title: Investigating the role of T follicular helper cells in naturally acquired immunity to malaria
Creators: name: Nyabundi, Diana
Publisher: name: The Open University
Year: 2024

description: Naturally acquired antibodies can be highly effective against malaria parasites and the resolution of clinical symptoms, as demonstrated from passive transfers of purified immune IgG from semi-immune adults to children with severe malaria in the 1960s. However, antimalarial immunity of individuals living with endemic exposure develops slowly, requiring multiple infections, and is not sterile. This is possibly due to the highly diverse antigenic challenge to the host’s immune response, with most studied <i>P. falciparum</i> antigens exhibiting either antigenic polymorphisms or antigenic variation, disruptions of the immune response by <i>Plasmodium falciparum</i>, resulting in inefficient acquisition of protective antibodies. The development of long-lasting high-affinity antibodies requires germinal centres, which are focal points for Tfh and B cell interactions resulting in B cell proliferation, affinity maturation and class switching.<br><br>
Previous studies of Tfh in malaria in humans have assessed the functions of Tfh either on malaria naïve populations or in cross-sectional studies in one transmission setting in malaria-exposed populations. Consequently, the impact of pre-exposure to malaria on the development and distribution of circulating Tfh (cTfh) subsets, their activation and how these factors are associated with antibody levels and quality remains unclear in individuals residing in areas with varying transmission intensities. It is important to investigate how these factors interplay with antibody production and functionality, as a better understanding could potentially lead to the development of more targeted and effective strategies that can improve vaccine design efforts and immunotherapies to combat malaria.<br><br>
My overall aim was to measure correlations between frequencies and functions of cTfh and their subsets with markers of antibody-dependent immunity in individuals from areas with different levels of <i>P. falciparum</i> exposure during either ongoing infections or comparing pre-season and peak-transmission levels. Specifically, I explore the role of Tfh in malaria in two cohorts: semi-immune Kenyan adults from different transmission intensities undergoing controlled human malaria infection (CHMI) and a cohort of children of a similar age living in the same area but with varying numbers of cumulative clinical malaria episodes.<br><br> 

I measured Tfh frequencies, antibody levels and avidity of anti-MSP1 antibodies using flow cytometry and ELISA, respectively. I also expressed novel <i>P. falciparum</i> pre-erythrocytic antigens, known to be expressed on the sporozoite surface for use in the measurements of levels for some of the binding antibodies.<br><br> 

I show that, whereas levels of pre-CHMI antibodies and their breadth were associated with reduced risk of the requirement for treatment for malaria, and/or the various parasite growth patterns following experimental infections, there was no association between Tfh frequencies from the same time point with post-CHMI antibody levels and their quality. Additionally, numbers of previously accumulated malaria episodes and the presence of concurrent asymptomatic parasitaemia were positively associated with circulating antibody levels and Tfh frequencies in the children's cohort.<br><br> 

I discuss the possible reasons for the lack of significance in the correlations between Tfh and markers of antibody-based immunity in the CHMI experiment and consider potential improvements for future studies doing similar analyses.<br>