Affinage · Plasmodium

CSP

PF3D7_0304600 · circumsporozoite (CS) protein

Annotated
2026-09-07
98 papers in source corpus 25 papers cited in narrative 25 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PF3D7_0304600 encodes the circumsporozoite protein (CSP), a GPI-anchored surface coat protein that densely covers the Plasmodium sporozoite and governs its motility, hepatocyte targeting, and immune interface (PMID:6204383, PMID:19633296). The protein is organized into an N-terminal conserved region, a central tandem repeat region (predominantly NANP tetrapeptides), and a C-terminal conserved region II shared across Plasmodium species (PMID:6204383, PMID:6204384). The central NANP repeat is highly extended and behaves as an elastic, spring-like element whose length-dependent stiffness is required for proper assembly and dynamics of TRAP-containing adhesion sites that drive gliding motility (PMID:19633296, PMID:40983687); consistent with this motile role, CSP is released apically and translocated posteriorly along the sporozoite surface by an actomyosin-based motor, depositing trails during gliding (PMID:3054075, PMID:1787427). Host cell targeting is mediated at multiple sites: conserved region II binds heparan sulfate proteoglycans, the LDL-receptor-related protein LRP, and sulfatides/cholesterol-3-sulfate via a disulfide-bonded loop, and is essential for sporozoite motility and infectivity (PMID:8478608, PMID:1518521, PMID:8920859, PMID:12244064), while the N-terminus is independently required for liver-cell binding and its proteolytic cleavage is a prerequisite for hepatocyte infection (PMID:11751898, PMID:25762791). Structurally, region III and the TSR domain fold into a single αTSR domain, and the repeat region adopts type I β-turns that can be organized into spiral/helical arrays by protective antibodies (PMID:22547819, PMID:29138320, PMID:30324137). After invasion, CSP is exported into the hepatocyte cytosol and nucleus, where it outcompetes NFκB nuclear import to suppress inflammatory gene expression and reprograms host metabolic genes to favor liver-stage growth, and can inhibit host protein synthesis through ribosome association (PMID:9669999, PMID:17981117). CSP-derived peptides are processed and presented on hepatocyte MHC class I to CD8+ T cells, and anti-repeat antibodies neutralize sporozoites in the skin and liver by disrupting motility, blocking invasion, and stripping the coat to expose the membrane to SPECT (PMID:30349082, PMID:1689762, PMID:17513754, PMID:39951341).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1984 High

    Establishing the primary structure of CSP defined its modular architecture and pointed to the conserved flanking regions as candidate liver-cell binding determinants.

    Evidence Gene cloning and sequencing with monoclonal antibody peptide inhibition in P. falciparum

    PMID:6204383 PMID:6204384

    Open questions at the time
    • Function of the conserved regions not yet tested experimentally
    • Repeat region role in motility unknown at this stage
  2. 1985 High

    Demonstrating that the NANP repeat alone elicits invasion-blocking antibodies identified the repeat as the dominant protective B-cell epitope and vaccine target.

    Evidence Recombinant and synthetic-peptide immunization with in vitro sporozoite invasion inhibition of hepatoma cells

    PMID:2988125 PMID:2988126

    Open questions at the time
    • Mechanism by which anti-repeat antibodies block invasion not defined
    • Role of region I and II antibodies unclear beyond lacking invasion inhibition
  3. 1991 High

    Live imaging showed CSP is deposited as trails and translocated apical-to-posterior by an actin-dependent surface motor, linking CSP directly to gliding motility.

    Evidence Immunolocalization and video/electron microscopy of cytochalasin B-immobilized P. berghei sporozoites; motility inhibition by anti-CSP

    PMID:1787427 PMID:3054075

    Open questions at the time
    • Molecular connection between CSP and the motor/adhesin machinery not resolved
    • Shown in P. berghei only
  4. 1996 High

    Biochemical identification of hepatocyte receptors defined the molecular basis of CSP-mediated host cell targeting.

    Evidence Disulfide-dependent region II binding to sulfatides/cholesterol-3-sulfate, HSPG binding via region II-plus, and quantitative LRP binding with invasion assays in P. falciparum/P. berghei

    PMID:1518521 PMID:8478608 PMID:8920859

    Open questions at the time
    • Relative in vivo contribution of each receptor not fully resolved
    • Whether receptor engagement precedes or follows N-terminal cleavage unknown
  5. 2002 High

    Genetic dissection assigned distinct in vivo roles to the conserved regions, establishing region II as essential for motility and infectivity.

    Evidence Gene replacement of P. berghei CSP with PfCSP region I/II deletion variants and phenotyping of motility, salivary gland invasion, and mouse infection

    PMID:12244064

    Open questions at the time
    • Region I dispensability in this system leaves its molecular role open
    • Mechanism by which region II supports motility not defined
  6. 2001 High

    Deletion mapping showed the N-terminus is essential for liver-cell binding independently of the TSR domain, distributing binding function across the protein.

