A randomized double blind, placebo-controlled study to assess the safety, tolerability, immunogenicity, and protective efficacy of 1, 6, 29-day PfSPZ-LARC2 Vaccine regimen given at a dose of 2 x10^5 PfSPZ or placebo in healthy WOCBP, who are on pregnancy prevention during vaccination, but report plans to become pregnant in the near future.

Participants will be randomized into two arms. Arm 1: (n= 150) will receive 3 doses of PfSPZ-LARC2 Vaccine (2x10^5 PfSPZ) via direct venous inoculation (DVI) at 1, 6, 29 days.

Arm 2: (n= 150) will receive 3 doses of normal saline (placebo) injection via DVI at 1, 6, 29 days.

All volunteers will receive antimalarial treatment with artemether/lumefantrine (AL) ~2 to 4 weeks prior to 1st (study day -14 to -28) and ~2 weeks prior to 3rd injection (study day 44). Participants will be monitored for safety, tolerability, immunogenicity, and malaria infection during the follow-up period. Participants will also be monitored closely for pregnancy as well post 3rd injection through the entire planned study duration (2 years post dose 1). If pregnant, women will be followed during the course of their pregnancy and for at least 1 year post-delivery (as well as their offspring) for safety and malaria infection. Malaria infections in participants and their offspring will be classified as asymptomatic or symptomatic (clinical cases).

This study will enroll healthy Malian adult, non-pregnant WOCBP, who agree to be on birth control during the immunization period, between 18 and 38 years of age to participate in a randomized, double blind, placebo-controlled study to assess the safety, immunogenicity and protective efficacy of PfSPZ-LARC2 Vaccine during two years' of follow up, including at least two malaria transmission seasons. Participants will be immunized with a 3-dose series of 2x10^5 PfSPZ of PfSPZ-LARC2 Vaccine or normal saline (NS); placebo) at 1, 6, 29 days. Vaccinated subjects and controls will then be assessed for malaria infection during the ensuing two malaria transmission seasons and subsequent dry seasons, including following prospectively women who become pregnant during follow up and their offspring. Volunteers will be randomized into two arms at a 1:1 ratio to receive PfSPZ-LARC2 Vaccine (N=150) versus NS control (N=150).

If a woman becomes pregnant during follow-up, she will continue to be followed through the course of her pregnancy and for at least one year after delivery. Subsequent offspring born from pregnancies from this time period will also be followed for one year post birth.

Two study arms will be enrolled in this study, with two PfSPZ-LARC2 vaccination arms and one NS control arm.

Arm 1: (N=150) will receive 3 doses of PfSPZ-LARC2 Vaccine (2x10^5) via direct venous inoculation (DVI) at 1, 6, 29 days.

Arm 2: (N=150) will receive 3 doses of placebo NS injection via DVI at 1, 6, 29 days.

All injections will be administered by DVI. All participants will receive antimalarial treatment with artemether/lumefantrine (AL) approximately 2-4 weeks prior to the 1st and 3rd injections. Post 3rd injection, participants will be followed through the malaria transmission (rainy) season, approximately 6 months, and then the ensuing dry season for an additional 6 months. Participants will be monitored for safety, immunogenicity, and protective efficacy (malaria infection) during the follow-up period.

During the second year of follow-up, which will start immediately at the conclusion of the first year of follow-up, participants will be followed through the malaria transmission (rainy) season, approximately 6 months, and then the second dry season for an additional 6 months. Participants will be monitored for safety (unsolicited AEs), immunogenicity, and protective efficacy (malaria infection) during the second year of follow-up. No vaccine boost is planned at the end of the first year.

For any women who becomes pregnant during the trial, follow up will continue through the end of pregnancy, and any viable newborns/infants and their mothers will be followed through at least the first year of life.

If a woman becomes pregnant and has a pregnancy outcome and/or post-partum follow-up that completes prior to the end of Year 2 scheduled non-pregnant follow-up (~July/August 2026) she can resume being followed with non-pregnant women until the end of Year 2. A woman may be followed for multiple pregnancies during the course of her follow-up.

Safety monitoring: All solicited adverse events (AEs) will be recorded through Day 7 after each injection and graded for severity. Injection site reactions will also be assessed until Day 7 after injection (PfSPZ-LARC2 Vaccine or normal saline) or until resolved. After the periods specified above only unsolicited AEs, Serious AEs (SAEs), unanticipated problems (UPs), and new onset of chronic illness (NOCIs) will be recorded.

