Vivax Malaria Human Infection Studies in Thailand

Study Overview
=================
Brief Summary
-----------------
This study is a human challenge study to assess the feasibility and safety of controlled human malaria infection (via P. vivax sporozites) in healthy volunteers, and to develop a bank of P. vivax-infected blood for use in future controlled human P. vivax malaria infection studies. Additional objectives are to obtain data on host immune response to P. vivax infection and pre-treatment gametocytaemia. This study is funded by the UK Wellcome Trust. The grant reference number are Oxford/MORU: 212336/Z/18/Z and 212336/Z/18/A, and Mahidol University: 212336/A/18/Z and 212336/A/18/A.

Detailed Description
-----------------
Six healthy, malaria-naïve Thai adults, aged between 18 and 55 years will be recruited at the Clinical Therapeutics Unit (CTU) in the Hospital for Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok. The overall period of participation will be 15 months: a 3-month screening process prior to the Day 0 challenge, followed by 1 year after challenge. All inclusion and exclusion criteria will be checked to ensure eligibility criteria have been met prior to Day 0. Volunteers will be admitted as inpatients to the CTU on Day -1 ( a day prior to the challenge day). Challenge (bites from 5 infected mosquitoes) will be administered at the Insectarium unit, Department of Entomology, Faculty of Tropical Medicine, Mahidol University. The infected mosquitoes will be prepared by the Malaria Vivax Research unit (MVRU, Faculty of Tropical Medicine, Mahidol University). Following successful feeding by the infectious mosquitoes, volunteers will be monitored daily as inpatients for parasitemia and clinical presentation of malaria infection (Days 1-5). Beginning on Day 6, volunteers will be assessed twice a day and, at a timepoint that will depend upon the level of parasitaemia and/or degree of the volunteer's symptoms, up to 250 mL of blood will be drawn and then antimalarial treatment will be prescribed. The standard malaria radical cure according to Thai national guideline will be chloroquine, followed by a 2-week course of direct observed oral primaquine (PQ). Upon confirmation of clinical recovery, completion of chloroquine treatment and laboratory absence of infection, volunteers will be discharged and followed daily as outpatients through completion of oral primoquine therapy. After completion of antimalarial therapy, all volunteers will continue to be followed for 1 year after Day 0: Outpatient CTU visits on Days 45, 90, and 365 post-challenge. Procedures to be performed during these visits will include review of symptom diary cards, medical history, physical examination and assessment of adverse events. Blood samples will also be obtained to detect malaria antigens and assess immune response. Volunteers will be contacted by study staff every 2 weeks between visits until Day 365, to inquire for malaria symptoms or other adverse events.

Official Title
-----------------
A Clinical Study to Assess the Feasibility of a Controlled Human Plasmodium Vivax Malaria Infection Model Through Sporozoite Infection in Thai Adults