    Evidence Systematic truncation of recombinant PfCSP tested in liver-cell binding and invasion inhibition assays

    PMID:11751898

    Open questions at the time
    • N-terminal receptor identity not determined
    • Interplay between N-terminal and region II binding sites unresolved
  7. 2007 High

    Discovery of a PEXEL/VTS and NLS in CSP revealed a post-invasion effector function in which CSP reprograms the hepatocyte to favor parasite growth.

    Evidence Motif identification, hepatocyte expression, NFκB nuclear import competition, transcriptional profiling, and parasite growth assays in P. falciparum/P. berghei

    PMID:17981117 PMID:9669999

    Open questions at the time
    • Direct binding partners in the host nucleus not identified
    • Ribosome-association mechanism single-lab and mechanistically incomplete
  8. 2011 High

    Antigen-processing studies defined how CSP epitopes reach MHC class I in hepatocytes and dendritic cells, clarifying the basis of protective CD8+ T-cell responses.

    Evidence Transgenic parasites, TAP-deficient and endosomal-mutant mice, proteasome/protease inhibitors, and CTL assays across P. yoelii/P. berghei/P. falciparum

    PMID:1689762 PMID:17513754 PMID:21445239

    Open questions at the time
    • Identity of the aspartic protease processing CSP not defined
    • PEXEL-independence of CSP secretion into hepatocytes not mechanistically explained
  9. 2013 High

    Biophysical and crystallographic work resolved the overall shape and domain organization of CSP, defining the extended rod and the composite αTSR domain.

    Evidence DLS, sedimentation, AFM of recombinant PfCSP and X-ray structure of the region III–TSR unit

    PMID:19633296 PMID:22547819

    Open questions at the time
    • Full-length structure including the repeat region not solved
    • Ligand for the αTSR hydrophobic pocket unknown
  10. 2015 High

    Blocking N-terminal proteolytic cleavage with a monoclonal antibody established that CSP processing is a required step for hepatocyte infection and a distinct protective target.

    Evidence mAb5D5 cleavage-inhibition assays and passive transfer in transgenic mice expressing the PfCSP N-terminus

    PMID:25762791

    Open questions at the time
    • Protease responsible for cleavage not identified
    • Functional consequence of cleavage for downstream events undefined
  11. 2018 High

    Structures of protective antibodies bound to the repeats revealed defined β-turn conformations and antibody-organized spiral arrays, explaining the potency of anti-repeat neutralization.

    Evidence X-ray of Fab–(NPNA) complexes, negative-stain EM, and ~3.4-Å cryo-EM of rsCSP–Fab complexes with inter-Fab mutational analysis

    PMID:29138320 PMID:30324137

    Open questions at the time
    • Conformation of the repeat on the native sporozoite surface not directly observed
    • In vivo relevance of Fab–Fab-stabilized arrays not established
  12. 2020 Medium

    Mechanistic dissection of antibody killing showed anti-repeat mAbs neutralize sporozoites in skin and liver by disrupting motility, blocking invasion, and stripping the coat to expose the membrane to SPECT.

    Evidence Intravital microscopy, passive transfer, and complement/FcRγ-deficient models across P. yoelii/P. berghei/P. falciparum, with bioluminescence-tracked late killing in P. berghei

    PMID:30349082 PMID:39951341

    Open questions at the time
    • Late intracellular killing mechanism studied with a single antibody in P. berghei
    • How coat stripping mechanistically engages SPECT not fully defined
  13. 2025 High

    Single-molecule force measurements established that the CSP repeat acts as an elastic spring whose length-dependent stiffness is required for TRAP-containing adhesion site assembly and gliding motility.

    Evidence Repeat truncation/scramble mutants, gliding assays, adhesion-site imaging, and single-molecule fluorescence-force spectroscopy in P. berghei/P. falciparum

    PMID:40983687

    Open questions at the time
    • Direct physical link between the CSP spring and TRAP not resolved
    • Whether repeat elasticity influences receptor binding untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The identities of the N-terminal receptor and the protease that cleaves the CSP N-terminus, and the direct host nuclear/ribosomal partners of exported CSP, remain unresolved.
  • N-terminal hepatocyte receptor unidentified
  • Cleavage protease unidentified
  • Direct host-factor targets of nuclear CSP not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification
Partners
HEPARAN SULFATE PROTEOGLYCANS (SYNDECAN-LIKE) [#6, #18]HOST RIBOSOMES / ROUGH MICROSOMES [#9]LDL RECEPTOR-RELATED PROTEIN (LRP) [#8]NFΚB (NUCLEAR IMPORT COMPETITION) [#12]SPECT (EXPOSED UPON COAT STRIPPING) [#20]SULFATIDES / CHOLESTEROL-3-SULFATE [#7]TRAP (ADHESION SITE) [#21]
Complex memberships
CSP–TRAP-containing adhesion site (functional association) [#21]recombinant shortened CSP–Fab helical/spiral complexes [#16, #17]

