VAC069: A Study of Blood-stage Controlled Human P. Vivax Infection

Study Overview
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Brief Summary
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This is a clinical study to assess the safety and feasibility of Plasmodium vivax (P. vivax) controlled blood-stage human malaria infection (CHMI), by inoculation using a newly created source of P. vivax malaria-infected blood. 25 healthy malaria-naïve UK volunteers, aged 18 - 50, will be recruited through the five phases of the study at the CCVTM, Oxford. Volunteers will undergo primary, secondary and tertiary P. vivax blood-stage challenges, which will be induced by injection of P. vivax infected blood. After the first challenge, the optimal dose for blood-stage CHMI will be selected and used for the second and third challenges. Through each challenge period, volunteers will have blood taken at regular intervals to measure the parasite growth, quantify the sexual parasite forms and assess the immune response to P. vivax infection. Transmission of P. vivax from volunteers to the Anopheline mosquito vectors will also be assessed. In each challenge, following diagnosis, volunteers will be treated with a standard antimalarial course of oral artemether-lumefantrine (Riamet), given over 60 hours. Volunteers who take part in this study will be involved in the trial for approximately 2 years, receiving each of the three challenges at intervals of approximately 5 (and up to 9) months. Volunteers will be followed for 3 months after their last challenge.

Detailed Description
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This study aims primarily to assess the safety and feasibility of controlled blood-stage human P. vivax malaria infection. This will be the first time that this source of P. vivax infected blood will be utilised and the first P. vivax bloodstage CHMI in Europe. If demonstrated to be safe, it is intended that this parasitised blood bank be used in future CHMI studies to evaluate candidate vaccines. This study will also assess parasite growth, including quantifying the sexual-stage parasites in the blood, as well as the transmission of P. vivax from volunteers to the Anopheline mosquito vectors and the immune responses in primary, secondary and tertiary P. vivax blood-stage challenge, as further secondary aims. Natural immunity to P. vivax is acquired over time, following repeated exposure. Repeated blood-stage challenge would improve understanding of how the human immune response to P. vivax infected is acquired, and how parasite growth changes in a second or third exposure. Repeated challenges can also be used to test if potential vaccine candidates can protect against repeated malaria infection. If proven to be safe and feasible in this study, this will provide a basis for conducting P. vivax blood-stage re-challenge studies for evaluation of new vaccine candidates. The study is funded through The Wellcome Trust and MultiViVax, a European Commission Horizon 2020 funded project.

Official Title
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VAC069: A Clinical Study to Assess the Safety and Feasibility of Controlled Blood-stage Plasmodium Vivax Human Malaria Infection Through Experimental Inoculation of Cryopreserved Infected Erythrocytes in Healthy Malaria-naïve UK Adults

Conditions
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Malaria, Vivax

Intervention / Treatment
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* Biological: P. vivax infected inoculum (parasitised red blood cells)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy adult aged 18 to 50 years. Red blood cells positive for the Duffy antigen/chemokine receptor (DARC). Normal serum levels of Glucose-6-phosphate dehydrogenase (G6PDH). Negative haemoglobinopathy screen Able and willing (in the Investigator's opinion) to comply with all study requirements. Willing to allow the Investigators to discuss the volunteer's medical history with their General Practitioner. Women only: Must practice continuous effective contraception for the duration of the clinic visits (first 3 months post-CHMI). Agreement to permanently refrain from blood donation Written informed consent to participate in the trial. Reachable (24/7) by mobile phone during the period between CHMI and completion of all antimalarial treatment. Willing to take a curative anti-malarial regimen following CHMI. Willing to reside in Oxford for the duration of the study, until antimalarials have been completed. Answer all questions on the informed consent quiz correctly. Exclusion Criteria: History of clinical malaria (any species). Travel to a clearly malaria endemic locality during the study period or within the preceding six months. Use of systemic