This will be a double-blind, individually randomised trial, to assess the safety, tolerability, immunogenicity, and protective efficacy of two and three doses of the R21/Matrix-M1 malaria vaccine or placebo given at 4 week intervals in healthy women of childbearing potential (WOCBP), who are on pregnancy prevention during vaccination, but report plans to become pregnant in the near future.

Participants will be randomised in Year 1 into three groups in a 1:1:1 ratio:

• Arm 1 (n=110): will receive three doses of R21/Matrix-M1 malaria vaccine at months 0, 1 and 2.
• Arm 2 (n=110): will receive normal saline (placebo) at month 0 and two doses of R21/Matrix-M1 malaria vaccine at months 1 and 2.
• Arm 3 (n=110): will receive three of doses normal saline (placebo) at months 0, 1 and 2. In Year 2: Non-pregnant participants in arms 1 and 2 will be randomised in a 1:1 ratio to receive a booster dose of R21/Matrix-M1 malaria vaccine or placebo at the beginning of the malaria transmission season. Participants in the control group (arm 3) will receive normal saline (placebo).

Initial follow-up will be for two years after dose three, with an efficacy analysis at 6, 12, 18 and 24 months after dose 3.

Participants will be monitored for safety, tolerability, immunogenicity, and malaria infection during the follow-up period.

Participants will also be monitored for pregnancy over 12 months post primary and booster vaccination and those who become pregnant will be followed during their pregnancy and for 1 year post-delivery (as well as their offspring) for safety and malaria infection

The design will be a double blind, placebo-controlled study. Malian adult WOCBP between 18 and 35 years of age who consent to participate will be randomised to receive R21/Matrix-M1vaccine or normal saline to assess the safety, immunogenicity and protective efficacy of R21/Matrix-M1 Vaccine.

Randomisation and Study Arms Consenting participants who have satisfied all the eligibility criteria and completed the baseline assessment will be individually randomised within the study groups using an electronic randomisation system into three arms in a 1:1:1 ratio.

• Arm 1: Participants will receive three doses of R21/Matrix-M1 malaria vaccine at months 0, 1 and 2.
• Arm 2: will receive normal saline (placebo) at month 0 and two doses of R21/Matrix-M1 malaria vaccine at month 1 and 2.
• Arm 3: will receive three doses of normal saline (placebo) at months 0, 1 and 2.

Participants will be assessed for safety, immunogenicity and efficacy for 12 months. After 12 months non-pregnant participants in arms 1 and 2, will be randomised in a 1:1 ratio; half in each of these two arms will receive a booster dose of R21/Matrix-M1 vaccine and half will receive a placebo injection (normal saline) and be followed up for an additional 12 months.

All injections will be administered intramuscularly in the deltoid region, preferably of the non-dominant arm. Post third 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.

For any women who become pregnant during the two-year period (first year and second year) of the trial, follow up will continue through the end of pregnancy, and any viable newborns/infants and their mothers will be followed through the first year of life.

Inclusion Criteria:

• Healthy females of childbearing potential aged ≥ 18 and ≤ 35 years
• Able and willing (in the Investigator's opinion) to comply with all study requirements.
• Agreement to release medical and other information concerning contra-indications for participation in the study, and to be attended by a study clinician for physical examination and any other clinical investigations.
• Provide written informed consent.
• Available for the duration of the study
• 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 study day 1 to 28 days after third vaccination and 21 days prior to the booster vaccination to 28 days after the booster vaccination.
• Report being interested in becoming pregnant within the next 1 year.

Exclusion Criteria:

• Pregnancy at the time of enrollment, as determined by a positive urine or serum human chorionic gonadotropin (β-hCG) test.
• Biologically unable to become pregnant secondary to: surgical sterilization, premature ovarian insufficiency (defined as no menses for ≥12 months without an alternative medical cause).
• 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.
• Hemoglobin (Hgb), WBC, absolute neutrophils, and platelets outside the local laboratory-defined limits of normal and ≥ Grade 2 (participants may be included at the investigator's discretion for 'not clinically significant' abnormal values).
• 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).
• Infected with human immunodeficiency virus (HIV).
• Known or documented sickle cell disease by history or lab test at screening (Note: known sickle cell trait is NOT exclusionary).
• 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.
• Participation in another research study involving receipt of an investigational product in the 30 days preceding enrolment or during the trial follow up period.
• Medical, occupational, or family problems as a result of alcohol or illicit drug use during the past 12 months.
• History of allergic disease or reactions likely to be exacerbated by any component of the vaccine.
• History of hereditary angioedema acquired angioedema, or idiopathic angioedema.
• History of a severe allergic reaction (Grade 2 or higher or per PI discretion) or anaphylaxis following administration of a vaccine.
• 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).
• 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.

• Any confirmed or suspected immunosuppressive or immunodeficient state, including asplenia; recurrent, severe infections and chronic (more than 14 days) systemically active immunosuppressant medication within the past 6 months.
• 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.
• Receipt of a live vaccine within the past 28 days or a killed vaccine within the past 14 days prior to Vaccination #1 and every subsequent vaccination day.
• Receipt of immunoglobulins and/or blood products within the past six months.
• Previous receipt of an investigational malaria vaccine in the last five years.
• 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.

Healthy females of childbearing potential