Molecular and functional properties of human Plasmodium falciparum CSP C‐terminus antibodies

Abstract

Human monoclonal antibodies (mAbs) against the central repeat and junction domain of Plasmodium falciparum circumsporozoite protein (PfCSP) have been studied extensively to guide malaria vaccine design compared to antibodies against the PfCSP C terminus. Here, we describe the molecular characteristics and protective potential of 73 germline and mutated human mAbs against the highly immunogenic PfCSP C‐terminal domain. Two mAbs recognized linear epitopes in the C‐terminal linker with sequence similarity to repeat and junction motifs, whereas all others targeted conformational epitopes in the α‐thrombospondin repeat (α‐TSR) domain. Specificity for the polymorphic Th2R/Th3R but not the conserved RII+/CS.T3 region in the α‐TSR was associated with IGHV3‐21/IGVL3‐21 or IGLV3‐1 gene usage. Although the C terminus specific mAbs showed signs of more efficient affinity maturation and class‐switching compared to anti‐repeat mAbs, live sporozoite binding and inhibitory activity was limited to a single C‐linker reactive mAb with cross‐reactivity to the central repeat and junction. The data provide novel insights in the human anti‐C‐linker and anti‐α‐TSR antibody response that support exclusion of the PfCSP C terminus from malaria vaccine designs.

Memory B cells dominate the early antibody-secreting cell response to SARS-CoV-2 mRNA vaccination in naïve individuals independently of their antibody affinity

“…SPR measurements were performed using a Biacore T200 (GE Health-care) instrument docked with Series S Sensor Chip CM5 (GE Healthcare), as previously described 36 . Briefly, anti-human Igκ and Igλ antibodies were immobilized on the chip using an amine coupling-based human antibody Fab capture kit.…”

Somatic hypermutation-mediated paratope flexibility improves the cross-reactivity of human malaria antibodies

“…To better understand the generalizability of these findings, we studied two additional VH3-49+Vκ3-20 mAbs that carried some of the SHMs that we observed in wt mAb 4493 (Murugan et al, 2020;Oludada et al, 2023). mAb 3686 was isolated from the same individual as wt mAb 4493 after repeated exposure to live sporozoites under chemoprophylaxis (Mordmüller et al, 2017), whereas mAb 0786 was isolated from an individual immunized with radiationattenuated sporozoites (Mordmüller et al, 2022;Oludada et al, 2023).…”

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

“…A significant portion of recent efforts have focussed on investigating the protective efficacy of human monoclonals (mAbs) against PfCSP that arise post‐vaccination. Oludada et al ( 2023 ), in this issue of EMBO Molecular Medicine, have returned to basics to explore the molecular characteristics and protective potential of mAbs against PfCSP following whole sporozoite immunisation. Their unique take, however, is the exclusive focus on the C‐terminal domain of the protein, CSP's “tail”.…”

“…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.…”