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1984 The CSP gene of P. falciparum encodes a 412 amino acid protein containing 41 tandem tetrapeptide repeats (37× Asn-Ala-Asn-Pro and 4× Asn-Val-Asp-Pro), flanked by two conserved non-repeat regions (region I and region II) shared with P. knowlesi CS protein, suggesting these conserved regions may mediate binding to liver cells. Gene cloning and nucleotide sequence determination; monoclonal antibody inhibition with synthetic peptides Science High 6204383
1984 A cDNA clone encoding the P. falciparum CSP repeat region (PNANP tandem repeats) was isolated; the CS-beta-lactamase fusion protein specifically binds monoclonal antibodies to native CSP and inhibits their binding to native sporozoite CSP. cDNA library screening with monoclonal antibody; competitive binding inhibition assay Science High 6204384
1985 Recombinant CSP proteins composed of 16, 32, or 48 tandem copies of the NANP tetrapeptide repeat expressed in E. coli elicit antibodies in mice that react with native sporozoite CSP and block sporozoite invasion of human hepatoma cells in vitro, establishing the repeat region as sufficient for inducing invasion-blocking antibodies. Recombinant protein expression in E. coli; in vitro sporozoite invasion inhibition assay; mouse immunization Science High 2988125
1985 Synthetic peptides from the NANP repeat region of P. falciparum CSP induce antibodies in mice and rabbits that recognize native CSP on sporozoites and block sporozoite invasion of human hepatoma cells in vitro; antibodies to region I and region II peptides had no invasion-blocking activity, though anti-region I antibodies recognized processed CSP by Western blot. Synthetic peptide immunization; sporozoite invasion inhibition assay; Western blot Science High 2988126
1988 P. berghei sporozoites undergoing gliding motility in vitro deposit trails of CSP corresponding to their movement patterns; CSP is released continuously as an exoantigen during motility, and anti-CSP antibodies inhibit sporozoite motility, suggesting CSP plays a direct role in gliding motility. Light microscopy with immunogold-silver staining (IGSS) using anti-CSP monoclonal antibody; motility inhibition by pre-treatment with inhibitory agents The Journal of protozoology High 3054075
1991 CSP is released from the apical (leading) end of cytochalasin B-immobilized P. berghei sporozoites and translocated posteriorly along the surface via a cytochalasin-sensitive, apparently actin-mediated surface motor, providing a mechanistic model for the circumsporozoite precipitation (CSP) reaction and CS protein trail formation during gliding motility. Video microscopy and electron microscopy of cytochalasin B-immobilized sporozoites; immunolocalization of CSP The Journal of protozoology High 1787427
1993 P. falciparum CSP binds to heparan sulfate proteoglycans (HSPGs) on the basolateral plasma membrane of hepatocytes via its region II-plus; binding is abolished by heparitinase treatment of hepatocytes; the CS-binding HSPGs from HepG2 cells have MW 400,000–700,000, are tightly membrane-associated, and share properties with the syndecan family. Heparitinase treatment of hepatocytes followed by CS binding assay; purification and partial characterization of HSPGs from HepG2 cells; trypsinization release assay The Journal of experimental medicine High 8478608
1992 Region II of P. falciparum, P. berghei, and P. vivax CSP specifically binds sulfatides and cholesterol-3-sulfate; this binding requires a disulfide bond between the two cysteines in region II (forming a small peptide loop); disruption of this disulfide (by reduction/alkylation) abolishes binding; sulfatide/cholesterol-3-sulfate recognition by region II is required during sporozoite invasion of liver cells, since dextran sulfate inhibits both CSP-sulfatide binding and P. berghei hepatocyte invasion. In vitro binding assay with recombinant CSP constructs (including region II deletion mutants); reduction/alkylation of disulfide bonds; dextran sulfate inhibition of sporozoite invasion of hepatocytes Molecular and biochemical parasitology High 1518521
1996 P. falciparum CSP interacts with both cell-surface heparan sulfate proteoglycans (HSPGs) and the low density lipoprotein receptor-related protein (LRP) on hepatocytes; binding of radiolabeled CSP to purified LRP occurs with Kd = 4.9 nM and is inhibited by receptor-associated protein (RAP); blockage of either LRP or HSPG alone reduces P. berghei invasion of hepatocytes by 60–70%, and combined blockage achieves ~65% inhibition; these two receptors represent the major mechanism for host cell invasion by sporozoites. Radiolabeled (125I) CSP binding to purified LRP; RAP and anti-LRP antibody blockade; heparinase treatment; invasion assays in LRP-deficient and HSPG-deficient cell lines The Journal of experimental medicine High 8920859
