Identifying functional antibody responses that protect against malaria in children, version 1.0
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Date
2022-08-03
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Kamuzu University of Health Sciences
Abstract
Type of study: Observational cohort study
The Problem: Although antibodies have been shown to be important for the
protection against malarial disease, the specific characteristics of these protective
antibodies have not been well delineated.
Methodology: The study population of interest will be children aged 1-8 years of age
drawn from three ongoing COMREC-approved studies. This is a secondary analysis
of samples already being collected from three ongoing COMREC-approved studies.
Children in the ongoing “Treatment of brain swelling in pediatric cerebral malaria”
study (P. 09/16/2024, PI: Taylor) with cerebral malaria will be matched with children
with uncomplicated malaria from the study “Characterization of Plasmodium
falciparum var/PfEMP1 type and immune response to PfEMP1 in severe and
uncomplicated clinical malaria” (P.01/15/1668, PI:Kim) and children with
asymptomatic parasitemia from the “Malaria pathogenesis: Progression cohort and
extremes, case control study” (P.11/18/2530, PI: Seydel). Children with no evidence
of malaria infection in the “Malaria pathogenesis” study will be used as uninfected
controls. After obtaining informed consent from their primary caretaker, a brief medical
history and demographic information will be collected from all participants.
Children with cerebral malaria are having a 10ml blood sample collected. Children in
the uncomplicated and asymptomatic cohorts are having 4mls of blood collected.
Plasma from this sample, as well as peripheral blood mononuclear cells from these
samples will be purposed for this proposed study. No additional blood will be drawn
for the purpose of this study. The serum from these studies will first be used in a Luminex assay to determine the
strongest candidates that might be leading to protective immunity. Antibody and PBMC
responses to these antigens will then be prioritized in the subsequent assays.
These assays will involve the functional and biochemical characterization of antibodies
in ~50 ways (see Research Strategy below). Comparison groups will be among the
three disease severity types as well as between acute and convalescent sera. Data
from these assays will be analyzed using elastic net regularized logistic regression
and partial least squares discriminant analysis to identify the antibody characteristics
associated with disease severity.
Broad Objective: To identify the biophysical and functional characteristics of
antibodies that protect against clinical malaria in children. Specific Objectives:
1) To use the Luminex bead approach to identify a subset of five P. falciparum
expressed proteins that serve as targets of protection against cerebral
malaria. To use the Systems Serology approach to identify biophysical and functional
characteristics of antibodies against the targets identified in Aim 1, that either protect from cerebral malaria or develop during convalescence from
cerebral malaria.
3) To use the Systems Serology approach to identify the biophysical and
functional characteristics of antibodies that are present in children with
asymptomatic P. falciparum infection and not in children with clinical
disease.
Expected Findings: We expect to find a subset of PfEMP1 domains, as well as a
subset of proteins expressed on the merozoite stage of the parasite, that are most
important in the protection of children from severe malaria. We also expect to find a
distinct antibody profile that is most effective at controlling the P. falciparum infection.
This will be accomplished by comparing the antibody characteristics seen in children
with severe disease to those seen in children with milder infection, and (for the second
question) comparing antibody responses in children with asymptomatic parasite
infection to children with symptomatic malaria.
Dissemination: Results will be disseminated to the medical community through peerreviewed
publications and presentations at relevant scientific conferences. Results will
also be shared with KUHeS at the annual Research Dissemination Conference.
Annually, we will also be providing COMREC updates as required in the annual report.
Description
Observational cohort study