antibiotics with known antimalarial activity within 30 days of CHMI (e.g.trimethoprim-sulfamethoxazole, doxycycline, tetracycline, clindamycin, erythromycin, fluoroquinolones and azithromycin). Haemoglobin <120 g/L for a female volunteer or <130 g/L for a male volunteer prior to primary CHMI. (However, for enrolment into secondary and tertiary CHMIs slightly lower haemoglobin values (≤0.5 g/L) will be permitted at the discretion of the Investigator, to account for the blood volume donated during the previous CHMI). Receipt of immunoglobulins within the three months prior to enrolment. Receipt of blood transfusion at any time in the past. Peripheral venous access unlikely to allow twice daily blood testing (as determined by the Investigator). Receipt of an investigational product in the 30 days preceding enrolment, 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. Planned receipt of a COVID-19 vaccine between 2 weeks before the day of CHMI until completion of antimalarial treatment Any confirmed or suspected immunosuppressive or immunodeficient state, including HIV infection; asplenia; recurrent, severe infections and chronic (more than 14 days) immunosuppressant medication within the past 6 months (inhaled and topical steroids are allowed). History of allergic disease or reactions likely to be exacerbated by malaria infection. Pregnancy, lactation or intention to become pregnant during the study. Use of medications known to cause prolongation of the QT interval and existing contraindication to the use of Malarone. Use of medications known to have a potentially clinically significant interaction with Riamet and Malarone. Any clinical condition known to prolong the QT interval. History of cardiac arrhythmia, including clinically relevant bradycardia. Disturbances of electrolyte balance, e.g. hypokalaemia or hypomagnesaemia. Family history of congenital QT prolongation or sudden death. Contraindications to the use of both of the proposed anti-malarial medications Riamet and Malarone. History of cancer (except basal cell carcinoma of the skin and cervical carcinoma in situ). History of serious psychiatric condition that may affect participation in the study. Any other serious chronic illness requiring hospital specialist supervision. Suspected or known current alcohol abuse as defined by an alcohol intake of greater than 25 standard UK units every week. Suspected or known injecting drug abuse in the 5 years preceding enrolment. Hepatitis B surface antigen (HBsAg) detected in serum. Seropositive for hepatitis C virus (antibodies to HCV) at screening or at C-7 (unless has taken part in a prior hepatitis C vaccine study with confirmed negative HCV antibodies prior to participation in that study, and negative HCV RNA PCR at screening for this study). Positive family history in both 1st AND 2nd degree relatives < 50 years old for cardiac disease. Volunteers unable to be closely followed for social, geographic or psychological reasons. Any clinically significant abnormal finding on biochemistry or haematology blood tests, urinalysis or clinical examination. In the event of abnormal test results, confirmatory repeat tests will be requested. Any other significant disease, disorder, or finding which may significantly increase the risk to the volunteer because of participation in the study, affect the ability of the volunteer to participate in the study or impair interpretation of the study data. Inability of the study team to contact the volunteer's GP to confirm medical history and safety to participate. Additional exclusion criteria for Groups 6-13: Body weight <50Kg, as measured at screening Exclusion criteria on day of CHMI: Acute disease, defined as moderate or severe illness with or without fever. Current COVID-19 infection, defined as ongoing symptoms with positive COVID-19 PCR swab test taken during current illness or positive COVID-19 PCR swab test within preceding 14 days without symptoms. Pregnancy. Potential volunteers who are due to have a COVID-19 vaccine in the period between 2 weeks before the day of malaria challenge and expected time of completion of malaria treatment will not be enrolled (estimate up to 3 weeks after day of challenge based on experience in this study to date). If a volunteer receives an appointment for COVID-19 vaccination after they have undergone malaria challenge but before reaching malaria diagnosis criteria, they will be advised to delay their COVID-19 vaccination until after reaching malaria diagnostic criteria and completion of antimalarial treatment. If a participant does not wish to delay their COVID-19 vaccination, they will be treated with antimalarial treatment at that time point and withdrawn from the study but will be encouraged to complete follow-up for safety.