1998 Native P. falciparum/P. berghei/P. vivax CSP translocated by sporozoites into host cell cytosol, as well as recombinant CSP introduced by liposome fusion or transfection, inhibits protein synthesis in mammalian cells; recombinant CSP associates with ribosomes (RNase-sensitive sites on rough microsomes); synthetic peptides of conserved region I and region II-plus displace CSP from rough microsomes (nanomolar Kd) and inhibit in vitro translation, suggesting CSP binds ribosomes to downregulate host protein synthesis. Liposome-mediated delivery and transient transfection of recombinant CSP; protein synthesis measurement; microsomal binding assay; synthetic peptide displacement assay; in vitro translation inhibition assay The EMBO journal High 9669999
2001 The amino terminus of P. falciparum CSP is essential for binding to liver cells and for inhibiting sporozoite invasion; deletion of as few as 6 amino acids from the N-terminus abolishes both binding activity and invasion inhibition; deletion of the TSR domain (region II) actually enhances binding 2–3-fold without losing receptor specificity but increases invasion inhibition, indicating the TSR domain is not the sole determinant of binding specificity. Eight truncated recombinant CSP constructs tested in liver cell binding assay and sporozoite invasion inhibition assay The Journal of biological chemistry High 11751898
2002 P. falciparum CSP functionally substitutes for P. berghei CSP in the rodent parasite; region I-deficient P. berghei sporozoites (carrying PfCSP lacking region I) show no impairment of motility, salivary gland invasion, or vertebrate host infection; region II-deficient sporozoites lose gliding motility and are severely impaired in mosquito salivary gland invasion and vertebrate host infection, establishing region II as essential for sporozoite motility and infectivity. Genetic replacement of P. berghei CSP gene with P. falciparum CSP gene and region I/II deletion variants; assessment of sporozoite motility, salivary gland invasion, and mouse infection The Journal of biological chemistry High 12244064
2007 P. falciparum/P. berghei CSP contains a PEXEL/VTS motif that mediates its export into the hepatocyte cytoplasm, and a nuclear localization signal (NLS) that enables it to enter the hepatocyte nucleus; nuclear CSP outcompetes NFκB nuclear import, downregulating NFκB-controlled genes including those involved in inflammation; CSP also modulates expression of >1,000 host genes involved in diverse metabolic processes; CSP presence in the hepatocyte enhances parasite liver stage growth in vitro and in vivo. PEXEL/VTS motif identification and NLS identification; transfection/expression in hepatocytes; NFκB nuclear import competition assay; gene expression profiling; parasite growth measurement in vitro and in vivo Cell High 17981117
2009 Recombinant P. falciparum CSP expressed in E. coli and Pichia pastoris forms highly extended, flexible, rod-like structures approximately 21–25 nm long and 1.5 nm wide as determined by dynamic light scattering, velocity sedimentation, and high-resolution atomic force microscopy; the protein is GPI-anchored; the TSR domain folds correctly as confirmed by conformation-dependent monoclonal antibodies that recognize live sporozoites and inhibit HepG2 cell invasion. Dynamic light scattering; velocity sedimentation; atomic force microscopy; in vitro sporozoite invasion inhibition assay The Journal of biological chemistry High 19633296
2012 Crystal structures of the region III–TSR portion of P. falciparum CSP reveal that region III and the TSR domain fold together into a single structural unit called the 'αTSR' domain, which contains a hydrophobic pocket absent in typical TSR domains; polymorphic T-cell epitopes map to specialized αTSR regions; the N and C termini are unexpectedly close to each other; notably, the αTSR domain does not bind heparin, unlike the N-terminal region. X-ray crystallography Proceedings of the National Academy of Sciences of the United States of America High 22547819
2015 A monoclonal antibody (mAb5D5) specific for the N-terminus of P. falciparum CSP inhibits proteolytic cleavage of CSP, which is a required step for sporozoite infection of hepatocytes; adoptive transfer of mAb5D5 strongly inhibits in vivo sporozoite infection in mice expressing PfCSP N-terminus, and protection is enhanced in combination with anti-repeat antibodies. Monoclonal antibody characterization; proteolytic cleavage assay; passive transfer in vivo infection assay in transgenic mouse model The Journal of infectious diseases High 25762791
2017 Crystal structures of Fab fragments of two protective monoclonal antibodies (mAb311 and mAb317) bound to an (NPNA)3 peptide show that one to three NPNA repeats adopt well-defined type I β-turns; negative-stain electron microscopy of a recombinant shortened CSP saturated with Fabs reveals a compact CSP with multiple Fabs bound, forming a highly organized helical structure for the rsCSP-Fab311 complex. X-ray crystallography of Fab–peptide complexes; negative-stain electron microscopy of rsCSP–Fab complexes Proceedings of the National Academy of Sciences of the United States of America High 29138320
