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.
Synopsis image Plasmodium falciparum circumsporozoite protein (PfCSP) is a promising malaria vaccine target. Antibodies against the PfCSP central repeat domain and N‐terminal junction mediate protection from the infection, but the role of antibodies against the C‐terminal domain (C‐CSP) remains controversial. High‐affinity human C‐CSP antibodies failed to bind live P. falciparum sporozoites and lacked parasite‐inhibitory activity at 100‐fold higher concentration than repeat antibodies or antibodies with C‐CSP and repeat/junction cross‐reactivity. IGHV3‐21 gene usage was linked to antibodies that bound polymorphic epitopes in the α‐TSR subdomain of recombinant C‐CSP, whereas rare antibodies against conserved α‐TSR epitopes were encoded by diverse genes. IGHV3‐21 ‐encoded C‐CSP‐reactive antibodies showed signs of more efficient affinity maturation than IGHV3‐33 ‐encoded anti‐repeat/junction antibodies. Crystal structure and molecular modeling help to explain the C‐CSP specificity of a unique IGHV3‐33 ‐encoded antibody against a linear epitope in the C‐linker with sequence similarity to the repeat/junction.
Plasmodium falciparum circumsporozoite protein (PfCSP) is a promising malaria vaccine target. Antibodies against the PfCSP central repeat domain and N‐terminal junction mediate protection from the infection, but the role of antibodies against the C‐terminal domain (C‐CSP) remains controversial. image