This is a study to evaluate the safety, immunogenicity, and efficacy of a recombinant circumsporozoite protein (rCSP) malaria vaccine administered with and without AP 10-602 [Glucopyranosyl Lipid A (GLA) in liposome Quillaja saponaria 21 formulation (LSQ)] adjuvant. 59 healthy adult, malaria naive volunteers aged 18 to 45 will receive vaccination with or without adjuvant (10 of those volunteers will receive rCSP alone) in five dose escalating groups. Each group will receive 3 vaccination doses total, with intramuscular (IM) injections on days 1, 29, and 85. A sixth group of 6 volunteers will receive no vaccinations and will participate as a control in a Controlled Human Malaria Infection (CHMI) challenge with two of the vaccinated groups. The study will be conducted at the Center for Vaccine Development (CVD) in Baltimore, Maryland. The patient participation duration is expected to be up to 886 days (up to 117 days for nonvaccination group). This study will test two hypotheses: (1) the rCSP/AP 10-602 [GLA-LSQ] candidate malaria vaccine will induce an immune response in a dose-dependent manner as measured by anti-CSP antibody titer via ELISA and (2) the rCSP/AP 10-602 [GLA-LSQ] candidate malaria vaccine will provide a minimum of 50% efficacy in vaccines compared to unvaccinated infectivity controls. The primary objective is to assess the safety and reactogenicity of candidate rCSP/AP 10-602 [GLA-LSQ] malaria vaccine when administered intramuscularly on a 1, 29, and 85 day schedule (Groups 1-3, 4B, 5) and on a 1 and 490 day schedule (Group 4) to healthy malaria-naive adults aged 18-45 years.

This is a phase I, single-site, dose escalation study to evaluate the safety, immunogenicity, and efficacy of the recombinant circumsporozoite protein (rCSP) antigen malaria vaccine administered with and without AP 10-602 [Glucopyranosyl Lipid A (GLA) in liposome Quillaja saponaria 21 formulation (LSQ)]. The study population will consist of 65 healthy male and female adults aged 18 to 45 years old and be conducted at the Center for Vaccine Development (CVD) in Baltimore, Maryland. 49 healthy, malaria-naïve volunteers will receive rCSP vaccination with AP 10-602 [GLA-LSQ] adjuvant. Ten volunteers will receive rCSP alone. Each dose-escalating group will receive 3 intramuscular (IM) total doses of vaccine on days 1, 29, and 85. Group 1 will receive a dose of 10 mcg rCSP + AP 10-602 [GLA-LSQ] (5 mcg GLA - 2 mcg LSQ) at each injection; Group 2 will receive 30 mcg rCSP + AP 10-602 [GLA-LSQ] (5 mcg GLA - 2 mcg LSQ); Group 3 will receive 30 mcg rCSP without adjuvant; and Group 4 will receive 60 mcg rCSP + AP 10-602 [GLA-LSQ] (5 mcg GLA - 2 mcg LSQ). The dose for Group 5 will depend on immunogenicity analysis from groups 1, 2 and 3. If immunogenicity analysis conducted 28 days post-2nd dose in Groups 1, 2 and 3 show promise (at least fourfold increase in geometric mean anti-CSP antibody or geometric mean anti-CSP titer of 20), the 10 volunteers in Group 5 will receive the lowest rCSP dose that gives this predefined immunogenic response ((either 10 or 30 mcg rCSP) + AP 10-602 [GLA-LSQ],]), otherwise, Group 5 will receive 60 mcg rCSP + AP 10-602 [GLA-LSQ]. Groups will be vaccinated in a stepwise manner following a "telescoped" design. A sixth group of 6 volunteers (Group 6) will receive no vaccinations and will be used as an infectivity control for a Controlled Human Malaria Infection (CHMI) challenge. Groups 4 and 5 will also undergo the CHMI challenge together, 28 days after the last vaccination. The patient participation duration is expected to be up to 886 days for Groups 1, 2, 3, 4, and 5; and up to 117 days for Group 6. This study will test two hypotheses: (1) the rCSP/AP 10-602 [GLA-LSQ] candidate malaria vaccine will induce an immune response in a dose-dependent manner as measured by anti-CSP antibody titer via ELISA and (2) the rCSP/AP 10-602 [GLA-LSQ] candidate malaria vaccine will provide a minimum of 50% efficacy in vaccines compared to unvaccinated infectivity controls. The primary objective is to assess the safety and reactogenicity of candidate rCSP/AP 10-602 [GLA-LSQ] malaria vaccine when administered intramuscularly on a 1, 29, and 85 day schedule (Groups 1-3, 4B, 5) and on a 1 and 461 day schedule (Group 4) to healthy malaria-naive adults aged 18-45 years. The secondary objectives are to (1) assess immunogenicity of rCSP/AP 10-602 [GLA-LSQ] malaria vaccine when administered intramuscularly on a 1, 29, and 85 day (Groups 1-3, 4B, 5) and on a 1 and 490 day schedule (Group 4) schedule and (2) to assess the preliminary efficacy of candidate rCSP/AP 10-602 [GLA-LSQ] malaria vaccine against infection with Plasmodium falciparum malaria (defined as P. falciparum asexual parasitemia or a delay in patency of infection > 2 days versus unimmunized infectivity controls) under Controlled Human Malaria Infection (CHMI).