2018 Cryo-EM structure (~3.4-Å) of recombinant shortened P. falciparum CSP bound to Fabs of a highly protective monoclonal antibody reveals an extended spiral conformation of the central NANP repeat region surrounded by antibodies; this unusual structure appears to be stabilized and/or induced by somatic mutations at inter-Fab contact residues (non-antigen-contact positions) that enhance adjacent Fab–Fab interactions. Cryo-electron microscopy structure determination (~3.4 Å); mutational analysis of inter-Fab contacts Science advances High 30324137
2007 Mosquito heparan sulfate isolated from Anopheles stephensi salivary glands and midguts contains the trisulfated disaccharide sequence found in human liver heparan sulfate (the CSP receptor), and whole-mosquito heparan sulfate binds to CSP in vitro, suggesting a role for CSP–HSPG interaction within the mosquito during infection and transmission. Heparan sulfate isolation from mosquito tissues; disaccharide microanalysis; in vitro binding of mosquito HSPG to CSP The Journal of biological chemistry Medium 17597060
2011 In dendritic cells (DCs), P. falciparum/P. berghei CSP epitopes are cross-presented to CD8+ T cells via an endosomal pathway requiring TAP transporters; in hepatocytes, CSP must be secreted directly into the cytosol and also uses TAP transporters to access the ER for MHC class I presentation; secretion of CSP into hepatocytes during liver stage infection is not dependent on the PEXEL/VTS export motifs in the protein. Transgenic parasite expressing mutant CSP (SIINFEKL insertion); endosomal pathway mutant mice (3d); cytochrome c treatment; TAP-deficient mice; in vivo T cell response assays PLoS pathogens High 21445239
2018 Anti-P. yoelii CSP repeat monoclonal antibody inhibits sporozoite motility and kills sporozoites in the host skin via a 'dotty death' phenotype that is complement- and Fc receptor γ-independent; cytotoxicity requires actomyosin motor-dependent translocation and stripping of the CSP surface coat, exposing the sporozoite membrane to the pore-forming-like protein SPECT; cognate anti-CSP repeat mAbs also kill P. berghei and P. falciparum sporozoites. Passive transfer of anti-CSP mAb in rodent model; intravital microscopy in skin; in vitro motility and cytotoxicity assays; complement/FcRγ-deficient mouse models Nature microbiology High 30349082
2025 P. berghei/P. falciparum CSP repeat region has elastic, spring-like biophysical properties: sporozoite mutants with truncated or scrambled CSP repeats exhibit impaired gliding motility due to altered adhesion site (containing TRAP) formation and dynamics; single-molecule fluorescence-force spectroscopy demonstrates the repeats behave as a stiff linear spring whose elasticity depends on repeat length and is lost when repeats are scrambled; CSP coat integrity affects the assembly of TRAP-containing adhesion sites. CSP repeat truncation and scramble mutant parasites; gliding motility assays; single-molecule fluorescence-force spectroscopy; adhesion site imaging The EMBO journal High 40983687
1990 A 16-amino acid epitope from the P. yoelii CSP is recognized by CD8+ cytotoxic T cells from immune mice; lymphocytes stimulated with this peptide kill P. yoelii liver stage parasites in vitro in an MHC-restricted, antigen-specific manner, demonstrating that CSP epitopes are presented on the surface of infected hepatocytes and can be targets for protective CTL even though intact CSP has not been detected on the hepatocyte surface. In vitro CTL killing assay with peptide-stimulated lymphocytes; MHC restriction confirmed The Journal of experimental medicine High 1689762
2007 P. berghei-infected primary hepatocytes process and present CSP-derived peptides to specific CD8+ T cells via a pathway involving the proteasome, antigen transport through a post-ER compartment, and aspartic proteases; both infected and traversed (but not productively infected) hepatocytes can present CSP epitopes in the context of H-2Kd MHC class I molecules. Primary hepatocyte infection with wild-type and spect−/− P. berghei sporozoites; proteasome inhibitors; protease inhibitors; CD8+ T cell activation assay Journal of immunology High 17513754
2025 Anti-P. berghei CSP monoclonal antibody 3D11 neutralizes sporozoites in the liver through a sequential late-killing mechanism: it first inhibits sporozoite motility and sinusoidal extravasation, then blocks hepatocyte invasion, and ultimately kills parasites inside invaded cells over several hours; bioluminescence imaging showed accumulation of 3D11 effects was necessary to eliminate liver parasites. Intravital microscopy; bioluminescence imaging in rodent malaria model; passive transfer of mAb 3D11 eLife Medium 39951341

