Study Type: Intervention

Expected Total Enrollment:

Study Dates:March 2009 -

This is a randomized trial of the aseptically raised anopheles mosquito malaria challenge. Adults aged 18-40 years will be randomized to one group of 18 subjects (Part A) or a second group of 20 subjects (Part B). Adults will be randomized to receive 1, 3 or 5 bites of Anopheles (A.) stephensi mosquitoes infected with the NF54 strain of chloroquine-sensitive Plasmodium (P.) falciparum. Part B will be informed by the results of Part A. Thus, a total of approximately 38 adults will receive a malaria challenge. The challenge for Part A will be given on day 0 with the subsequent group (Part B) commencing after a 56 day safety review. Solicited adverse events will be recorded on the days of malaria challenge, outpatient days 5-7, 19-28, 35, 42, 49, and 56 post-challenge event. Inpatient analysis will occur from Days 8-18 or until three-day directly observed therapy for P. falciparum infection is complete. Additional outpatient, post-malaria infection follow-up will occur weekly for 4 weeks. Unsolicited adverse events will be recorded for 56 days after each malaria challenge event. Participants will receive a telephone follow-up six and twelve months after enrollment. The primary objective is to develop and evaluate the safety and tolerability of a new human malaria challenge model using aseptically-raised anopheles mosquitoes infected with the NF54 isolate of P. falciparum and reared under current Good Manufacturing Practices (cGMPs) conditions. Secondary objectives are to obtain information on the minimum number of A. stephensi bites required to safely achieve 100 percent adult human volunteer infectivity (Malaria challenge, Part A); obtain information on the minimum quantity of A. stephensi bites in a second challenge study to achieve 100 percent adult human volunteer infectivity (Malaria challenge, Part B); develop molecular diagnostic techniques for rapid and accurate real-time diagnosis of P. falciparum infection to assess the role as a new diagnostic standard for P. falciparum challenge studies.

Inclusion Criteria:

Male or nonpregnant female between the ages of 18 and 40 years, inclusive.

Women who are not surgically sterile (no history of bilateral tubal ligation,
bilateral salpingo-oophorectomy, or hysterectomy), post-menopausal (1 year without
menses) or determined otherwise by medical evaluation to be sterile must agree to
practice adequate contraception [such as double barrier methods (condoms plus foam or
spermicide, diaphragm plus foam or spermicide), some intrauterine devices (IUDs),
intravaginal or transdermal hormonal methods initiated at least 1 month prior to
inoculation, or a vasectomized partner] for the entire study period (56 days).
Serologic pregnancy tests will be conducted upon screening. Urine testing will be
done on the day of malaria challenge, on the day of the first positive malaria smear
and at the conclusion of active surveillance (Day 56).

Is in good health, as determined by vital signs (heart rate, blood pressure, oral
temperature), medical history, screening 12-lead electrocardiogram (ECG) and a
physical examination.

Has normal laboratory values [urinalysis (assessing blood and protein presence as
greater than trace by dipstick), hemoglobin, white blood cells, platelet count,
aspartate aminotransferase (AST), (alanine aminotransferase) ALT, glucose and
creatinine] prior to challenge study.

Able to understand and comply with planned study procedures including an inpatient
stay from Day 8-18 after malaria challenge.

Provides informed consent prior to any study procedures, correctly answers greater
than or equal to 70 percent on the post consent quiz and is available for all study
visits.

Willing to avoid non-study related blood donation for 3 years following Plasmodium
falciparum challenge.

Exclusion Criteria:

Has any known history of malaria infection, is a long-term resident (> 5 years) of a
malaria-endemic area, was born and resided in a malaria-endemic area, or has traveled
to a malaria-endemic area within the previous 6 months.

Has a positive urine pregnancy test prior to malaria challenge (if female of
childbearing potential), is lactating, or has the intention to become pregnant within
2 months after enrollment in this study.

Use of any antibiotic or antimalarial drug beginning 28 days prior to the screening
and extending to Day 56 of study surveillance.

Has evidence of increased cardiovascular disease risk (defined as > 10 percent, 5
year risk) as determined by the method of Gaziano. Risk factors include sex, age
(years), systolic blood pressure (mm Hg), smoking status (current versus past or
never), body mass index (BMI) (kg/mm^2), reported diabetes status (yes/no), current
treatment for raised blood pressure (yes/no).

Is immunosuppressed (e.g., poorly-controlled diabetes mellitus, cirrhosis, renal
insufficiency, active malignancy, connective tissue disease, organ transplant) as a
result of an underlying illness or treatment.

An abnormal electrocardiogram (EKG), 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.

Has an active neoplastic disease (excluding nonmelanotic skin cancer) or neoplastic
disease within the past 5 years or any history of hematologic malignancy.

Is using or intends to continue using oral or parenteral steroids, high-dose inhaled
steroids (>800 mcg/day of beclomethasone dipropionate or equivalent) or other
immunosuppressive or cytotoxic drugs (an exception includes asthma for which any oral
or inhaled steroid intake will mean exclusion from study enrollment).

Has a known active history of human immunodeficiency virus, hepatitis B surface
antigen positivity, or hepatitis C infection.

Has a history of active alcohol or drug abuse in the last 5 years.

Has a history of receiving blood products within the 3 months prior to enrollment in
this study.

Has a history of psoriasis or porphyria, which may be exacerbated after treatment
with chloroquine.

Has an acute or chronic medical condition that, in the opinion of the investigator,
would render malaria challenge unsafe or would interfere with the evaluation of
responses (this includes, but is not limited to: known liver disease, renal disease,
neurological disorders, visual field defects, cardiac disorders, pulmonary disorders,
auditory damage, diabetes mellitus, and transplant recipients).

Has a history of anaphylactic response to mosquito bites or known allergy to
chloroquine, 4-aminoquinoline derivatives [atovaquone/proguanil (Malarone®)],
ibuprofen, or acetaminophen that may be used to treat volunteers developing malaria
after Plasmodium falciparum challenge.

Is using or intends to continuing using a medication known to cause drug reactions
with chloroquine or Malarone®, such as cimetidine, metoclopramide, antacids or kaolin
(antacids and kaolin can be administered at least 4 hours from intake of
chloroquine).

History of retinal or visual field changes, auditory damage, or seizures.

History of splenectomy.

Has known sickle cell trait or laboratory evidence of sickle cell trait.

Has an acute illness, including an oral temperature greater than 100.4 degrees
Fahrenheit, within 1 week prior to malaria challenge.

Plans to undergo surgery (elective or otherwise) between enrollment and 4 weeks (28
days) post-challenge.

Received an experimental agent (vaccine, drug, biologic, device, blood product, or
medication) within 1 month prior to enrollment in this study, or expects to receive
an experimental agent during the 2-month post-challenge period.

Has a diagnosis of schizophrenia, bi-polar disease or other major psychiatric
disease.

Has any condition that would, in the opinion of the site investigator, place the
subject at an unacceptable risk of injury or render the subject unable to meet the
requirements of the protocol.