and until 1 month after the last vaccination.

Exclusion Criteria:

1. Pregnant and breastfeeding females.
2. Hemoglobin, white blood cell (WBC), absolute neutrophil count, or platelet levels outside the local laboratory-defined reference ranges.
3. Alanine transaminase (ALT) or creatinine (Cr) level above the local laboratory-defined upper limit of reference range.
4. Infected with HIV, hepatitis B, hepatitis C.
5. Evidence of clinically significant neurologic, cardiac, pulmonary, hepatic, endocrine, rheumatologic, autoimmune, hematological, oncologic, or renal disease by history, physical examination, and/or laboratory studies.
6. Current or planned participation in an investigational product study until the time period of the last required study visit under this protocol.
7. Medical, occupational, or family problems as a result of alcohol or illicit drug use during the past 12 months.
8. History of a severe allergic reaction or anaphylaxis.
9. Known: Severe asthma, Autoimmune or antibody-mediated disease, Immunodeficiency, Seizure disorder, Asplenia or functional asplenia, Use of chronic oral or intravenous corticosteroids (excluding topical or nasal), Sickle cell disease.
10. Any other condition that in the opinion of the investigator might jeopardize the safety or rights of a subject participating in the trial, interfere with the evaluation of the study objectives, or might render the subject unable to comply with the protocol.