Source papers

Stage 0 corpus · 98 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1984 Structure of the gene encoding the immunodominant surface antigen on the sporozoite of the human malaria parasite Plasmodium falciparum. Science (New York, N.Y.) 720 6204383
1988 Human T-cell recognition of the circumsporozoite protein of Plasmodium falciparum: immunodominant T-cell domains map to the polymorphic regions of the molecule. Proceedings of the National Academy of Sciences of the United States of America 307 2448793
1993 Malaria circumsporozoite protein binds to heparan sulfate proteoglycans associated with the surface membrane of hepatocytes. The Journal of experimental medicine 292 8478608
1989 Circumsporozoite protein heterogeneity in the human malaria parasite Plasmodium vivax. Science (New York, N.Y.) 264 2672336
2011 Plasmodium knowlesi: reservoir hosts and tracking the emergence in humans and macaques. PLoS pathogens 254 21490952
1985 Expression of Plasmodium falciparum circumsporozoite proteins in Escherichia coli for potential use in a human malaria vaccine. Science (New York, N.Y.) 254 2988125
1985 Circumsporozoite protein of Plasmodium vivax: gene cloning and characterization of the immunodominant epitope. Science (New York, N.Y.) 242 2414847
1984 DNA cloning of Plasmodium falciparum circumsporozoite gene: amino acid sequence of repetitive epitope. Science (New York, N.Y.) 241 6204384
1988 Oral Salmonella typhimurium vaccine expressing circumsporozoite protein protects against malaria. Science (New York, N.Y.) 231 3281260
2017 Enhancing protective immunity to malaria with a highly immunogenic virus-like particle vaccine. Scientific reports 210 28422178
1985 Immunogenicity of synthetic peptides from circumsporozoite protein of Plasmodium falciparum. Science (New York, N.Y.) 210 2988126
2003 Protective immunity induced with malaria vaccine, RTS,S, is linked to Plasmodium falciparum circumsporozoite protein-specific CD4+ and CD8+ T cells producing IFN-gamma. Journal of immunology (Baltimore, Md. : 1950) 207 14662904
1990 Cytotoxic T cells recognize a peptide from the circumsporozoite protein on malaria-infected hepatocytes. The Journal of experimental medicine 203 1689762
1991 Protection against malaria by vaccination with sporozoite surface protein 2 plus CS protein. Science (New York, N.Y.) 182 1827210
2019 Antigens reversibly conjugated to a polymeric glyco-adjuvant induce protective humoral and cellular immunity. Nature materials 181 30643235
2018 A public antibody lineage that potently inhibits malaria infection through dual binding to the circumsporozoite protein. Nature medicine 175 29554084
2007 Plasmodium circumsporozoite protein promotes the development of the liver stages of the parasite. Cell 172 17981117
1995 Natural selection on Plasmodium surface proteins. Molecular and biochemical parasitology 163 7630387
1991 Human cytotoxic T lymphocytes against the Plasmodium falciparum circumsporozoite protein. Proceedings of the National Academy of Sciences of the United States of America 161 1707538
1988 Malaria sporozoites leave behind trails of circumsporozoite protein during gliding motility. The Journal of protozoology 139 3054075
1995 Thrombospondin-related adhesive protein (TRAP) of Plasmodium falciparum: expression during sporozoite ontogeny and binding to human hepatocytes. The EMBO journal 137 7664729
2012 Self-assembled peptide nanofibers raising durable antibody responses against a malaria epitope. Biomaterials 135 22695068
2009 Structure of the Plasmodium falciparum circumsporozoite protein, a leading malaria vaccine candidate. The Journal of biological chemistry 135 19633296
2017 Structural basis for antibody recognition of the NANP repeats in Plasmodium falciparum circumsporozoite protein. Proceedings of the National Academy of Sciences of the United States of America 132 29138320
1996 Comparison of circumsporozoite proteins from avian and mammalian malarias: biological and phylogenetic implications. Proceedings of the National Academy of Sciences of the United States of America 120 8876233
2008 Protective CD8 T cells against Plasmodium liver stages: immunobiology of an 'unnatural' immune response. Immunological reviews 117 18837788
1991 Circumsporozoite protein genes of malaria parasites (Plasmodium spp.): evidence for positive selection on immunogenic regions. Genetics 117 1706291
1991 Monoclonal, but not polyclonal, antibodies protect against Plasmodium yoelii sporozoites. Journal of immunology (Baltimore, Md. : 1950) 114 1988490
2017 Natural Parasite Exposure Induces Protective Human Anti-Malarial Antibodies. Immunity 112 29195810
2010 Poly(I:C) is an effective adjuvant for antibody and multi-functional CD4+ T cell responses to Plasmodium falciparum circumsporozoite protein (CSP) and αDEC-CSP in non human primates. Vaccine 112 20846528
2007 Baculovirus-based vaccination vectors allow for efficient induction of immune responses against plasmodium falciparum circumsporozoite protein. Molecular therapy : the journal of the American Society of Gene Therapy 111 17164791
1993 Humoral immune responses in volunteers immunized with irradiated Plasmodium falciparum sporozoites. The American journal of tropical medicine and hygiene 109 8357078
2000 Cutting edge: the IgG response to the circumsporozoite protein is MHC class II-dependent and CD1d-independent: exploring the role of GPIs in NK T cell activation and antimalarial responses. Journal of immunology (Baltimore, Md. : 1950) 106 10799852
