Infection-Treatment-Vaccination for Plasmodium Falciparum
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| City: |
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Seattle |
| State: |
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Washington |
| Zip Code: |
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98109 |
| Conditions: |
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Malaria |
| Purpose: |
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The purpose of this study is to determine if sterile, protective immunity to malaria can be
induced by malaria parasite exposure limited to the early liver stage of the parasite
lifecycle.
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| Study Summary: |
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This randomized, partial double-blind, placebo-controlled phase 1 study is designed to
evaluate whether sterile protective immunity to P. falciparum can be induced by wild-type
(non-attenuated) sporozoite immunizations when exposure is limited to sporozoite and early
liver stage of the parasite life cycle and at a low dose sporozoite inoculum relative to
other whole parasite vaccination models using live attenuated P. falciparum parasites (e.g.
irradiated sporozoites). A secondary objective of the study is to evaluate newly identified
antigens as potential targets of an immune response preferentially induced in individuals
protected by whole sporozoite vaccination. Once identified as immune targets, these
antigens can then be prioritized for subunit vaccine development. Subjects will be closely
monitored for signs and symptoms of malaria and/or drug toxicity throughout the study.
A total of 36 healthy, malaria-naive adult subjects will be enrolled in the study. Six
subjects will be randomized to the Pilot Phase (Arm 1), 24 to the Main ITV Phase (Arms 2, 3,
and 4), and six subjects will be randomized for challenge control (Arm 5) to start on the
day of challenge of the Challenge Phase.
Subjects in Arms 1-4 will receive three episodes of ITV immunization and a subsequent
challenge with homologous P. falciparum sporozoites in the absence of chemoprophylaxis. The
ITV immunization in this study consists of:
1. Experimental infection with wild-type (non-attenuated) NF54 strain P. falciparum
sporozoites delivered by the bites of 12 - 15 infected A. stephensi mosquitoes (ITV
infection) administered in conjunction with
2. Causal prophylaxis with PQ or placebo, timed to eliminate parasites early in the liver
stage of development, after hepatocyte invasion but prior to maturation and release
into the bloodstream, and
3. Continuous suppressive prophylaxis with the blood-stage antimalarial drug CQ to prevent
development of patent parasitemia and clinical malaria.
The study includes a Pilot Phase because the timing of PQ dosing relative to parasite
exposure is critical to the efficacy of PQ as causal prophylaxis yet still allowing for
maximized antigenic exposure to liver-stage parasites. The Pilot Phase will compare the
prevention of blood-stage parasitemia by PQ administered two days vs. three days after a
single ITV infection. Based on protection data from the Pilot Phase, a dosing algorithm
will be used to determine timing of the PQ dose for the Main ITV Phase.
In the Challenge phase, which occurs after the three ITV events, sterile protective immunity
will be assessed by challenge with homologous P. falciparum sporozoites in the absence of
chemoprophylactic drugs. Five weeks after stopping chemoprophylaxis, subjects will undergo
experimental P. falciparum infection by the bites of five infective mosquitoes and will be
closely monitored for signs and symptoms of malaria in a hotel setting.
Subjects who develop patent parasitemia will be immediately treated with a standard dose of
Malarone and withdrawn from the study. Treated subjects will continue to be monitored with
daily blood smears until three consecutive daily blood smears are negative and any residual
symptoms of malaria are mild or resolved.
Subjects are closely monitored throughout the study for solicited and unsolicited adverse
events related to any part of the ITV immunization. The study is expected to last 4 to 9
months depending on which the subject is assigned, and may have up to 64 scheduled study
visits during the time period.
Subjects will be followed in the clinic for 35 days after the challenge and a follow up
phone call will be conducted at six months after the challenge. In an effort to evaluate
the duration of an immune response to ITV, all subjects will be invited to return for
optional evaluations at three and six months post challenge.
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| Criteria: |
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Inclusion Criteria:
- Male and non-pregnant females age 18 to 50 years
- Good general health status as demonstrated by medical history, physical exam, and
screening laboratory test performed within 90 days of enrollment
- Ability and willingness to provide informed consent
- No laboratory evidence of hematologic, hepatic, or renal disease
- Assessment of Understanding questionnaire completed and passed prior to enrollment
- Reliable access to the clinical trials centers and availability to participate for
duration of study
- If the subject is biologically female and of reproductive potential she must agree to
consistent pregnancy prevention
Exclusion Criteria:
- Recent travel to a malaria endemic area within 6 months of enrollment
- Planned travel to a malaria endemic area during the study period
- History of confirmed malaria diagnosis on peripheral blood smear
- Anticipated use during the study period, or use within the following periods prior to
enrollment:
1. Investigational malaria vaccine at any time
2. Malaria chemoprophylaxis within 6 months
3. Chronic systemic immunosuppressive medications within 6 months
4. Blood products or immunoglobulins within 120 days
5. Investigational product or vaccine within 30 days
6. Systemic antibiotics with antimalarial effects within 30 days
7. Receipt of a live vaccine within 28 days or a killed vaccine within the 14 days
prior to each ITV infection and challenge
8. Medications known to interact with primaquine, chloroquine or
atovaquone/proguanil (only during the study period)
- History of:
1. Sickle cell disease, sickle cell trait, or other hemoglobinopathies
2. Splenectomy or functional asplenia
3. Systemic anaphylaxis
4. Gelatin allergy
5. Severe allergic reactions to mosquito bites of study drugs
6. Documented history of chronic or active neurologic disease
7. Psoriasis or porphyria
8. Ocular diseases including retinopathy or visual field defects
- Glucose 6 phosphate dehydrogenase (G6PD) deficiency
- Clinically significant medical condition, physical examination findings, other
clinically significant abnormal laboratory results, or past medical history that may
have clinically significant implications for current health status in the opinion of
the Investigator.
- Weight <55 kg or >90 kg; body mass index (BMI) <18.5% or >31%
- History of known active cardiac disease or stroke
- Clinically significant abnormal screening electrocardiogram (ECG)
- Moderate or high risk for coronary heart disease (CHD) based on NHANES I
cardiovascular risk assessment
- Acute illness at the time of enrollment
- Pregnant or nursing female
- Infection with HIV, Hepatitis B, Hepatitis C
- Psychiatric condition that precludes compliance with the protocol
- Suspected or known current alcohol or drug abuse
- Any other finding that, in the judgment of the investigator, would interfere with, or
serve as a contraindication to, protocol adherence, assessment of safety or
reactogenicity, or a subject's ability to give informed consent, or increase the risk
of having an adverse outcome from participating in the study
- Clinical trial staff with direct involvement in the conduct of the trial
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| NCT ID: |
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NCT01500980 |
| Primary Contact: |
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Principal Investigator
Sara Healy, M.D. MPH
Seattle Biomedical Research Institution
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| Backup Contact: |
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N/A |
| Location Contact: |
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Seattle, Washington 98109
United States
There is no listed contact information for this specific location.
Site Status: N/A |
| Data Source: |
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ClinicalTrials.gov |
| Date Processed: |
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May 21, 2013 |
| Modifications to this listing: |
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