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

NCT03797989 | Completed Early Phase 1 Results DMC

• 1 other identifier: VAC069
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 1

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.

Conditions

Malaria, Vivax

Outcome Measures

Primary Outcomes (3)

• 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

  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)

  Number of participants developing detectablable parasitaemia during primary CHMI with P. vivax (PvW1 clone)

  36 months

Secondary Outcomes (5)

• 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

  36 months

• Gametocytaemia

  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

Study Arms (12)

Phase A: Group 1

EXPERIMENTAL

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)

Phase A: Group 2

EXPERIMENTAL

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)

Phase A: Group 3

EXPERIMENTAL

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)

Phase B: Group 4

EXPERIMENTAL

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)

Phase B: Group 6

EXPERIMENTAL

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)

Phase C: Group 5

EXPERIMENTAL

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)

Phase C: Group 7

EXPERIMENTAL

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)

Phase C: Group 9

EXPERIMENTAL

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)

Phase D: Group 8

EXPERIMENTAL

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)

Phase D: Group 10

EXPERIMENTAL

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)

Phase D: Group 12

EXPERIMENTAL

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)

Phase E: Group 13

EXPERIMENTAL

Volunteers from Groups 10 and 12 who completed at least one P. vivax CHMI in Phase D will be re-enrolled into Group 13 to undergo repeat heterlogous CHMI with P. falciparum in Phase E. This will occur occur approximately 12 months after their last P. vivax challenge.

Biological: P. vivax infected inoculum (parasitised red blood cells)

Interventions

P. vivax infected inoculum (parasitised red blood cells) BIOLOGICAL

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.

Phase A: Group 1; Phase A: Group 2; Phase A: Group 3; Phase B: Group 4; Phase B: Group 6; Phase C: Group 5; Phase C: Group 7; Phase C: Group 9; Phase D: Group 10; Phase D: Group 12; Phase D: Group 8; Phase E: Group 13

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Oxford: lead

Study Sites (1)

Centre for Clinical Vaccinology & Tropical Medicine

Oxford, Oxfordshire, OX3 7LE, United Kingdom

Location

Related Publications (4)

• Hou MM, Harding AC, Barber NM, Kundu P, Bach FA, Salkeld J, Themistocleous Y, Greenwood NM, Cho JS, Barrett JR, Nugent FL, Rawlinson TA, Hodgson SH, Khozoee B, Mac Lochlainn DJ, Cowan RE, Poulton ID, Baker M, Kingham L, Mitton CH, Platt A, Lopez Ramon R, Ramos Lopez F, Thomas M, Skinner K, Quinkert D, Pipini D, Lias AM, Bardelli M, Edwards NJ, Donnellan FR, Biswas S, Rayner JC, Nielsen CM, Silk SE, Draper SJ, Nahrendorf W, Spence PJ, Minassian AM. Development of clinical immunity to Plasmodium vivax following repeat controlled human malaria infection. Nat Commun. 2025 Sep 25;16(1):8385. doi: 10.1038/s41467-025-63104-y.

  PMID: 40998768 DERIVED

• Bach FA, Munoz Sandoval D, Mazurczyk M, Themistocleous Y, Rawlinson TA, Harding AC, Kemp A, Silk SE, Barrett JR, Edwards NJ, Ivens A, Rayner JC, Minassian AM, Napolitani G, Draper SJ, Spence PJ. A systematic analysis of the human immune response to Plasmodium vivax. J Clin Invest. 2023 Oct 16;133(20):e152463. doi: 10.1172/JCI152463.

  PMID: 37616070 DERIVED

• Hou MM, Barrett JR, Themistocleous Y, Rawlinson TA, Diouf A, Martinez FJ, Nielsen CM, Lias AM, King LDW, Edwards NJ, Greenwood NM, Kingham L, Poulton ID, Khozoee B, Goh C, Mac Lochlainn DJ, Salkeld J, Guilotte-Blisnick M, Huon C, Mohring F, Reimer JM, Chauhan VS, Mukherjee P, Biswas S, Taylor IJ, Lawrie AM, Cho JS, Nugent FL, Long CA, Moon RW, Miura K, Silk SE, Chitnis CE, Minassian AM, Draper SJ. Impact of a blood-stage vaccine on Plasmodium vivax malaria. medRxiv [Preprint]. 2022 May 30:2022.05.27.22275375. doi: 10.1101/2022.05.27.22275375.

  PMID: 35664997 DERIVED

• Minassian AM, Themistocleous Y, Silk SE, Barrett JR, Kemp A, Quinkert D, Nielsen CM, Edwards NJ, Rawlinson TA, Ramos Lopez F, Roobsoong W, Ellis KJ, Cho JS, Aunin E, Otto TD, Reid AJ, Bach FA, Labbe GM, Poulton ID, Marini A, Zaric M, Mulatier M, Lopez Ramon R, Baker M, Mitton CH, Sousa JC, Rachaphaew N, Kumpitak C, Maneechai N, Suansomjit C, Piteekan T, Hou MM, Khozoee B, McHugh K, Roberts DJ, Lawrie AM, Blagborough AM, Nugent FL, Taylor IJ, Johnson KJ, Spence PJ, Sattabongkot J, Biswas S, Rayner JC, Draper SJ. Controlled human malaria infection with a clone of Plasmodium vivax with high-quality genome assembly. JCI Insight. 2021 Dec 8;6(23):e152465. doi: 10.1172/jci.insight.152465.

  PMID: 34609964 DERIVED

MeSH Terms

Conditions

Malaria, Vivax

Condition Hierarchy (Ancestors)

Malaria; Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Results Point of Contact

• Title: Dr. Angela Minassian
• Organization: University of Oxford

angela.minassian@bioch.ox.ac.uk

07973684040

Study Officials

• Angela M Minassian, MBBS MA DPhil MRCP FRCPath

  University of Oxford

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 29, 2018
• First Posted: January 9, 2019
• Study Start: January 10, 2019
• Primary Completion: December 20, 2022
• Study Completion: December 20, 2022
• Last Updated: April 25, 2025
• Results First Posted: April 25, 2025

Record last verified: 2023-03

Locations

GB (1)