Malaria, Vivax
Conditions
Brief summary
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
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.
Interventions
BIOLOGICALP. vivax infected inoculum (parasitised red blood cells)
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.
Sponsors
University of Oxford
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Serious Adverse Events | 36 months | — |
| Number of Participants Who Developed Infection/Reached Diagnosis Criteria, Used to Select the Optimal Inoculation Dose to Take Forward to Future P. Vivax CHMI Studies Based on a Protocol-specified Algorithm | 3 months | 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. |
| 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 | Number of participants developing detectablable parasitaemia during primary CHMI with P. vivax (PvW1 clone) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| Safety of Secondary and Tertiary P. Vivax Controlled Blood-stage CHMI as Measured by (S)AE Occurrences | 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 | — |
| Immune Response to Primary, Secondary and Tertiary P. Vivax Pre-treatment | 36 months | As measured by antibody, B cell and T cell responses through experimental injection of P. vivax infected erythrocytes |
| Gametocytaemia | 36 months | As measured by qPCR in primary, secondary and tertiary P. vivax blood-stage CHMI. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase A: Group 1 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. | 2 |
| Phase A: Group 2 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. | 2 |
| Phase A: Group 3 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. | 2 |
| Phase B: Group 6 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. | 2 |
| Phase C: Group 9 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. | 7 |
| Phase D: Group 12 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. | 4 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| VAC069A | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Phase A: Group 1 | Phase A: Group 2 | Phase A: Group 3 | Phase B: Group 6 | Phase C: Group 9 | Phase D: Group 12 | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 32 years | 25.5 years | 22.5 years | 26 years | 27 years | 25.5 years | 26 years |
| Race/Ethnicity, Customized Arab | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Mixed - White and Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 2 Participants | 1 Participants | 1 Participants | 2 Participants | 4 Participants | 4 Participants | 14 Participants |
| Region of Enrollment United Kingdom | 2 participants | 2 participants | 2 participants | 2 participants | 7 participants | 4 participants | 19 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 4 Participants | 2 Participants | 9 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 3 Participants | 2 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 12 | 0 / 2 | 0 / 6 |
| other Total, other adverse events | 12 / 19 | 2 / 12 | 1 / 2 | 2 / 6 |
| serious Total, serious adverse events | 1 / 19 | 0 / 12 | 0 / 2 | 0 / 6 |
Outcome results
Primary
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)
Number of participants developing detectablable parasitaemia during primary CHMI with P. vivax (PvW1 clone)
Time frame: 36 months
Population: All volunteers undergoing primary controlled human malaria infection with P. vivax (PvW1 clone)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Primary P. Vivax CHMI | 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) | 19 Participants |
Primary
Number of Participants Who Developed Infection/Reached Diagnosis Criteria, Used to Select the Optimal Inoculation Dose to Take Forward to Future P. Vivax CHMI Studies Based on a Protocol-specified Algorithm
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.
Time frame: 3 months
Population: All 6 volunteers who underwent primary CHMI during phase VAC069A of the study developed malaria infection and reached diagnostic criteria. An inoculation dose of 1:10 dilution of 1 vial of inoculum per volunteer was chosen for subsequent phases of the study VAC069B to VAC069D.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Primary P. Vivax CHMI | Number of Participants Who Developed Infection/Reached Diagnosis Criteria, Used to Select the Optimal Inoculation Dose to Take Forward to Future P. Vivax CHMI Studies Based on a Protocol-specified Algorithm | 2 Participants who developed infection |
| Phase A: Group 2 | Number of Participants Who Developed Infection/Reached Diagnosis Criteria, Used to Select the Optimal Inoculation Dose to Take Forward to Future P. Vivax CHMI Studies Based on a Protocol-specified Algorithm | 2 Participants who developed infection |
| Phase A: Group 3 | Number of Participants Who Developed Infection/Reached Diagnosis Criteria, Used to Select the Optimal Inoculation Dose to Take Forward to Future P. Vivax CHMI Studies Based on a Protocol-specified Algorithm | 2 Participants who developed infection |
Primary
Number of Participants With Serious Adverse Events
Time frame: 36 months
Population: Number of SAEs occuring during study period
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Primary P. Vivax CHMI | Number of Participants With Serious Adverse Events | 1 Participants |
Secondary
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)
Time frame: 36 months
Secondary
Gametocytaemia
As measured by qPCR in primary, secondary and tertiary P. vivax blood-stage CHMI.
Time frame: 36 months
Secondary
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
Time frame: 36 months
Secondary
Safety of Secondary and Tertiary P. Vivax Controlled Blood-stage CHMI as Measured by (S)AE Occurrences
Time frame: 36 months
Population: Number of SAEs occuring during study period
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Primary P. Vivax CHMI | Safety of Secondary and Tertiary P. Vivax Controlled Blood-stage CHMI as Measured by (S)AE Occurrences | 0 Participants |
| Phase A: Group 2 | Safety of Secondary and Tertiary P. Vivax Controlled Blood-stage CHMI as Measured by (S)AE Occurrences | 0 Participants |
| Phase A: Group 3 | Safety of Secondary and Tertiary P. Vivax Controlled Blood-stage CHMI as Measured by (S)AE Occurrences | 0 Participants |
Secondary
Transmissibility of Gametocytes From the Infected Volunteer to Anopheline Mosquito Vector, Which Will be Assesed by Direct Membrane Feeding Assays (DMFA)
Time frame: 36 months