Biological Mechanisms in Afebrile P. Falciparum Malaria (AsintMal)

Unravelling Disease Tolerance and Host Resistance in Afebrile P. Falciparum Infections: a Prospective Study in Mozambican Adults

This project aims to disentangle the role of host immune resistance and disease tolerance in afebrile malaria infections, with the goal of guiding context-adapted tactics to target this hidden reservoir, as well as to develop new approaches to clear malaria infection and reduce its severity through host-directed therapies.

Study Overview

• Status: Completed
• Conditions: Falciparum Malaria
• Intervention / Treatment: Other: No intervention

Detailed Description

Asymptomatic Plasmodium falciparum (Pf) infections debilitate the health of affected population while representing a hidden source of parasite transmission that can compromise elimination efforts. The lack of consensus on the best strategy to deal with this asymptomatic reservoir is partly due to the poor knowledge on the biological mechanisms underlying these subclinical infections. Preliminary results in Mozambique show that afebrile adults with a Pf infection detected by rapid diagnostic tests can progress to fever (10%), clear the infection (20%) and stabilize at low-density (50%) or high-density (20%) parasitemias. The study hypothesis is that these four main trajectories are driven by antibodies against Pf variant antigens, codified by the var gene family and expressed on the surface of infected erythrocytes, which would clear the infection unless the parasites develop immune evasion mechanisms, and by tolerance factors that minimize parasite-induced pathology and sustains host homeostasis.With the overarching goal of identifying key biological factors sustaining afebrile malaria infections, this project will establish a cohort of afebrile Mozambican adults followed during one month to identify subjects who can reduce pathogen load and eventually clear the infection, those who maintain infections at high-density and afebrile levels (tolerant), and those who fail to establish disease tolerance and progress to fever. Circulating and overall parasite biomass will be quantified, and new infections will be identified during follow-up using next-generation sequencing. Clinical samples from individuals with low and high parasite densities will be used to test whether parasitological trajectories of afebrile Pf infections correlate with host antibody immunity against erythrocyte surface antigens and the transcription of Pf var genes involved in cytoadhesion and immune evasion. Cytometry by time of flight and global mass spectrometry will be applied on clinical samples from afebrile individuals with high parasite densities (tolerant) and those progressing to fever (non-tolerant) to identify leukocyte populations and metabolic pathways involved in the regulation of inflammation, tissue damage and normoglycemia that support host-parasite relationships at afebrile levels. The expected outcome of this project is the identification of key molecular drivers of afebrile Pf infections for a better understanding of the relevance of these infections in different transmission setting which may require context-specific control approaches, as well as for the development of new tools to achieve sterilizing immunity and enhance disease tolerance.

• Study Type: Observational
• Enrollment (Actual): 475

Contacts and Locations

Study Locations

• Mozambique
  • Manhiça, Mozambique, 1929
    • Fundação Manhiça/Manhiça Health Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Healthy individuals (temperature below 37.5ºC) with a P. falciprum infection confirmed by RDT and microscopy

Description

Inclusion Criteria:

• Age ≥ 18 years and ≤60 years
• A positive RDT and microscopy for P. falciparum
• Axillary temperature < 37.5ºC without history of fever during the last 24h
• No danger signals for severe malaria (Impaired consciousness, respiratory distress, multiple convulsions, prostration, shock, abnormal bleeding, jaundice)
• Ability and willingness to comply with the study protocol for the duration of the study and to comply with the study visit schedule; and
• Signed informed consent after explaining the purpose of the study

Exclusion Criteria:

• Age <18 years or >60 years
• Axillary temperature ≥37.5ºC
• Reported pregnancy
• Presence of any sign/symptom of malaria (Vomiting, diarrhea, weakness, dizziness, fainting, itching, urticarial)
• Presence of any other co-existing clinical condition that would not allow the individual to be considered a "healthy" afebrile carrier
• Having received antimalarial medication in the preceding 30 days.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of individuals developing fever	Development of axilary temperature higher or equal than 37.5ºC	1 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of individuals clearing the infection	Clearance of parasite infection as detected by qPCR	1 month
Proportion of individuals maintaining infections without fever	Confirmed P. falciparum ifection at day 28 by qPCR	1 month

Collaborators and Investigators

• Sponsor: Alfredo Mayor
• Collaborators: University of Florida; Stanford University; Centro de Investigação em Saúde de Manhiça

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2020
• Primary Completion (Actual): March 31, 2021
• Study Completion (Actual): March 31, 2021

Study Registration Dates

• First Submitted: June 4, 2020
• First Submitted That Met QC Criteria: June 4, 2020
• First Posted (Actual): June 9, 2020

Study Record Updates

• Last Update Posted (Actual): September 1, 2023
• Last Update Submitted That Met QC Criteria: August 29, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: tolerance; resistance; afebrile
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Malaria, Falciparum
• Other Study ID Numbers: 1R01AI150521 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No