2002 Function of region I and II adhesive motifs of Plasmodium falciparum circumsporozoite protein in sporozoite motility and infectivity. The Journal of biological chemistry 101 12244064
1994 Influenza and vaccinia viruses expressing malaria CD8+ T and B cell epitopes. Comparison of their immunogenicity and capacity to induce protective immunity. Journal of immunology (Baltimore, Md. : 1950) 98 7525709
2008 Local adaptation and vector-mediated population structure in Plasmodium vivax malaria. Molecular biology and evolution 96 18385220
1991 Malaria sporozoites release circumsporozoite protein from their apical end and translocate it along their surface. The Journal of protozoology 94 1787427
2012 Unexpected fold in the circumsporozoite protein target of malaria vaccines. Proceedings of the National Academy of Sciences of the United States of America 91 22547819
2012 Protective antibody and CD8+ T-cell responses to the Plasmodium falciparum circumsporozoite protein induced by a nanoparticle vaccine. PloS one 91 23144750
2017 Development of amplicon deep sequencing markers and data analysis pipeline for genotyping multi-clonal malaria infections. BMC genomics 90 29132317
1997 Binding of malaria T cell epitopes to DR and DQ molecules in vitro correlates with immunogenicity in vivo: identification of a universal T cell epitope in the Plasmodium falciparum circumsporozoite protein. Journal of immunology (Baltimore, Md. : 1950) 90 9233633
1988 Limited immunological recognition of critical malaria vaccine candidate antigens. Science (New York, N.Y.) 90 2902690
1986 Circumsporozoite protein of Plasmodium berghei: gene cloning and identification of the immunodominant epitopes. Molecular and cellular biology 90 2432395
2011 Dendritic cells and hepatocytes use distinct pathways to process protective antigen from plasmodium in vivo. PLoS pathogens 89 21445239
2001 Fluorescent Plasmodium berghei sporozoites and pre-erythrocytic stages: a new tool to study mosquito and mammalian host interactions with malaria parasites. Cellular microbiology 88 11422080
2001 Binding and invasion of liver cells by Plasmodium falciparum sporozoites. Essential involvement of the amino terminus of circumsporozoite protein. The Journal of biological chemistry 83 11751898
2005 Safety and enhanced immunogenicity of a hepatitis B core particle Plasmodium falciparum malaria vaccine formulated in adjuvant Montanide ISA 720 in a phase I trial. Infection and immunity 82 15908388
2012 Antigen-specific IL-2 secretion correlates with NK cell responses after immunization of Tanzanian children with the RTS,S/AS01 malaria vaccine. Journal of immunology (Baltimore, Md. : 1950) 78 22504653
2017 Rare PfCSP C-terminal antibodies induced by live sporozoite vaccination are ineffective against malaria infection. The Journal of experimental medicine 77 29167197
1994 Immunity to malaria elicited by hybrid hepatitis B virus core particles carrying circumsporozoite protein epitopes. The Journal of experimental medicine 77 7520465
1989 ELISA method for detecting Plasmodium falciparum circumsporozoite antibody. Bulletin of the World Health Organization 76 2692869
2015 Proteolytic Cleavage of the Plasmodium falciparum Circumsporozoite Protein Is a Target of Protective Antibodies. The Journal of infectious diseases 75 25762791
1993 Identification of Plasmodium vivax-like human malaria parasite. Lancet (London, England) 75 8095999
1990 Malaria sporozoite detection by dissection and ELISA to assess infectivity of afrotropical Anopheles (Diptera: Culicidae). Journal of medical entomology 75 2185363
1986 Effectiveness of liposomes as potential carriers of vaccines: applications to cholera toxin and human malaria sporozoite antigen. Vaccine 75 3532603
2015 Population genomic structure and adaptation in the zoonotic malaria parasite Plasmodium knowlesi. Proceedings of the National Academy of Sciences of the United States of America 74 26438871
1991 Cytotoxic CD4+ T cells from a sporozoite-immunized volunteer recognize the Plasmodium falciparum CS protein. International immunology 74 1721837
2018 Cryo-EM structure of P. falciparum circumsporozoite protein with a vaccine-elicited antibody is stabilized by somatically mutated inter-Fab contacts. Science advances 73 30324137
2007 Plasmodium berghei-infected primary hepatocytes process and present the circumsporozoite protein to specific CD8+ T cells in vitro. Journal of immunology (Baltimore, Md. : 1950) 73 17513754
1985 Structure of the circumsporozoite protein gene in 18 strains of Plasmodium falciparum. Molecular and biochemical parasitology 71 3897857
2018 Cytotoxic anti-circumsporozoite antibodies target malaria sporozoites in the host skin. Nature microbiology 70 30349082
2005 Safety and elicitation of humoral and cellular responses in colombian malaria-naive volunteers by a Plasmodium vivax circumsporozoite protein-derived synthetic vaccine. The American journal of tropical medicine and hygiene 70 16291760
1991 Use of adjuvant containing mycobacterial cell-wall skeleton, monophosphoryl lipid A, and squalane in malaria circumsporozoite protein vaccine. Lancet (London, England) 70 1673211
2012 Full-length Plasmodium falciparum circumsporozoite protein administered with long-chain poly(I·C) or the Toll-like receptor 4 agonist glucopyranosyl lipid adjuvant-stable emulsion elicits potent antibody and CD4+ T cell immunity and protection in mice. Infection and immunity 69 23275094
1996 Dual interaction of the malaria circumsporozoite protein with the low density lipoprotein receptor-related protein (LRP) and heparan sulfate proteoglycans. The Journal of experimental medicine 69 8920859