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase A: Group 1<br>Each volunteer will receive one vial of P. vivax infected inoculum (parasitised red blood cells) at the first blood-stage controlled human malaria infection (CHMI). The optimal dose will be determined following the first CHMI and the selected dose will be administered to all volunteers (Groups 1-3) at both the second and third CHMI. | Biological: P. vivax infected inoculum (parasitised red blood cells)<br>* In the first controlled human malaria infection (CHMI, Phase A), inoculation of parasitised red blood cells will be at three different doses (1 vial, 1:5 dilution, 1:20 dilution). The optimal inoculation dose will then be selected and administered to all participants in each of the second and third CHMI.<br>|
| Experimental: Phase A: Group 2<br>Each volunteer will receive a fifth of a vial (1:5 dilution) of P. vivax infected inoculum (parasitised red blood cells) at the first blood-stage controlled human malaria infection (CHMI). The optimal dose will be determined following the first CHMI and the selected dose will be administered to all volunteers (Groups 1-3) at both the second and third CHMI. | Biological: P. vivax infected inoculum (parasitised red blood cells)<br>* In the first controlled human malaria infection (CHMI, Phase A), inoculation of parasitised red blood cells will be at three different doses (1 vial, 1:5 dilution, 1:20 dilution). The optimal inoculation dose will then be selected and administered to all participants in each of the second and third CHMI.<br>|
| Experimental: Phase A: Group 3<br>Each volunteer will receive one twentieth of a vial (1:20 dilution) of P. vivax infected inoculum (parasitised red blood cells) at the first blood-stage controlled human malaria infection (CHMI). The optimal dose will be determined following the first CHMI and the selected dose will be administered to all volunteers (Groups 1-3) at both the second and third CHMI. | Biological: P. vivax infected inoculum (parasitised red blood cells)<br>* In the first controlled human malaria infection (CHMI, Phase A), inoculation of parasitised red blood cells will be at three different doses (1 vial, 1:5 dilution, 1:20 dilution). The optimal inoculation dose will then be selected and administered to all participants in each of the second and third CHMI.<br>|
| Experimental: Phase B: Group 4<br>The six volunteers from Groups 1, 2 and 3 in will undergo secondary challenge using the optimal inoculum, as determined in Phase A of the study. They will constitute 'Group 4' in Phase B. This will occur approximately eight months (and up to nine months) later after their primary challenge. | Biological: P. vivax infected inoculum (parasitised red blood cells)<br>* In the first controlled human malaria infection (CHMI, Phase A), inoculation of parasitised red blood cells will be at three different doses (1 vial, 1:5 dilution, 1:20 dilution). The optimal inoculation dose will then be selected and administered to all participants in each of the second and third CHMI.<br>|
| Experimental: Phase B: Group 6<br>Three new malaria naïve volunteers will be recruited to undergo primary challenge using the optimal inoculum, as determined in Phase A of the study. They will act as controls to Group 4. | Biological: P. vivax infected inoculum (parasitised red blood cells)<br>* In the first controlled human malaria infection (CHMI, Phase A), inoculation of parasitised red blood cells will be at three different doses (1 vial, 1:5 dilution, 1:20 dilution). The optimal inoculation dose will then be selected and administered to all participants in each of the second and third CHMI.<br>|
| Experimental: Phase C: Group 5<br>The six volunteers from Group 4 in Phase B will undergo tertiary challenge, again using the optimal inoculum as determined in Phase A, and will constitute Group 5 in Phase C. This will occur approximately sixteen months (and up to twenty months) later after their secondary challenge. | Biological: P. vivax infected inoculum (parasitised red blood cells)<br>* In the first controlled human malaria infection (CHMI, Phase A), inoculation of parasitised red blood cells will be at three different doses (1 vial, 1:5 dilution, 1:20 dilution). The optimal inoculation dose will then be selected and administered to all participants in each of the second and third CHMI.<br>|
