This is a Phase 2, randomized, double-blind, controlled study designed to evaluate the safety, tolerability, immunogenicity, vaccine efficacy, and functional activity of Pfs230D1-CRM197 conjugate vaccine with R21 nanoparticle vaccine formulated on Matrix-M1. Participants (9-50 years of age) will be drawn from Bancoumana and Donéguébougou, Mali and the surrounding areas.

Participants aged 9 - 17 years in the immunobridging cohort (n=540) will be randomized to one of the study arms ( 2:2:1:1) to receive 10μg R21 alone in 50μg of Matrix-M1, control vaccine (RABIVAX-S), or 6μg Pfs230D1-CRM197 with 10μg R21 in 50μg of Matrix-M1 as either a bedside mixture or a single-vial coformulation.

Participants in the main cohort who are aged 9-17 years will be randomized to one of the study arms (1:1:1) to receive 10μg R21 alone in 50μg of Matrix-M1, control vaccine (RABIVAX-S), or 6μg Pfs230D1-CRM197 with 10 μg R21 in 50μg of Matrix-M1 single-vial coformulation. Enrollment of participants aged 9-17 years in the main cohort will be done after DSMB reviews the 7-day safety data post dose 1 from the immunobridging cohort.

Participants in the main cohort who are aged 18 - 50 years will be randomized to one of the study arms (1:1:1) to receive either 10μg R21 alone in 50μg of Matrix-M1, control vaccine (RABIVAX-S), or 6μg Pfs230D1-CRM197 with 10μg R21 in 50μg of Matrix-M1 single-vial coformulation.

Enrollment of adult participants aged 18 -50 years in the main cohort (n=300) will be done from the start of the study and will be independent of enrollment into of the pediatric cohort (9-17 years).

All vaccines will be administered as an intramuscular (IM) injection on a 0, 28, 56 day schedule with an option for additional follow-up for a subsequent malaria transmission season with or without a fourth dose approximately 52 weeks after the third vaccine dose (based on year 1 results).

Initial enrollment will be staggered over time for safety, but all participants will be analyzed together for primary, secondary, and exploratory endpoints.

A total 1200 participants will be randomized into the study as below:

Immunobridging cohort (Participants 9-17 years of age, n = 540) (2:2:1:1 randomization)

• Arm 1a (n = 180): 10µg of R21 with 50µg Matrix-M1 on study day 0, 28, 56 +/- 392
• Arm 2a (n = 180): Control vaccine (rabies vaccine) on study day 0, 28, 56 +/- 392
• Arm 3a (n = 90): 6µg of Pfs230D1-CRM197 + 10µg of R21 with 50µg Matrix-M1 single vial coformulation on study day 0, 28, 56 +/- 392
• Arm 4a (n = 90): 6µg of Pfs230D1-CRM197 + 10µg of R21 with 50µg Matrix-M1 bedside mix on study day 0, 28, 56 +/- 392

Main cohort:

Participants 9-17 years of age (n = 360) (1:1:1 randomization):

• Arm 1b (n=120): 10µg of R21 with 50µg Matrix-M1 on study day 0, 28, 56 +/- 392
• Arm 2b (n = 120): Control vaccine (rabies vaccine) on study day 0, 28, 56 +/- 392
• Arm 3b (n = 120): 6µg of Pfs230D1-CRM197 + 10µg of R21 with 50µg Matrix-M1 single vial coformulation on study day 0, 28, 56 +/- 392

Participants 18-50 years of age (n = 300) (1:1:1 randomization):

• Arm 1c (n=100): 10µg of R21 with 50µg Matrix-M1 on study day 0, 28, 56 +/- 392
• Arm 2c (n = 100): Control vaccine (rabies vaccine) on study day 0, 28, 56 +/- 392
• Arm 3c (n = 100): 6µg of Pfs230D1-CRM197 + 10µg of R21 with 50µg Matrix-M1 single vial coformulation on study day 0, 28, 56 +/- 392

Inclusion Criteria:

1. Age:>/= 9 years old and </= 50 years old.

2. Provides written informed consent if >/=18 years of age.

3. Provides written informed consent of parent/guardian if <18 years of age, with additional participant written assent obtained from children > 12 years of age.

