This is an open-label evaluation of the safety, tolerability immunogenicity and efficacy of the PfSPZ Vaccine administered by Direct Venous Inoculation (DVI) in healthy, malaria-naïve subjects. There will be 3 groups and a total of 69 subjects (45 immunized subjects and 24 infectivity controls).

Group 1 (n=15) and Group 2 (n = 15) subjects will receive five doses by DVI of 2.7 x 10^5 PfSPZ per dose (4 doses at 4 week intervals and the 5th dose 8 weeks after the fourth dose). Group 3 (n = 15) will receive 3 doses by DVI of 4. 5 x 10^5 PfSPZ/dose at 8 week intervals. Subjects who complete all immunizations will receive a total 13.5 x 10^5 PfSPZ. Protective efficacy will be assessed by Controlled Human Malaria Infection (CHMI) by exposure to the bites of five Pf-infected mosquitoes. Groups 1 and 3 (n = 30) will undergo each of two CHMIs at the same time with mosquitoes infected with PfSPZ (3D7) (homologous) along with 6 Infectivity Controls. Group 2 will undergo each of two CHMIs separately with mosquitoes infected with PfSPZ (7G8) (heterologous) along with 6 Infectivity Controls. CHMI will occur at approximately 2 to 3 weeks and 24 weeks after the final immunization. Subjects may proceed to CHMI provided they have received no fewer than three scheduled immunizations. Immunized subjects may participate in the second CHMI whether or not they were protected in the first CHMI; boosting of immune responses in CHMI #1 may lead to protection in CHMI #2.

One subject in each of Groups 1 and 2 and 3 subjects in Group 3 will be immunized approximately 24 hours prior to the rest of the group (referred to as "pilot subjects"). For the Group1/Group 2 pilot subjects: the first subject will be immunized and observed on site for a minimum of one hour; at this point, the second subject may be immunized and he/she will also be observed for a minimum of one hour. For Group 3: the three subjects will be immunized sequentially with a minimum 2 hour observation period between subjects (and a two hour observation of the third subject as well). If there are no safety concerns identified in the pilot subjects after 24 hours that trigger the stopping rules, then the rest of subjects in Groups 1, 2 and 3 will be immunized as scheduled. Subjects in Group 3 will receive their first immunization approximately 4 weeks after subjects in Groups 1 and 2 receive their first immunizations. Subjects will be followed for 8 weeks after the last CHMI for safety purposes.

Inclusion Criteria:

• Healthy adults (male or non-pregnant female) 18 - 45 years of age, inclusive.
• Able and willing to participate for the duration of the study.
• Able and willing to provide written (not proxy) informed consent.
• 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. Women with a history of surgical or chemical sterilization (e.g. tubal ligation, hysterectomy, other) must provide written documentation of infertility from a Primary Care Provider.
• Willing to refrain from blood donation (except as required in this study) for 3 years following CHMI.
• Agree not to travel to a malaria endemic region during the entire course of the trial.

Exclusion Criteria:

• Any history of malaria infection, or travel to a malaria endemic region within 6 months prior to first immunization.
• History of long-term residence (>5 years) in area known to have significant transmission of P. falciparum.
• Has evidence of increased cardiovascular disease risk (defined as > 10%, 5 year risk) as determined by the method of Gaziano [Gaziano, 2008]. Risk factors include sex, age, systolic blood pressure (mm Hg), smoking status, body mass index (BMI, kg/mm2), and reported diabetes status.
• Positive HIV, HBsAg or HCV serology.
• Positive sickle cell screening test.
• 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.
• Current use of systemic immunosuppressant pharmacotherapy.
• Current significant medical condition (cardiovascular, hepatic, renal, or hematological) or evidence of any other serious underlying medical condition identified by medical history, physical examination, or laboratory examination.
• History of a splenectomy.
• History of neurologic disorder (including seizures) or migraine headache.
• History of psychiatric disorders (such as personality disorders, anxiety disorders, or schizophrenia) or behavioral tendencies (including active alcohol or drug abuse) discovered during the screening process that in the opinion of the investigator would make compliance with the protocol difficult.
• Plan for surgery between enrollment and CHMI.
• Females who are pregnant or nursing, females who plan on becoming pregnant or plan to nurse during the study period.
• Known allergy to any component of the vaccine formulation, history of anaphylactic response to mosquito-bites, or any history of anaphylactic reaction, retinal or visual field changes, or known allergy to anti-malarials including chloroquine phosphate, atovaquone/proguanil (Malarone®), or artemether/lumefantrine (Coartem®)
• Receipt of another investigational vaccine or drug within 30 days prior to the first immunization, or plan to participate in another investigational vaccine/drug research during or within 1 month following participation in this study.
• Receipt of more than three other vaccines within 60 days prior to the screening visit, or plan to receive more than three other vaccines during or within 1 month following participation in this study.
• Personal beliefs that prohibit the receiving of vaccine product containing human serum albumin within the diluent (vaccine recipients only).
• Use or planned use of any drug with anti-malarial activity that would coincide with the periods of immunization or CHMI.
• History of psoriasis or porphyria, which may be exacerbated after treatment with chloroquine.
• Anticipated use of medications known to cause drug reactions with chloroquine, atovaquone-proguanil (Malarone®), or artemether/lumefantrine (Coartem®) such as cimetidine, metoclopramide, antacids, and kaolin.
• History of any other illness or condition which, in the investigator's judgment, may substantially increase the risk associated with the subject's participation in the protocol or compromise the scientific objectives.