Immunization Via Mosquito Bite With Radiation-attenuated Sporozoites

This is a Phase 1 open-labeled study. In addition to safety and tolerability of Plasmodium
falciparum Sporozoites (PfRAS), this study is a comprehensive, systems biology-based effort
to identify and validate biomarkers of protection with PfRAS immunization, comparing
sterility protected to nonprotected study subjects. The goal of the trial design is to
achieve approximately 50% sterile protection in order to facilitate the identification of
biomarkers and correlates of protection.

Following true-immunization or mock-immunization, study subjects and nonimmunized infectivity
controls will receive a challenge via the bites of 5 An stephensi mosquitoes carrying
infectious P falciparum sporozoites within a controlled clinical environment (controlled
human malaria infection, CHMI) to determine the level of sterile protection.

Inclusion Criteria:

- Healthy adults (male or non-pregnant, non-breastfeeding female) 18-50 years of age
(inclusive).

- Available and willing to participate for duration of study.

- Able and willing to provide written informed consent.

- Able to complete an Assessment of Understanding with a score of at least 70% correct.

- In good general health with no clinically significant health problems as established
by medical history, physical exam and laboratory screening.

- Females of childbearing potential must have a negative pregnancy test at screening and
agree to not become pregnant or breastfeed for the duration of the study. She must be
willing to use a reliable form of contraception during the study. Reliable forms of
birth control include use of condoms, diaphragm or cervical cap, birth control pills,
IUD or sperm killing products.

- Agree to refrain from blood donation (except as required in this study) for 3 years
following P falciparum challenge.

- Agree not to travel to a malaria-endemic region during the study.

- Good peripheral venous access.

Exclusion Criteria:

- Positive HIV, HBsAg, or HCV serology.

- Positive sickle cell screening test, including evidence of sickle trait.

- Reactivity by CSP or AMA1 ELISpot assay or ELISA as determined by IMRAS Study Specific
Procedure #204.

- Anemia (below normal reference laboratory value of hemoglobin) on screening.

- Weight less than 110 pounds (this does not apply to infectivity controls as it is a
weight cut-off for subjects undergoing leukapheresis procedure)

- 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 Pf [cumulative lifetime exposure].

- Use of systemic immunosuppressant pharmacotherapy for greater than 10 days within 60
days of scheduled first immunization (inhaled and topical steroids are allowed; short
duration or tapered corticosteroid regimens of 10 days or less that have been
discontinued prior to first immunization are allowed).

- Current significant medical condition (cardiovascular, hepatic, renal, pulmonary, or
hematological) or evidence of any other serious underlying medical condition
identified by medical history, physical examination, or laboratory examination
(includes bleeding disorders).

- Plan for surgery between enrollment and day 28 post-challenge (minor procedures,
elective corrective vision surgery, and dental procedures are allowed).

- Receipt of immunoglobulin and/or any blood products within 90 days of scheduled
leukapheresis or immunization. Version 13.0 (08May2015) 70 US Government Proprietary
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- Has evidence of increased cardiovascular disease risk (defined as > 5%-10%, 5-year
risk) as determined by the method of Gaziano (2008). Risk factors include sex, age
(years), systolic blood pressure (mm Hg), smoking status, body mass index (BMI,
kg/m2), reported diabetes status, and blood pressure.

- An abnormal electrocardiogram (ECG), defined as one showing pathologic Q waves and
significant ST-T wave changes; left ventricular hypertrophy; any non-sinus rhythm
excluding isolated premature atrial contractions; right or left bundle branch block;
or advanced (secondary or tertiary) A-V heart block.

- History of a splenectomy.

- History of any other illness or condition that, in the investigator's judgment, may
substantially increase the risk associated with the subject's participation in the
protocol or compromise the scientific objectives. This may include 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.

- History of anaphylactic or severe response to mosquito bites, retinal or visual field
changes, or known allergy to the antimalarial chloroquine phosphate, which will be
used to treat subjects developing malaria after CHMI.

- Participation in any study involving any investigational vaccine or drug within 30
days prior to the screening visit, or plan to participate in another investigational
vaccine/drug research during or within 1 month following participation in this study.

- Use or planned use of any drug with antimalarial activity that would coincide with
immunization or challenge.

- History of psoriasis or porphyria, which may be exacerbated after treatment with
chloroquine.

- Anticipated use of medications known to cause drug reactions with chloroquine or
atovaquone-proguanil (Malarone) such as cimetidine, metoclopramide, antacids, and
kaolin during the day 7 to 28 post-challenge period.

- Any other significant findings which, in the investigator's judgment, may
substantially increase the risk associated with the subject's participation in the
study or compromise the scientific objectives.