Inclusion Criteria:
* Healthy adults (male or non-pregnant female) 18 to 45 years of age.
* Able and willing to participate for the duration of the study.
* Able and willing to provide written informed consent.
* Physical examination and laboratory results without clinically significant findings.
* Women of childbearing potential must agree to use effective means of birth control (e.g. oral or implanted contraceptives, IUD, female condom, diaphragm with spermicide, cervical cap, abstinence, use of a condom by the sexual partner or sterile sexual partner) during the entire study.
* Due to the potential for reduced effectiveness of hormonal contraceptives during artemether and/or lumefantrine treatment, participants will be counseled to add an additional barrier method of contraception during treatment.
* Women with a history of surgical or chemical sterilization (e.g. tubal ligation, hysterectomy, other) must provide written documentation of the procedure from a health care provider.
* Agree not to travel to a malaria endemic region during the course of the trial.
Exclusion Criteria:
* Unable to provide informed consent including inability to pass the test of understanding.
* Receipt of a malaria vaccine in a prior clinical trial.
* History of a splenectomy or sickle cell disease.
* History of a neurologic disorder (including non-febrile seizures or complex febrile seizures) or formal history of migraine headache.
* Current use of systemic immunosuppressant pharmacotherapy.
* Receipt of a live vaccine within 4 weeks of first immunization or of 3 or more non-live vaccines within 2 weeks of first immunization.
* Women who are breast-feeding, pregnant or planning to become pregnant during the study period.
* Known allergy or hypersensitivity reaction (e.g., anaphylaxis, erythema multiforme or Stevens-Johnson syndrome, angioedema, vasculitis) to atovaquone-proguanil (Malarone®), artemether-lumefantrine (Coartem®), any components of these formulations, or any component of the investigational products.
* History of anaphylaxis or other life-threatening reaction to a vaccine.
* Participation in any study involving investigational vaccine or drug within 4 weeks prior to enrollment that in the estimation of the site PI might adversely affect the individual's safety or the quality of data to be collected.
* Evidence of increased cardiovascular disease risk; defined as \>10% five-year risk by non-laboratory method (Gaziano, 2008) \[80\].
* Plan to participate in another investigational vaccine/drug research during the study.
* Plan for major surgery between enrollment until 28 days post-CHMI.
* Use or planned use of any drug with anti-malarial activity that would precede or coincide with malaria challenge or vaccination.
* Anticipated use of medications known to cause drug reactions with atovaquone-proguanil or artemether-lumefantrine such as tetracycline, rifampin, rifabutin, cimetidine, metoclopramide, antacids, anti-coagulants such as coumarin, indinavir, and kaolin.
* Anticipated use of medications known to:
* Be substrates, inhibitors or strong inducers of CYP3A4 (e.g., rifampin, carbamazepine, phenytoin, and/or St. John's wort) \[strong inducers of CYP3A4 when taken concomitantly with artemether and/or lumefantrine can result in decreased concentration(s) and loss of antimalarial efficacy\].
* Be metabolized by the cytochrome enzyme CYP2D6 (e.g., primaquine, tafenoquine, flecainide, imipramine, amitriptyline, clomipramine).
* Have a mixed effect on CYP3A4 (e.g., antiretrovirals).
* Prolong the QT interval (e.g., quinine, quinidine, halofantrine, mefloquine, procainamide, disopyramideamiodarone, sotalol, pimozide, ziprasidone, tetracycline, doxycline, fluoroquinolone, imidazole, and triazole antifungal agents). Note: in the case of halofantrine, this drug may not be used within a month of artemether/lumefantrine due to its very significant effect on QT interval.
* Positive HIV, HBsAg or HCV serology.
* An abnormal electrocardiogram, defined as one showing pathologic Q waves and significant ST-T wave changes; left ventricular hypertrophy; any non-sinus rhythm including isolated premature ventricular contractions, but excluding isolated premature atrial contractions; right or left bundle branch block; or advanced (secondary or tertiary) A-V heart block; or other clinically significant abnormalities on the electrocardiogram.
* History of symptomatic cardiac arrhythmias, with clinically relevant bradycardia or with severe cardiac disease.
* Family history (grandparents, parents or siblings) of congenital prolongation of the QT interval or sudden death.
* History of disturbances of the electrolyte balance (e.g., hypokalemia or hypomagnesemia).
* History of severe renal impairment (creatinine clearance \<30 mL/min) (risk of pancytopenia in patients with severe renal impairment treated with proguanil).
* History of chronic liver disease.
* Any clinically significant deviation from the normal range in biochemistry or hematology tests measured at screening and not resolving.
* Any medical, psychiatric, social, behavioral or occupational condition or situation (including active alcohol or drug abuse) that, in the judgment of the site PI, impairs the participant's ability to give informed consent, increases the risk to the participant of participation in the study, affects the ability of the participant to participate fully in the study, or might negatively impact the quality, consistency, integrity or interpretation of data derived from their participation in the study. This includes persons in emergency situations such as refugees.