| Experimental: Phase C: Group 7<br>The three volunteers from Group 6 who underwent primary challenge in Phase B undergo secondary challenge, again using the optimal inoculum as determined in Phase A, and will now form Group 7 in Phase C. This will occur approximately six months (and up to nine months) later after their primary challenge. | Biological: P. vivax infected inoculum (parasitised red blood cells)<br>* In the first controlled human malaria infection (CHMI, Phase A), inoculation of parasitised red blood cells will be at three different doses (1 vial, 1:5 dilution, 1:20 dilution). The optimal inoculation dose will then be selected and administered to all participants in each of the second and third CHMI.<br>|
| Experimental: Phase C: Group 9<br>Four to eight new malaria-naïve volunteers will be recruited to undergo primary challenge using the optimal inoculum, as determined in Phase A of the study. They will act as controls for Groups 5 and 7. | Biological: P. vivax infected inoculum (parasitised red blood cells)<br>* In the first controlled human malaria infection (CHMI, Phase A), inoculation of parasitised red blood cells will be at three different doses (1 vial, 1:5 dilution, 1:20 dilution). The optimal inoculation dose will then be selected and administered to all participants in each of the second and third CHMI.<br>|
| Experimental: Phase D: Group 8<br>The three volunteers from Group 7 in Phase C will undergo tertiary challenge, again using the optimal inoculum as determined in Phase A, and will constitute Group 8 in Phase D. This will occur approximately five months (and up to ten months) after their secondary challenge. | Biological: P. vivax infected inoculum (parasitised red blood cells)<br>* In the first controlled human malaria infection (CHMI, Phase A), inoculation of parasitised red blood cells will be at three different doses (1 vial, 1:5 dilution, 1:20 dilution). The optimal inoculation dose will then be selected and administered to all participants in each of the second and third CHMI.<br>|
| Experimental: Phase D: Group 10<br>The four to eight volunteers from Group 9 in Phase C will undergo secondary challenge, using the optimal inoculum as determined in Phase A, and form Group 10 in Phase D. This will occur approximately six months (and up to nine months) later after their primary challenge. | Biological: P. vivax infected inoculum (parasitised red blood cells)<br>* In the first controlled human malaria infection (CHMI, Phase A), inoculation of parasitised red blood cells will be at three different doses (1 vial, 1:5 dilution, 1:20 dilution). The optimal inoculation dose will then be selected and administered to all participants in each of the second and third CHMI.<br>|
| Experimental: Phase D: Group 12<br>Four to eight new malaria-naïve volunteers will be recruited to undergo primary challenge using the optimal inoculum, as determined in Phase A of the study. They will act as controls for Groups 8 and 10. | Biological: P. vivax infected inoculum (parasitised red blood cells)<br>* In the first controlled human malaria infection (CHMI, Phase A), inoculation of parasitised red blood cells will be at three different doses (1 vial, 1:5 dilution, 1:20 dilution). The optimal inoculation dose will then be selected and administered to all participants in each of the second and third CHMI.<br>|
| Experimental: Phase E: Group 11<br>The four to eight volunteers from Group 10 in Phase D will undergo tertiary challenge, again using the optimal inoculum as determined in Phase A, and will constitute Group 11 in Phase E. This will occur approximately five months (and up to ten months) after their secondary challenge. | Biological: P. vivax infected inoculum (parasitised red blood cells)<br>* In the first controlled human malaria infection (CHMI, Phase A), inoculation of parasitised red blood cells will be at three different doses (1 vial, 1:5 dilution, 1:20 dilution). The optimal inoculation dose will then be selected and administered to all participants in each of the second and third CHMI.<br>|
