Immunization Via Mosquito Bite With Radiation-attenuated Sporozoites

Study Overview
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Brief Summary
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This study is to assess the safety, tolerability, and biomarkers of protection in healthy malaria-naïve adults, who will receive bites from Anopheles stephensi mosquitoes either infected with Plasmodium falciparum Sporozoites (PfRAS) (true-immunization) or noninfected (mock-immunization).

Detailed Description
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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.

Official Title
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Phase 1 Trial With Challenge to Assess the Safety and Biomarkers of Protection in Malaria-naïve Adults of Immunization Via Mosquito Bite With Radiation-Attenuated Plasmodium Falciparum Sporozoites (IMRAS)

Conditions
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Malaria

Intervention / Treatment
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* Biological: PfRAS
* Biological: Placebo
* Other: Challenge


Participation Criteria
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Eligibility Criteria
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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 Deleted: 8 Deleted: 08JULY2014 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: PfRAS-infected<br>5 doses (immunizations) of approximately 200 infectious bites (200-400 bites total) from PfRAS-infected mosquitoes (true-immunization). The target dose is 960 infectious bites. Challenge occurs 3 weeks after final immunization. | Biological: PfRAS<br>* Radiation-attenuated Plasmodium falciparum sporozoites (PfRAS) administered by the bite of infected Anopheles stephensi mosquitoes<br>* Other names: PfRAS infected Anopheles stephensi mosquitoes;Other: Challenge<br>* 5 infectious Anopheles stephensi mosquito bites carrying infectious Plasmodium falciparum sporozoites within a controlled clinical environment.<br>|
| Placebo Comparator: Cohort 1: Noninfected<br>Placebo immunization. 5 doses of approximately 200 noninfected bites (200-400 bites total) from irradiated uninfected mosquitoes (mock-immunization). The target dose is 960 noninfected bites. Challenge occurs 3 weeks after final immunization. | Biological: Placebo<br>* Administered by the bite of noninfected Anopheles stephensi mosquitoes<br>* Other names: Noninfected Anopheles stephensi mosquites;Other: Challenge<br>* 5 infectious Anopheles stephensi mosquito bites carrying infectious Plasmodium falciparum sporozoites within a controlled clinical environment.<br>|
| Other: Cohort 1: Nonimmunized<br>No protective intervention given. Challenge occurs directly after screening. | Other: Challenge<br>* 5 infectious Anopheles stephensi mosquito bites carrying infectious Plasmodium falciparum sporozoites within a controlled clinical environment.<br>|
| Experimental: Cohort 2: PfRAS-infected<br>3 to 7 doses (immunizations) of approximately 200 infectious bites (200-400 bites total) from PfRAS-infected mosquitoes (true-immunization). The target dose is dependent on protection results in cohort 1. Challenge occurs 3 weeks after final immunization. | Biological: PfRAS<br>* Radiation-attenuated Plasmodium falciparum sporozoites (PfRAS) administered by the bite of infected Anopheles stephensi mosquitoes<br>* Other names: PfRAS infected Anopheles stephensi mosquitoes;Other: Challenge<br>* 5 infectious Anopheles stephensi mosquito bites carrying infectious Plasmodium falciparum sporozoites within a controlled clinical environment.<br>|
| Placebo Comparator: Cohort 2: Noninfected<br>Placebo. 3 to 7 doses of approximately 200 noninfected bites (200-400 bites total) from irradiated, uninfected mosquitoes (true-immunization). The target dose is dependent on protection results in cohort 1. Challenge occurs 3 weeks after final immunization. | Biological: Placebo<br>* Administered by the bite of noninfected Anopheles stephensi mosquitoes<br>* Other names: Noninfected Anopheles stephensi mosquites;Other: Challenge<br>* 5 infectious Anopheles stephensi mosquito bites carrying infectious Plasmodium falciparum sporozoites within a controlled clinical environment.<br>|
| Other: Cohort 2: Nonimmunized<br>No protective intervention given. Challenge occurs directly after screening. | Other: Challenge<br>* 5 infectious Anopheles stephensi mosquito bites carrying infectious Plasmodium falciparum sporozoites within a controlled clinical environment.<br>|
| Experimental: Hyperimmunity PfRAS-infected<br>Cohort 1 sub-cohort 3 doses (immunizations) of approximately 200 infectious bites (200-400 bites total) from PfRAS-infected mosquitoes. This arm will receive the first 3 immunizations of Cohort 2. Challenge occurs at the same time as Cohort 2 (3-20 weeks after the final immunization) | Biological: PfRAS<br>* Radiation-attenuated Plasmodium falciparum sporozoites (PfRAS) administered by the bite of infected Anopheles stephensi mosquitoes<br>* Other names: PfRAS infected Anopheles stephensi mosquitoes;Other: Challenge<br>* 5 infectious Anopheles stephensi mosquito bites carrying infectious Plasmodium falciparum sporozoites within a controlled clinical environment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Solicited adverse events | Occurrence of solicited adverse events (AE) from administration of study immunization (PfRAS) | 7 days | 
| Unsolicited adverse events | Occurrence of unsolicited adverse events (AEs) from administration of immunization (PfRAS) | 14 days | 
| Laboratory adverse events | Occurrence of laboratory AEs from administration of study immunization (PfRAS) | 7 days | 
| Serious adverse events | Occurrence of serious adverse events (SAEs) from administration of immunization (PfRAS) | 52 weeks | 
| Signs and symptoms related to malaria infection | Occurrence of signs and symptoms related to malaria infection starting 7 days post-Controlled Human Malaria Infection (CHMI) (these will not be recorded as adverse events because they are expected as a result of malaria infection) | 7 days | 
| Parasitemia | Development of parasitemia and time to parasitemia after malaria challenge | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Identify and validate immunological PBMC biomarkers | Compare Peripheral Blood Mononuclear Cell(s) (PBMC) read-outs between protected and nonprotected subjects and between immunized and mock-immunized subjects. | 52 weeks | 
| Identify and validate immunological serum biomarkers | Compare serum read-outs between protected and nonprotected subjects and between immunized and mock-immunized subjects. | 52 weeks | 
| Identify and validate whole blood immunological biomarkers | Compare whole blood read-outs between protected and nonprotected subjects and between immunized and mock-immunized subjects. | 52 weeks |