Conditions
-----------------
Plasmodium Vivax Infection

Intervention / Treatment
-----------------
* Other: Mosquito bites


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy adult aged 18 to 55 years. Blood group O. Red blood cells positive for the Duffy antigen/chemokine receptor (DARC). Normal CYP2D6 genotype. Normal blood levels of Glucose-6-phosphate dehydrogenase (G6PDH) by WHO definition. Able and willing to comply with all study requirements. Must practice continuous effective contraception for the duration of the clinic visits (first 3 months post-challenge). Agreement to refrain from blood donation during the course of the study and for at least 5 years after the end of their involvement in the study. Willing to take a curative antimalarial regimen following challenge. Willing to be admitted to the FTMCTU in the Hospital of Tropical Medicine for blood donation and clinical monitoring, until antimalarial treatment is completed and their symptoms are settling. Willing to reside in Bangkok for the duration of the study, until all antimalarial treatment has been completed. Reachable (24/7) by mobile phone during the period between challenge CHMI and completion of all antimalarial treatment. Able to read and write and able to answer ALL questions on the informed consent questionnaire correctly. Provided written informed consent to participate in the trial. Exclusion Criteria: History of clinical malaria. Positive malaria PCR OR malaria film OR malaria serology History of severe allergy to mosquito bite Presence of any medical condition (either physical or psychological) which in the judgment of the investigator would place the participant at undue risk or interfere with the results of the study (e.g. serious underlying cardiac, renal, hepatic or neurological disease; severe malnutrition; congenital defects or febrile condition). Plan to travel outside of Bangkok within the period of challenge until 3 months after. Use of systemic antibiotics with known antimalarial activity in the 30 days before challenge (e.g. trimethoprim-sulfamethoxazole, doxycycline, tetracycline, clindamycin, erythromycin, fluoroquinolones and azithromycin). Use of immunoglobulins or blood products (e.g. blood transfusion) at any time in the past. Venipuncture unlikely to allow a 250 mL blood donation (as determined by the investigator). Receipt of an investigational product in the 30 days preceding enrolment (D0), or planned receipt during the study period. Prior receipt of an investigational vaccine likely to impact on interpretation of the trial data or the P. vivax parasite as assessed by the Investigator. Any confirmed or suspected immunosuppressive or immunodeficient state, including HIV infection, asplenia, history of splenectomy, recurrent, severe infections, and chronic infection. Immunosuppressant medication within the past 6 months preceding enrolment (D0) (inhaled and topical steroids are allowed). History of allergic disease or reactions likely to be exacerbated by malaria infection. Female participant who is pregnant, lactating or planning pregnancy during the course of the study. Contraindications to the use of antimalarial treatment (ex. chroroquine or primaquine). Use of medications known to have a potentially clinically significant interaction with antimalarial drug (ex. chroroquine or primaquine). Suspected or known current alcohol abuse Suspected or known injecting drug abuse. Use of medications known to cause prolongation of the QT interval and existing positive family history in both 1st AND 2nd degree relatives < 50 years old for cardiac disease. Family history of congenital QT prolongation or sudden death. Any clinical condition known to prolong the QT interval. History of cardiac arrhythmia, including clinically relevant bradycardia. Concurrently participating in another clinical study, at any time during the study period. Screening ECG demonstrates a QTc interval ≥ 450 ms Haemoglobin < 13 g/dL in male, < 12g/dL in female (Thai Red Cross). Mean corpuscular volume (MCV) < 70 fL/cell Any clinically significant abnormal finding on biochemistry or haematology blood tests, urinalysis or clinical examination. Thalassemia or hemoglobinopathies. Positive for blood borne and vector borne infectious diseases (HIVI-II, HBV, HCV, Dengue, Zika, Chikungunya, Filariasis, JE, and malaria antigen, Anti HTLVI and Anti-HTLVII antibody, Syphilis test (VDRL, TPHA) Serum pregnancy test positive

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Interventional Model Description: Mosquito-bite controlled human challenge infection
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Malaria challenge<br>Malaria Sporozoite Challenge by mosquito bites. | Other: Mosquito bites<br>* Successful feeding of 5 infected P. vivax mosquitoes<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Successful infection of controlled P. vivax sporozoite human challenge | Measured by successful infection (development of detectable persistent parasitaemia) and malaria clinical symptoms, if any, after mosquito bite malaria sporozoite challenge | up to 21 days after challenge | 
| (Serious) Adverse Event(s) occurrences of controlled P. vivax sporozoite human challenge | Measured by (S)AE(s) occurrences after mosquito bite malaria sporozoite challenge. | up to 90 days after challenge | 
| Collection and freezing down of up to 250 mL P. vivax-infected blood from each of the 6 volunteers. | measured by successful collection and freezing down of up to 250 mL P. vivax-infected blood from each of the 6 volunteers. | up to 21 days after challenge | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cellular Immune response to primary P. vivax infection. | immune cells including Innate and adaptive immune cells react and express during the PV infection (profile and frequency) | up to 1 year after challenge | 
| Humoral Immune response to primary P. vivax infection. | Immune cells defense PV antigen by determining the level of antibody response and inflammatory cytokine | up to 1 year after challenge | 
| Gametocytaemia following primary P. vivax infection delivered by the mosquito bite | Gametocyte qPCR following primary P. vivax infection delivered by the mosquito bite | up to 1 year after challenge |