Inclusion Criteria:

1. Healthy adults (males and non-pregnant, non-lactating females) between the ages of 18 and 45 years, inclusive

2. Able and willing to participate for the duration of the study

3. Able and willing to provide written (not proxy) informed consent

4. Provides informed consent and correctly answers > / = 70 percent on the post consent quiz before any study procedures and is available for all study visits

5. Females of childbearing potential and males must agree to practice highly effective contraception*

   *Contraception must be practiced from 30 days before the time of enrollment until at least 30 days following the third vaccine dose for groups 1, 2 and 3, and the malaria challenge event for groups 4, 4B, 5 and 6 (such as double barrier methods (condoms plus foam or spermicide, diaphragm plus foam or spermicide), licensed intrauterine devices (IUDs), intravaginal or intra/transdermal or oral hormonal methods initiated at least 30 days before inoculation or challenge, documented surgical sterilization via tubal ligation the essure procedure or hysterectomy, abstinence or a vasectomized partner). The contraceptive method should remain unchanged throughout the study participation

6. Is in good health, as determined by vital signs (heart rate, blood pressure, oral temperature); medical history; laboratory values* that do not meet toxicity grading criteria, except when Grade 1 and clinically insignificant; and a physical examination

   *Laboratory values include: hemoglobin, white blood cell count, platelet count, glucose (random), serum alanine aminotransferase (ALT), serum creatinine, urine protein and urine blood

7. Agree not to travel to a malaria endemic region during the entire course of the trial

8. Willing to avoid non-study related blood donation for the duration of participation in the study or until at least 1 year after receiving the last investigational vaccine, whichever is longer

9. Able to understand and comply with planned study procedures including daily outpatient follow-up visits beginning 5 days after malaria challenge (groups 4, 4B, 5 and 6 only)

10. Willing to avoid non-study related blood donation for 3 years following P. falciparum challenge (groups 4, 4B, 5 and 6 only)

Exclusion Criteria:

1. Any history of malaria infection, or travel to a malaria endemic region within 6 months before first vaccination

2. History of long-term residence (> / = 5 years) in an area known to have significant transmission of P. falciparum

3. Positive serology for human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B surface antigen (HBsAg)

4. Positive sickle cell screening test or known hemoglobinopathy (groups 4, 4B, 5 and 6 only)

5. Current or recent (within the last four weeks) treatment with parenteral or oral corticosteroids (intranasal or inhaled steroids are acceptable), or other immunosuppressive agents, or chemotherapy

6. History of splenectomy

7. Participants who have a clinically significant (as determined by the PI or designee) baseline Grade 1 or greater toxicity, or any Grade 2 or greater toxicity (regardless of clinical significance) by the toxicity table, except hematuria > 1+ detected during menses for females*

   * For females who are menstruating, urinalysis frequently tests positive for blood and is not an indicator of poor health status or increased risk.

8. Vaccination with a live vaccine within the past 30 days or with a nonreplicating, inactivated, or subunit vaccine within the last 14 days

9. Known hypersensitivity to components of the vaccine for groups 1, 2, 3, 4, 4B and 5; or to the adjuvant for groups 1, 2, 4, 4B and 5

10. History of acute or chronic medical conditions including, but not limited to, disorders of the liver, kidney, lung, heart, nervous system, or other metabolic or autoimmune/inflammatory conditions

11. History of anaphylaxis or severe hypersensitivity reaction

12. History of Guillain-Barre syndrome or severe adverse reaction to any vaccination

13. Severe asthma, as defined by an emergency room visit or hospitalization within the last 12 months

14. Pregnant or breastfeeding women or women who plan to become pregnant before day 115 in groups 1, 2 and 3; or before 30 days post-malaria challenge in groups 4, 4B, 5 and 6

15. Concurrent participation in other investigational protocols prior to Day 141 or receipt of an investigational product within the previous 30 days

16. Planned receipt of an investigational product within 28 days following the last vaccination dose or malaria challenge

17. Any condition that, in the opinion of the investigator, would affect a participant's ability to understand or comply with the study protocol or would jeopardize a participant's safety or rights

18. History of previous receipt of a candidate malaria vaccine or a vaccine containing the GLA-LSQ adjuvant

19. Use or planned use of any drug with anti-malarial* activity 30 days before, or after malaria challenge (groups 4, 4B, 5 and 6 only)

    *Medications with antimalarial activity include trimethoprim-sulfamethoxazole, azithromycin, erythromycin, tetracycline, doxycycline, minocycline, clindamycin, ciprofloxacin, levofloxacin, norfloxacin and rifampin

20. Planned surgery 30 days before or after vaccination or malaria challenge

21. History of drug or alcohol abuse within the last five years

22. Receipt of blood or blood products in the previous six months or donation of a unit of blood within two months before screening

23. History of schizophrenia, bipolar disorder or other psychiatric condition that makes study compliance difficult*

    * Subjects with psychoses or history of suicide attempt or gesture in the 3 years before study entry, ongoing risk for suicide

24. History of diabetes mellitus with the exception of pregnancy-induced diabetes that has resolved

25. Has evidence of increased cardiovascular disease risk* (defined as > 10 percent, 5 year risk) as determined by the method of Gaziano (groups 4, 4B, 5 and 6 only)

    * Risk factors include sex, age (years), systolic blood pressure (mm Hg), smoking status, body mass index (BMI, kg / mm^2), reported diabetes status, and blood pressure

26. Abnormal screening ECG* (groups 4, 4B, 5, and 6 only)

    * Pathologic Q wave and significant ST-T wave changes, left ventricular hypertrophy, non-sinus rhythm except isolated premature atrial or ventricular contractions, right of left bundle branch block, advanced A-V heart block (secondary or tertiary), QT/QTc interval > 450 ms

27. Known hypersensitivity to mosquito bites, artemether-lumefantrine or atovaquone-proguanil (groups 4, 4B, 5 and 6 only)

28. Anticipated medication use during the 28-day post-challenge period that are known to interact with artemether/lumefantrine or atovaquone/proguanil, such as cimetidine, metoclopramide, antacids, and kaolin (groups 4, 4B, 5 and 6 only)

29. Previous participation in a CHMI study