Establishment of a Sporozoite Challenge Model for Plasmodium Vivax in Human Volunteers

Study Overview
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Brief Summary
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A clinical trial aimed to standardize a vivax sporozoite infection model in human volunteers was conducted at the Malaria Vaccine and Drug Development Center (MVDC) in collaboration with the Immunology Institute at Valle State University and the Fundación Clínica Valle del Lili (FCVL) in Cali, Colombia. The primary objective was to determine if naïve human volunteers could be safely and reproducibly infected by the bite of An. albimanus mosquitoes carrying P. vivax sporozoites in their salivary glands and a secondary objective consisted in determining the minimal number of infected mosquitoes required to infect all volunteers, with a reproducible pre-patent period. The trial was divided into two steps: Step A directed to obtain human blood infected with P.vivax parasite used to infect anopheles mosquitoes and Step B to produce P. vivax sporozoites in Anopheles mosquitoes to determine the dose response of naive human volunteers exposed to 3 +/- 1, 6 +/- 1 y 9 +/- 1 mosquitoes bites. A total of 15 samples of P. vivax infected donors were used to infect different batches of mosquitoes.

Detailed Description
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Study design: The study was a randomized open label clinical trial to establish a sporozoite challenge model for Plasmodium vivax in humans. The development and standardization of such a model will make it possible to evaluate the efficacy of candidate P. vivax vaccines in Phase 2a trials. The study is divided into two successive steps: Step A Parasite Blood Donation: Volunteers were recruited passively from a group of patients who presented with active P. vivax infection and accepted to donate infected blood. Samples of P. vivax infected blood was collected and was screened for infectious diseases, according to standard blood bank procedures. Colonized Anopheles albimanus mosquitoes were fed with this blood using a Membrane Feeding Assay (MFA). Sixteen (16) days after, selected positive mosquito batches were used for step B. Step B Challenge: After informed consent signature, a total of 18 healthy volunteers were randomly allocated to Groups 1, 2 and 3, of 6 volunteers each and were challenged with the bite of 3±1, 6±1 or 9±1 P. vivax infected mosquitoes. Volunteers were closely monitored post infection, and were treated as soon as blood infection becomes patent as ascertained by microscopic examination of thick blood smears (TBS). Comparison of three bite patterns was used to select the optimal number of P. vivax-infected mosquito bites needed to provide reliable and reproducible blood infection. Infection was expected to occur in the first 30 days. After that time, if infection was not documented, antimalarial treatment was planned. Nevertheless all exposed volunteers presented malarial infection. Despite infection was expected before day 30, a 18 month follow-up was performed with to be sure no delay malaria infection presented without detection. So, the total duration of the study was 18 months. Infection was determined by the detection of P. vivax parasites on TBS from volunteers included. Eligibility criteria for Blood donors Step A were: Adult, male or female (18-60 years of age). Capacity to freely understand and sign an informed consent form of participation. TBS Positive for P.vivax but negative for all other malaria species. P.vivax gametocytemia > 0.2%. Exclusion criteria Unable to provide free and willing written informed consent. Have or have had any illness or condition which, in the investigator's judgment, may substantially increase the risk associated with the blood donation. Eligibility and exclusion criteria for Challenge is described below in this format. Close monitoring of adverse events was performed, both by medical examination as by telephone contact.

Official Title
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Establishment of a Sporozoite Challenge Model for Plasmodium Vivax in Human Volunteers

Conditions
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Malaria, Vivax

Intervention / Treatment
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* Biological: Sporozoite Challenge Model for Plasmodium vivax in Humans


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male or non-pregnant female adults (18- 50 years of age). Use of adequate contraceptive method from the initiation of the study until two months after sporozoite challenge for females. No plans to travel to a malaria endemic area during the course of the study and agree to not travel outside the study area from Day 7 to Day 23 post-challenge (the high risk period for becoming parasitemic). Reachable by phone during the entire study period Duffy positive phenotype Exclusion Criteria: Are <18 or >49 years of age. Any female who is pregnant at serum positive B-HCG screening or who is nursing. Duffy negative phenotype. G-6-PD deficiency or any other hemoglobinopathy. Current or past infection with any species of malaria History of allergy to antimalarial drugs or immediate type hypersensitivity reactions to mosquito bites. Clinical or laboratory evidence of significant systemic disease, including hepatic, renal, cardiac, immunologic or hematological disease. Are HIV positive or have any other known immunodeficiency (including receiving immunosuppressive therapy or a history of splenectomy); are infected with hepatitis B or C virus; have a history of autoimmune disease (including inflammatory bowel disease, hemolytic anemia, autoimmune hepatitis, rheumatoid arthritis, lupus, etc.) or connective tissue disease or have any other serious underlying medical condition. Clinically significant laboratory abnormalities as determined by the Investigator(s). Plan to have surgery between enrollment and the end of the challenge follow-up. Have any other conditions that are determined by at least two concurring investigators that may interfere with the capacity to provide free and willing informed consent.

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

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 3 +/- 1 bite<br>Volunteers were exposed to mosquito biting for 10 min | Biological: Sporozoite Challenge Model for Plasmodium vivax in Humans<br>* Eighteen naïve volunteers were exposed to the bite of carrying P. vivax sporozoites. Volunteers were randomly allocated to 1 of 6 groups and exposed to different numbers of mosquito biting, for 10 min. After feeding, dissection of all mosquitoes exposed in the cage was performed, to confirm the presence of a blood meal in their midguts and sporozoites in their salivary glands. If a volunteer did not get the number of infective bites assigned for his/her group, he/she was allowed to be bitten for a new group of mosquitoes until a total of 3±1, 6±1, or 9±1 mosquito bites were achieved.<br>* Other names: Controlled malaria vivax infection challenge;|
| Active Comparator: 6 +/- 1 bite<br>Volunteers were exposed to mosquito biting for 10 min | Biological: Sporozoite Challenge Model for Plasmodium vivax in Humans<br>* Eighteen naïve volunteers were exposed to the bite of carrying P. vivax sporozoites. Volunteers were randomly allocated to 1 of 6 groups and exposed to different numbers of mosquito biting, for 10 min. After feeding, dissection of all mosquitoes exposed in the cage was performed, to confirm the presence of a blood meal in their midguts and sporozoites in their salivary glands. If a volunteer did not get the number of infective bites assigned for his/her group, he/she was allowed to be bitten for a new group of mosquitoes until a total of 3±1, 6±1, or 9±1 mosquito bites were achieved.<br>* Other names: Controlled malaria vivax infection challenge;|
| Active Comparator: 9 +/- 1 bite<br>Volunteers were exposed to mosquito biting for 15 min | Biological: Sporozoite Challenge Model for Plasmodium vivax in Humans<br>* Eighteen naïve volunteers were exposed to the bite of carrying P. vivax sporozoites. Volunteers were randomly allocated to 1 of 6 groups and exposed to different numbers of mosquito biting, for 10 min. After feeding, dissection of all mosquitoes exposed in the cage was performed, to confirm the presence of a blood meal in their midguts and sporozoites in their salivary glands. If a volunteer did not get the number of infective bites assigned for his/her group, he/she was allowed to be bitten for a new group of mosquitoes until a total of 3±1, 6±1, or 9±1 mosquito bites were achieved.<br>* Other names: Controlled malaria vivax infection challenge;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of infected naïve human volunteers after different number of infected mosquito biting |  | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Minimal number of infected mosquitoes required to infect all volunteers with a reproducible prepatent period |  | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Malaria, Sporozoite, Challenge Model, Plasmodium vivax, Human Volunteers