Any laboratory abnormalities (other than those specified as safety labs in the protocol as defined by the values in the toxicity table) will be reported as AEs if they require intervention. In pregnant women and neonates, safety monitoring involves assessing incidence of maternal obstetric outcomes (miscarriage/stillbirth, intrauterine growth restriction, hypertensive diseases in pregnancy, preterm delivery) and neonatal outcomes (neonatal death, low birth weight, small for gestational age, major malformations, and microcephaly).

Inclusion Criteria:

1. Females of childbearing potential aged ≥ 18 and ≤ 38 years
2. Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process
3. In good general health and without clinically significant medical history
4. Willing to have blood samples stored for future research
5. Available for the duration of the study
6. Must be willing to use reliable contraception (defined as: pharmacologic contraceptives [parental delivery] or pre-existing intrauterine or implantable device) from 21 days prior to first vaccination (study day 1) to 28 days after last vaccination (study day 57)
7. Willingness to undergo HIV testing
8. Report being interested in becoming pregnant within the next 1 year

Exclusion Criteria:

1. Pregnancy at the time of enrollment/vaccination, as determined by a positive urine or serum human chorionic gonadotropin (β-hCG) test
2. Biologically unable to become pregnant secondary to: surgical sterilization, premature ovarian insufficiency (defined as no menses for ≥12 months without an alternative medical cause)
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
4. Hemoglobin (Hgb), WBC, absolute neutrophils, and platelets outside the local laboratorydefined limits of normal and ≥ Grade 2 (participants may be included at the investigator's discretion for 'not clinically significant' abnormal values)
5. Alanine transaminase (ALT) or creatinine (Cr) level above the local laboratory-defined upper limit of normal and ≥ Grade 2 (participants may be included at the investigator's discretion for 'not clinically significant' abnormal values)
6. Infected with human immunodeficiency virus (HIV)
7. Known or documented sickle cell disease by history (Note: known sickle cell trait is NOT exclusionary)
8. Clinically significant abnormal electrocardiogram (ECG) such as abnormal QTc.
9. 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
10. History of receiving any investigational product within the past 30 days
11. Participation or planned participation in a clinical trial with an investigational product prior to completion of the follow-up visit 28 days following last vaccination OR planned participation in an investigational vaccine study until the last required protocol visit
12. Medical, occupational, or family problems as a result of alcohol or illicit drug use during the past 12 months
13. History of a severe allergic reaction (Grade 2 or higher or per PI discretion) or anaphylaxis
14. Severe asthma (defined as asthma that is unstable or required emergent care, urgent care, hospitalization, or intubation during the past two years, or that has required the use of oral or parenteral corticosteroids at any time during the past two years)
15. Pre-existing autoimmune or antibody-mediated diseases including but not limited to: systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sjögren's syndrome, or autoimmune thrombocytopenia
16. Known immunodeficiency syndrome
17. Known seizure disorder or history of seizures (exclusion: simple febrile seizure during childhood) or history of migraine headaches
18. Laboratory evidence of hepatitis B or C
19. Known asplenia or functional asplenia
20. Use of chronic (≥14 days) oral or IV corticosteroids (excluding topical or nasal) at immunosuppressive doses (i.e., prednisone ≥20 mg/day) or immunosuppressive drugs within 30 days of vaccination
21. Receipt of a live vaccine within the past four weeks or a killed vaccine within the past two weeks prior to Vaccination #1 and every subsequent vaccination day
22. Receipt of immunoglobulins and/or blood products within the past six months
23. Previous receipt of an investigational malaria vaccine in the last ten years
24. Known allergies or other contraindications against use of artemether/lumefantrine
25. Other condition(s) that, in the opinion of the investigator, would jeopardize the safety or rights of a participant participating in the trial, interfere with the evaluation of the study objectives, or would render the participant unable to comply with the protocol

During the study, the list linking randomization numbers to study product (PfSPZ-LARC2 Vaccine or control) will be made available only to the study statistician and associated team members, pharmacy team/syringe preparers (at the start of the study), independent safety monitor (if needed to review), and SMC chair (if needed for closed session unblinded review). On vaccination days, the vaccines associated with each randomization number will be obtained from the pharmacist.