Host Immune and Metabolic Determinants of Sexual Conversion in Plasmodium Parasites IMMETASEX

Severe Malaria Clinical Trial

— IMMETASEX  

Official title:

Host Immune and Metabolic Determinants of Sexual Conversion in Plasmodium Parasites IMMETASEX

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06064591
• Other study ID #: IMMETASEX 1704/23
• Secondary ID: G067823N
• Status: Recruiting
• Start date: December 13, 2023
• Est. completion date: December 2026

Study information

• Verified date: January 2024
• Source: Institute of Tropical Medicine, Belgium
• Contact: Vera EA Kühne, PhD
• Phone: +32(0)33455833
• Email: vkuhne[@]itg.be
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial Summary

Understanding the sexual conversion of the malaria parasite is essential to interrupt malaria transmission. A new tool is developed that, based on expression analysis of sexual stage biomarkers, will estimate sexual conversion rates in natural infections.

Description:

Understanding the sexual conversion of the malaria parasite is essential to interrupt malaria transmission. At each replicating cycle within erythrocytes, a proportion of asexual parasites converts into non-replicative sexual stages, which are the only forms able to infect mosquitos. The rate at which sexual stages are produced, is known as basal sexual conversion rate. Changes in the host immune and metabolic environment associated with the development of malaria disease, such as depletion of lysophosphatidylcholine in plasma, have been associated with increased sexual conversion rates in vitro. It is hypothesised that immune and metabolite factors that are altered during malaria infection induce sexual conversion in Plasmodium falciparum parasites. In this project, a new tool is developed that, based on expression analysis of sexual stage biomarkers, will estimate sexual conversion rates in natural infections. The aim is to identify immune factors and metabolites that induce sexual conversion using in-house developed sexual conversion assays, and experimental mosquito infections. Finally, transcriptional mechanisms are explored driving parasite sexual conversion in the host environment during disease using single-cell RNA-sequencing approaches. This research will provide essential knowledge on the factors that affect sexual conversion in the host and potentially inform novel strategies to interrupt transmission.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 430
• Est. completion date: December 2026
• Est. primary completion date: December 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 1 Year and older

Eligibility

Inclusion Criteria:

• Age: = 1 year
• Willing and able to provide written informed consent (or assent for minors with written informed consent by parent(s) and/or guardian(s). Pilot: -symptomatic for P. falciparum -/Travel to P. falciparum endemic area within the last month

WP1:

• Resident in Nanoro district
• non-symptomatic individuals

WP2:

• Positive for P. falciparum infection via Rapid Diagnostic Tests (RDT)
• Age: = 1 and = 12 years
• Patients are included when suspected of the following conditions:

I. Severe malaria by infection with P. falciparum is defined in the presence of P.

falciparum asexual parasitemia, and as one or more of the following:

1. Impaired consciousness: A Blantyre coma score < 3 (when patients are = 6 years) or Glasgow coma score < 10 (when patients are = 6 years).

2. Prostration: Generalized weakness so that the person is unable to sit, stand or walk without assistance.

3. Multiple convulsions: More than two episodes within 24 hours.

4. Clinical manifestation of respiratory distress (e.g., rapid, deep and labored breathing).

5. Diagnosis through exclusion: absence of an identified alternative cause. II. Uncomplicated malaria by infection with P. falciparum is defined as a patient who presents with lethargic profile (e.g. fever) and a positive parasitological test for P. falciparum, but with no features of severe malaria.

Exclusion Criteria:

• Delayed developmental status or history of chronic illness
• Participation in another study
• Previous malaria treatment or prophylaxis in the last week
• Inability or unwillingness of the parents or guardians to provide informed consent

WP1:

• Symptoms of malaria, as defined by presence of fever (body temperature >37.5 °C or history of fever during the past 48 hours) with a positive RDT (RDT are performed always when there is presence of fever)
• Any plans to leave the study are in the coming 10 days

WP2:

• Severe anemia (will be determined via clinical examination), since blood samples can hardly be withdrawn, co-morbidities.
• A questionnaire will be used during the clinical assessment that addresses following exclusion criteria: x Antimalarial drug treatment or other medication during the past week x If the patient had a meal within 4 hours before admission x Patients with acute meningitis (as clinically evaluated according to the local guidelines) x Patients with developmental delay or history of chronic illness x Vaccination during the past week

Related Conditions & MeSH terms

• Malaria
• Severe Malaria
• Uncomplicated Malaria

Locations

Country	Name	City	State
Belgium	Institute of Tropical Medicine Antwerp	Antwerp
Burkina Faso	Institut de Recherche en Sciences de la Santé - Clinical Research Unit of Nanoro	Nanoro
Mozambique	Instituto Nacional de Saúde (INS)	Maputo

Sponsors (6)

Lead Sponsor	Collaborator
Institute of Tropical Medicine, Belgium	Barcelona Institute for Global Health, Clinical Research Unit of Nanoro (CRUN), Burkina Faso, Instituto Nacional de Saúde, Mozambique, KU Leuven, Leiden University Medical Center

Countries where clinical trial is conducted

Belgium,  Burkina Faso,  Mozambique, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To validate a Sexual Conversion Estimator tool	To validate a Sexual Conversion Estimator tool to accurately estimate SC rates and future transmission potential in epidemiological samples. First, the investigators will measure expression levels of SRBs and directly determine SC rates in samples from malaria asymptomatic patients. Second, the investigators will use a machine learning classifier to determine the combination of SRBs that best predicts SC rates; and third, the investigators will measure the predictive value of the Estimator tool for future transmission potential	2023-2025
Secondary	To investigate in malaria patients associations between host immune and metabolic factors and P. falciparum sexual conversion and infection potential	In patients with uncomplicated and severe malaria, the investigators will investigate associations between host inflammatory molecules, parasite-specific Ab and metabolic factors, with parasite SC rates. The investigators hypothesize that SC rates will be higher in severe malaria patients and associated with specific molecules and metabolites.	2023-2025
Secondary	To validate associations between sexual conversion and host immune and metabolic factors in vitro	An in vitro assay, based on recently described gametocyte-reporter parasite lines 16 will be used to validate candidate associations identified in Objective 2. First, the effect of patient serum samples and specific metabolites and inflammatory factors via in vitro SC assays is tested. Next, in vitro cultures with significantly induced SC will be fed to Anopheles stephensi mosquitoes to assess infection potential via standard membrane feeding assays. It is hypothesized that plasma/factors identified in Objective 2, induce SC in vitro and increase mosquito infections.	2024-2026
Secondary	To explore transcriptional mechanisms driving parasite sexual conversion in the host environment during uncomplicated and severe malaria disease	Use of a single cell RNA-sequencing (scRNA-seq) approaches to generate the first in-depth characterization of gene expression patterns of very early sexual stages in the host circulation during natural infections in uncomplicated and severe clinical presentations (samples collected in Objective 2).	2024-2026