A sting in the tail-are antibodies against the C-terminus of Plasmodium falciparum circumsporozoite protein protective?

Abstract

Malaria remains a huge burden on global public health. Annually there are more than 200 million cases with > 600,000 deaths worldwide, the vast majority of which occur within Sub-Saharan Africa (WHO; World Malaria Report, 2021). Malaria disease is the consequence of infection by a protozoan parasite from the genus Plasmodium with most morbidity and mortality caused by P. falciparum. With rates of infection plateauing and rebounding in some areas (in particular, as a result of the disruption caused by the COVID-19 pandemic), there have been increasing calls for new initiatives that can reduce malaria incidence towards local elimination or the hoped for goal of global eradication. In 2021, the World Health Organisation approved the first malaria vaccine RTS,S/AS01 (also called Mosquirix™), indicating it to be safe for use in young children and advocating its integration into routine immunisation programmes. Approval of this vaccine clearly represents a major landmark in global efforts towards malaria control and eradication aspirations. RTS,S modest efficacy, however, points at the need to better understand immune responses to the parasite if we hope to design next generation malaria vaccines with increased potency.

Figure 1. The circumsporozoite protein, CSP, coats the outer surface of Plasmodium sporozoites with ~ 1 million copies per cell

The C‐terminal TSR domain is inaccessible to antibodies, shielded by the N‐terminal domain and likely only revealed by processing 8. Proteolytic cleavage of the N‐terminal domain at RI (the junctional region) just before parasite entry into hepatocytes may indicate an immune evasion strategy by the parasite to shield its key cell‐surface‐binding/interacting domain, minimising its exposure to immune surveillance. Anti‐C‐terminal (from Oludada et al, 2023) and anti‐N‐terminal antibodies (previous work) are for the most part non‐protective, in contrast to the well‐characterised CIS43, L9, 317 and 2A10 antibodies which confer protection via their targeting of the exposed repeat domains.