1990 Recognition of dominant T cell-stimulating epitopes from the circumsporozoite protein of Plasmodium falciparum and relationship to malaria morbidity in Gambian children. Transactions of the Royal Society of Tropical Medicine and Hygiene 69 1703674
1991 Immunogenicity of multiple antigen peptides (MAP) containing T and B cell epitopes of the repeat region of the P. falciparum circumsporozoite protein. European journal of immunology 68 1721025
2019 Optimization of an in vivo model to study immunity to Plasmodium falciparum pre-erythrocytic stages. Malaria journal 66 31849326
2007 Mosquito heparan sulfate and its potential role in malaria infection and transmission. The Journal of biological chemistry 66 17597060
2002 A modified hepatitis B virus core particle containing multiple epitopes of the Plasmodium falciparum circumsporozoite protein provides a highly immunogenic malaria vaccine in preclinical analyses in rodent and primate hosts. Infection and immunity 66 12438363
2003 Opsonization by antigen-specific antibodies as a mechanism of protective immunity induced by Plasmodium falciparum circumsporozoite protein-based vaccine. Parasite immunology 65 12753434
1988 Human T cells recognize polymorphic and non-polymorphic regions of the Plasmodium falciparum circumsporozoite protein. The EMBO journal 65 2461298
1991 Location of human cytotoxic T cell epitopes within a polymorphic domain of the Plasmodium falciparum circumsporozoite protein. International immunology 64 1716144
1989 Immunization of Saimiri sciureus boliviensis with recombinant vaccines based on the circumsporozoite protein of Plasmodium vivax. The American journal of tropical medicine and hygiene 64 2658634
2007 Malaria vaccines: are we getting closer? Current opinion in molecular therapeutics 63 17330398
1998 Malaria circumsporozoite protein inhibits protein synthesis in mammalian cells. The EMBO journal 63 9669999
2007 Vector bionomics and malaria transmission in the Upper Orinoco River, Southern Venezuela. Memorias do Instituto Oswaldo Cruz 62 17568935
1992 Binding of malarial circumsporozoite protein to sulfatides [Gal(3-SO4)beta 1-Cer] and cholesterol-3-sulfate and its dependence on disulfide bond formation between cysteines in region II. Molecular and biochemical parasitology 60 1518521
2025 Sensitive and modular amplicon sequencing of Plasmodium falciparum diversity and resistance for research and public health. Scientific reports 42 40155691
2025 Repertoire, function, and structure of serological antibodies induced by the R21/Matrix-M malaria vaccine. The Journal of experimental medicine 10 40719751
2025 Targeting Bottlenecks in Malaria Transmission: Antibody-Epitope Descriptions Guide the Design of Next-Generation Biomedical Interventions. Immunological reviews 7 39907429
2025 Long lived liver-resident memory T cells of biased specificities for abundant sporozoite antigens drive malaria protection by radiation-attenuated sporozoite vaccination. PLoS pathogens 5 40424562
2025 Late killing of Plasmodium berghei sporozoites in the liver by an anti-circumsporozoite protein antibody. eLife 3 39951341
2025 Analysis of Fc-dependent effector functions of anti-malaria circumsporozoite protein antibodies. Microbiology spectrum 3 40698943
2025 The Plasmodium CSP repeats have elastic properties with a critical role in sporozoite motility. The EMBO journal 2 40983687
2025 A Plasmodium-derived nanoparticle vaccine elicits sterile protection against malaria in mice. Nature microbiology 2 41420060
2026 Vaccine-Induced Antibodies to a C-Terminal Plasmodium falciparum Circumsporozoite Protein Epitope Associated With Protection Against Malaria Challenge. The Journal of infectious diseases 1 40826493
2026 A Multivalent Peptide Vaccine Against Malaria, Targeting Plasmodium Circumsporozoite Protein and Mosquito AgTRIO. The Journal of infectious diseases 0 40804022
2026 Malaria immunity in the infant: progress and pitfalls. Current opinion in immunology 0 41831390
2026 Deep learning-enabled scaffolding of spatial arrays of PfCSP epitopes. Proceedings of the National Academy of Sciences of the United States of America 0 41945436
2026 Haplotype diversity of Plasmodium falciparum circumsporozoite protein prior to malaria vaccine implementation in Kaelé Health District, Cameroon, 2022-2023. Frontiers in parasitology 0 42023409
2026 Antibody fine specificity correlates with protection from malaria for the RTS,S vaccine in young African children: A post hoc analysis of a phase IIb randomised controlled trial. PLoS medicine 0 42133737
2026 A prime-and-trap vaccination strategy to evaluate minimal requirements for malaria liver stage protection in mice. Malaria journal 0 42192444
2026 Bivalent virus-like particles expressing SPECT1 and CSP trigger pre-erythrocytic malaria immunity and protect against transgenic Plasmodium falciparum sporozoite challenge in mice. Frontiers in immunology 0 42220505
2026 Evaluation of immunogenicity and efficacy of a Plasmodium vivax nanoparticle vaccine in mice. Vaccine 0 42322682
2026 Addition of blood-stage antibody enhances anti-sporozoite antibody protection in a humanized mouse model of Plasmodium falciparum infection. Cell reports 0 42329767
2026 A structure-based epitope tagging approach identifies vulnerable sites on the malarial P36-P52 protein complex for antibody-mediated neutralization of Plasmodium sporozoites. PLoS pathogens 0 42418521
2026 Chemovaccination with a late-liver-stage antimalarial induces durable immunity against malaria. Science (New York, N.Y.) 0 42594189