A Clinical Trial of the PfSPZ Vaccine Administered by Direct Venous Inoculation in Healthy Malaria-Naïve Adults: Heterologous vs. Homologous Controlled Human Malaria Infection and Reduction in Number of Doses

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.