4. Known resident or long-term resident (more than 1 year) of trial site or surrounding villages.

5. Available for the duration of the trial.

6. Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process.

7. In good general health and without clinically significant medical history in the opinion of the investigator.

8. Permission for long term storage of blood samples.

   • Note: If a participant withdraws consent or at the time of study completion or end of participation wishes to withdraw permission for long term storage of blood samples, this can be requested, and sample destruction will be documented.

9. Females of reproductive potential aged 12 years and above who have attained menarche and are sexually active must be willing to use reliable contraception from 21 days prior to Study Day 1 and 21 days prior to Study Day 392 (booster dose) and until 1 month after the last vaccination in primary series and after booster dose.

   • A reliable method of birth control includes one of the following:

     • Confirmed pharmacologic contraceptives (parenteral) delivery.
     • Intrauterine or implantable device.
     • Barrier methods.

EXCLUSION CRITERIA:

1. Pregnant and breastfeeding females. Pregnant, as determined by a positive urine or serum beta human choriogonadotropin (βhCG) test.

   NOTE: Pregnancy is also a criterion for discontinuation of any further vaccine dosing

2. Menstruating females less than 12 years of age. (In order to avoid cultural implications of further assessing pregnancy potential i.e. sexual activity in this age group).

   NOTE: If a female less than 12 years of age starts menarche while on study it will not be exclusionary for them to continue participation, but will undergo pregnancy testing prior to each vaccination.

3. Behavioral, cognitive, or psychiatric disease that in the opinion of the investigator affects the ability of the participant to understand and comply with the study protocol at a level appropriate for the participant's age.

4. Evidence of clinically significant neurologic, cardiac, pulmonary, hepatic, endocrine, rheumatologic, autoimmune, hematological, oncologic, or renal disease by history, physical examination, and/or laboratory studies including urinalysis.

5. Current or planned participation in an investigational product study until the time period of the last required study visit under this protocol.

6. Medical, occupational, or family problems as a result of alcohol or illicit drug use during the past 12 months.

7. History of a severe allergic reaction or anaphylaxis.

8. Known:

   • Severe asthma, defined as asthma that is unstable or required emergent care, urgent care, hospitalization, or intubation during the past 2 years, or that has required the use of oral or parenteral corticosteroids at any time during the past 2 years.
   • Autoimmune or antibody-mediated disease including but not limited to: systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sjögren's syndrome, or autoimmune thrombocytopenia.
   • Immunodeficiency.
   • Seizure disorder (exception: history of simple febrile seizures).
   • Asplenia or functional asplenia.
   • Use of chronic (≥14 days) oral or intravenous (IV) corticosteroids (excluding topical or nasal) at immunosuppressive doses (i.e., prednisone >10 mg/day) or immunosuppressive drugs within 30 days of enrollment.
   • Hypersensitivity reaction to rabies vaccine in the past.

9. Receipt of:

   • Live vaccine within 4 weeks prior to enrollment or a killed vaccine within 2 weeks prior to enrollment.
   • Immunoglobulins and/or blood products within the past 3 months.
   • Any malaria vaccine in the past.
   • Any investigational product in the last 6 months

10. Any other condition that in the opinion of the investigator might jeopardize the safety or rights of a participant participating in the trial, interfere with the evaluation of the study objectives, or might render the participant unable to comply with the protocol.

The study will be conducted with a double blind. Because there is some variation in vaccine volumes, the unblinded pharmacy team will cover all syringes (after vaccine preparation) with opaque tape to maintain blinding. The participants, the clinical staff, laboratory staff and the study team involved in study endpoint assessments will be blinded to study treatment allocation. An additional layer to be implemented to promote blinding is that designated clinical staff who administer the vaccinations will only participate in study product administration and will remain separate from the team of blinded investigators who conduct all subsequent follow-up study assessments. The pharmacy team at the study site where vaccine preparation and administration is taking place will be unblinded, and they are responsible for maintaining security of study treatment assignments.