| Experimental: Phase E: Group 13<br>The four to eight volunteers from Group 12 in Phase D will undergo secondary challenge, again using the optimal inoculum as determined in Phase A, and will constitute Group 13 in Phase E. This will occur approximately five months (and up to ten months) after their secondary challenge. | Biological: P. vivax infected inoculum (parasitised red blood cells)<br>* In the first controlled human malaria infection (CHMI, Phase A), inoculation of parasitised red blood cells will be at three different doses (1 vial, 1:5 dilution, 1:20 dilution). The optimal inoculation dose will then be selected and administered to all participants in each of the second and third CHMI.<br>|
| Experimental: Phase E: Group 15<br>Two new malaria-naïve volunteers will be recruited to undergo primary challenge using the optimal inoculum, as determined in Phase A of the study. They will act as controls for Groups 11 and 13. | Biological: P. vivax infected inoculum (parasitised red blood cells)<br>* In the first controlled human malaria infection (CHMI, Phase A), inoculation of parasitised red blood cells will be at three different doses (1 vial, 1:5 dilution, 1:20 dilution). The optimal inoculation dose will then be selected and administered to all participants in each of the second and third CHMI.<br>|
| Experimental: Phase F: Group 14<br>The four to eight volunteers from Group 13 in Phase E will undergo tertiary challenge, again using the optimal inoculum as determined in Phase A, and will constitute Group 14 in Phase F. This will occur approximately five months (and up to ten months) after their secondary challenge. | Biological: P. vivax infected inoculum (parasitised red blood cells)<br>* In the first controlled human malaria infection (CHMI, Phase A), inoculation of parasitised red blood cells will be at three different doses (1 vial, 1:5 dilution, 1:20 dilution). The optimal inoculation dose will then be selected and administered to all participants in each of the second and third CHMI.<br>|
| Experimental: Phase F: Group 16<br>Two new malaria-naïve volunteers will be recruited to undergo primary challenge using the optimal inoculum, as determined in Phase A of the study. They will act as controls for Group 14. | Biological: P. vivax infected inoculum (parasitised red blood cells)<br>* In the first controlled human malaria infection (CHMI, Phase A), inoculation of parasitised red blood cells will be at three different doses (1 vial, 1:5 dilution, 1:20 dilution). The optimal inoculation dose will then be selected and administered to all participants in each of the second and third CHMI.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of primary P. vivax blood-stage CHMI as measured by (S)AE occurrences |  | 36 months | 
| The optimal inoculation dose to take forward to future P. vivax CHMI studies | Choosing the optimal inoculation dose to take forward to future P. vivax CHMI studies will be decided based on the following algorithm: Ideal choice = the first group (2/2 volunteers) to reach diagnosis criteria (within 21 days). N.B. If both volunteers in Group 1 develop infection AND both volunteers in Group 2 (or 3) reliably develop infection within 5 days of Group 1 (and within the 21-day window) then the lowest dose group should be chosen. | 3 months | 
| Feasibility of primary P. vivax blood-stage CHMI as measured by successful infection (development of detectable persistent parasitaemia by thick film and qPCR +/- clinical symptoms) |  | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of secondary and tertiary P. vivax controlled blood-stage CHMI as measured by (S)AE occurrences |  | 36 months | 
| Immune response to primary, secondary and tertiary P. vivax pre-treatment | As measured by antibody, B cell and T cell responses through experimental injection of P. vivax infected erythrocytes | 36 months | 
| Gametocytaemia | As measured by qPCR in primary, secondary and tertiary P. vivax blood-stage CHMI. | 36 months | 
| Feasibility of secondary and tertiary P. vivax controlled blood-stage CHMI as measured by successful infection (development of detectable persistent parasitaemia by thick film and qPCR +/- clinical symptoms) |  | 36 months | 
| Transmissibility of gametocytes from the infected volunteer to Anopheline mosquito vector, which will be assesed by Direct Membrane Feeding Assays (DMFA) |  | 36 months |