In-vivo Transmission Model in Semi-immune Adults

Summary

Controlled human malaria infection (CHMI) has revolutionized the development of malaria vaccines. It involves the administration of either known numbers of sporozoites or infected erythrocytes to healthy human volunteers under a controlled environment. The use of highly sensitive molecular malaria diagnostic methods informs treatment decisions before symptom development and allows the characterization of parasite growth dynamics. Sporozoite CHMI has safely been used in six countries in Africa providing a platform to assess the efficacy of candidate malaria vaccines and study the natural immunity to malaria. Blood stage CHMI involves administration of known number of Artemether Lumefantrine sensitive infected erythrocytes in healthy volunteers, and it is a more sensitive model for modelling parasite growths and study the efficacy of blood-stage malaria vaccines. It has been safely used in Australia and Europe but not in Africa. Adaptation of this model by administration of combination of suboptimal and optimal antimalarial drugs lead to increased gametocytaemia, and infection rates in mosquitoes following standard membrane feeding assay. Such adaptation allows the model to be used to study parasite transmission from human to mosquitoes and evaluate transmission blocking malaria interventions.

There is an urgent need to establish an in vivo model for early-stage clinical evaluation of transmission blocking interventions (TBI) in volunteers living in malaria endemic countries. This would allow rapid and cost-effective way to down-select transmission blocking candidate malaria vaccine and gametocidal antimalarial drugs before larger, more complex, and expensive field efficacy studies are conducted. A study done in naïve individual showed 100% success in establishing a malaria infection using 2800 P. falciparum infected RBCs, while a recent study (manuscript in development) has demonstrated success in establishing infection in Tanzanian semi-immune individuals with low malaria exposure using 1000 P. falciparum infected RBCs. We will use 1000 ALU-sensitive 3D7 P. falciparum infected RBCs to establish an in vivo transmission model for studying Transmission blocking interventions and assess the efficiency of two antimalarial drugs regimens (Piperaquine and doxycycline) to induce high levels of gametocytaemia and mosquito infection rates in healthy African adults. We will also investigate the determinants of successful transmission to mosquitoes including underlying immune responses to both asexual and sexual malaria antigens, asexual parasite dynamics and gametocyte burden, sex ratio of male and female gametocytes, and the relationship between gametocyte density and mosquito infection rate

Conditions

• Controlled Human Malaria Infection
• Induced Blood Stage Malaria Infection
• Malaria Transmission
• Malaria Challenge

Interventions

DRUG

Piperaquine tablets , which will be administered orally as a single dose of 480mg (320mg+160mg).

The first arm will receive Piperaquine tablets, that will be administered orally. Sub-curative regimen will be given as two tablets of 320mg and 160mg (total of 480mg).

DRUG

Doxycycline (100mg tablets strength as Doxycycline Hyclate) will also be administered orally and will be given as 1 tablet (100mg) Once daily for 7 days.

The second arm will receive Doxycycline (100mg tablets strength as Doxycycline hyclate) that will also be administered orally. Sub-curative regimen will be given as 1 tablet (100mg) once daily for 7 days.

Sponsors & Collaborators

• University of Oxford

  collaborator OTHER

• Ifakara Health Institute

  lead OTHER

Principal Investigators

• Ally Olotu, MD,Dphil · Ifakara Health Institute

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

45 Years

Sex

MALE

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2024-01-09

Primary Completion

2024-02-13

Completion

2024-06-30

Countries

• Tanzania

Study Locations