Assessing the early development of functional antibody responses and target antigens in controlled human malaria infection to inform vaccine development

Previous controlled experimental malaria infection (CHMI) studies have shown that limited exposure of naïve individuals to parasites can lead to protective immune responses, both in the context of pre-erythrocytic and blood stage immunity. This project will address the lack of data on the acquisition of an anti-blood-stage functional antibody responses upon first infections of naïve adults.

Aim 1: Identifying the most immunogenic antigens targeted by antibodies upon first encounter with P. falciparum: Individuals from exposed populations develop a range of antigen-specific antibodies in response to repeated infection. In order to dissect the order and magnitude of antibody responses upon first infection, we will coat beads with recombinant merozoite antigens (approx. n=30 antigens) and test CHMI sera using the Magpix bead array platform established at Burnet. Recombinant antigens are available from our established in-house expression system, and/or from our established collaboration with Ehime University. We will determine the presence and levels of antibodies (IgG, IgM, IgG 1-4) to each antigen, patterns of acquisition among subjects, and correlations between antigens and with antibodies to whole merozoites. We will assess associations between antibodies and the parasitemia in study participants, and other clinical parameters.

Aim 2: Assessing functional properties of antibodies generated in first infection: We will use CHMI samples in our established functional assays to assess the acquisition and functional capacity of acquired antibodies. We will specifically test their capacity to fix complement and promote Fcg receptor interactions in a high throughput Magpix bead array platform. Further, we aim to quantify the capacity of antibodies to induce phagocytosis activity using antigen-coated beads by flow cytometry. This will enable us to identify which antigens are most effectively targeted by functional antibodies during the initial infection, and how functional activity relates to antibody magnitude and type. We will examine correlations between antigens and functional antibodies to whole merozoites. Results will be related to parasite density and other clinical parameters. All functional assays are established in our lab.

Aim 3: Compare antibody signatures of early responses in previously unexposed individuals with those of acquired immunity in exposed populations: We will compare results from Aim 1 and 2 with data we have previously generated using samples from malaria-endemic populations where subjects have had repeated exposure and identify differences in the immune profiles from CHMI subjects. We have previously identified protective associations between functional antibody activities and disease outcome, and will determine whether these protective responses are present amongst the early immune responses mounted in naïve individuals.

Enabling Technologies & Assays
Vaccines (Immune Correlates)

Mar 2021 — Oct 2023

$15,000

Australia

Australian Centre for Research Excellence in Malaria Elimination (ACREME)