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

Journal Article · · EMBO Molecular Medicine
 [1];  [2];  [3];  [1];  [3];  [4];  [5];  [6];  [7];  [4];  [8];  [2];  [4]
  1. German Cancer Research Center, Heidelberg (Germany); Heidelberg Univ. (Germany)
  2. Max Planck Institute for Infection Biology, Berlin (Germany)
  3. The Hospital for Sick Children Research Institute, Toronto, ON (Canada)
  4. German Cancer Research Center, Heidelberg (Germany)
  5. Sanaria Inc., Rockville, MD (United States)
  6. Institute of Tropical Medicine, Tübingen (Germany); Centre de Recherches de Lambaréné (CERMEL) (Gabon)
  7. Institute of Tropical Medicine, Tübingen (Germany); Radboud Univ., Nijmegen (Netherlands)
  8. The Hospital for Sick Children Research Institute, Toronto, ON (Canada); Univ. of Toronto, ON (Canada)
+ Show Author Affiliations
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.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
Bill and Melinda Gates Foundation; National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
2423519
Journal Information:
EMBO Molecular Medicine, Journal Name: EMBO Molecular Medicine Journal Issue: 6 Vol. 15; ISSN 1757-4676
Publisher:
EMBO PressCopyright Statement
Country of Publication:
United States
Language:
English

References (58)

Single‐cell based high‐throughput sequencing of full‐length immunoglobulin heavy and light chain genes journal October 2013
Disordered epitopes as peptide vaccines journal April 2018
Efficacy of RTS,S/AS02 malaria vaccine against Plasmodium falciparum infection in semi-immune adult men in The Gambia: a randomised trial journal December 2001
Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anti-circumsporozoite antibody titres and protection in children aged 5–17 months in Kenya and Tanzania: a randomised controlled trial journal February 2011
Safety and efficacy of the RTS,S/AS01 E candidate malaria vaccine given with expanded-programme-on-immunisation vaccines: 19 month follow-up of a randomised, open-label, phase 2 trial journal October 2011
Natural Parasite Exposure Induces Protective Human Anti-Malarial Antibodies journal December 2017
A Potent Anti-Malarial Human Monoclonal Antibody Targets Circumsporozoite Protein Minor Repeats and Neutralizes Sporozoites in the Liver journal October 2020
The RTS,S malaria vaccine journal July 2010
Liposomes containing monophosphoryl lipid A and QS-21 serve as an effective adjuvant for soluble circumsporozoite protein malaria vaccine FMP013 journal July 2017
Safety, toxicity and immunogenicity of a malaria vaccine based on the circumsporozoite protein (FMP013) with the adjuvant army liposome formulation containing QS21 (ALFQ) journal June 2019
Breadth of humoral immune responses to the C-terminus of the circumsporozoite protein is associated with protective efficacy induced by the RTS,S malaria vaccine journal February 2021
First-in-human assessment of safety and immunogenicity of low and high doses of Plasmodium falciparum malaria protein 013 (FMP013) administered intramuscularly with ALFQ adjuvant in healthy malaria-naïve adults journal September 2022
Sterile protection against human malaria by chemoattenuated PfSPZ vaccine journal February 2017
A human monoclonal antibody prevents malaria infection by targeting a new site of vulnerability on the parasite journal March 2018
A public antibody lineage that potently inhibits malaria infection through dual binding to the circumsporozoite protein journal March 2018
Concentration and avidity of antibodies to different circumsporozoite epitopes correlate with RTS,S/AS01E malaria vaccine efficacy journal May 2019
A PfSPZ vaccine immunization regimen equally protective against homologous and heterologous controlled human malaria infection journal August 2022
Glycosylated nanoparticle-based PfCSP vaccine confers long-lasting antibody responses and sterile protection in mouse malaria model journal April 2023
Evolution of protective human antibodies against Plasmodium falciparum circumsporozoite protein repeat motifs journal May 2020
A Preliminary Evaluation of a Recombinant Circumsporozoite Protein Vaccine against Plasmodium falciparum Malaria journal January 1997
Seven-Year Efficacy of RTS,S/AS01 Malaria Vaccine among Young African Children journal June 2016
Unexpected fold in the circumsporozoite protein target of malaria vaccines journal April 2012
Structural basis for antibody recognition of the NANP repeats in Plasmodium falciparum circumsporozoite protein journal November 2017
Comparison of circumsporozoite proteins from avian and mammalian malarias: biological and phylogenetic implications. journal October 1996
Circumsporozoite proteins of human malaria parasites Plasmodium falciparum and Plasmodium vivax. journal July 1982
Circumsporozoite proteins of malaria parasites contain a single immunodominant region with two or more identical epitopes journal June 1983
Surrogate Light Chain Expressing Human Peripheral B Cells Produce Self-reactive Antibodies journal December 2003
The Plasmodium circumsporozoite protein is proteolytically processed during cell invasion journal January 2005
Rare PfCSP C-terminal antibodies induced by live sporozoite vaccination are ineffective against malaria infection journal November 2017
A high-affinity antibody against the CSP N-terminal domain lacks Plasmodium falciparum inhibitory activity journal August 2020
Change-O: a toolkit for analyzing large-scale B cell immunoglobulin repertoire sequencing data: Table 1. journal June 2015
Safety, Immunogenicity, and Efficacy of a Recombinantly Produced Plasmodium falciparum Circumsporozoite Protein-Hepatitis B Surface Antigen Subunit Vaccine journal June 1995
Proteolytic Cleavage of the Plasmodium falciparum Circumsporozoite Protein Is a Target of Protective Antibodies journal March 2015
Phaser crystallographic software journal July 2007
XDS journal January 2010
PHENIX: a comprehensive Python-based system for macromolecular structure solution journal January 2010
Features and development of Coot journal March 2010
Mutational analysis of the GPI-anchor addition sequence from the circumsporozoite protein of Plasmodium journal July 2005
Predominant Autoantibody Production by Early Human B Cell Precursors journal September 2003
Rationale for development of a synthetic vaccine against Plasmodium falciparum malaria journal June 1985
Structure of the gene encoding the immunodominant surface antigen on the sporozoite of the human malaria parasite Plasmodium falciparum journal August 1984
Antihomotypic affinity maturation improves human B cell responses against a repetitive epitope journal June 2018
Clonal selection drives protective memory B cell responses in controlled human malaria infection journal February 2018
Clonal evolution and TCR specificity of the human T FH cell response to Plasmodium falciparum CSP journal June 2022
Reversible Conformational Change in the Plasmodium falciparum Circumsporozoite Protein Masks Its Adhesion Domains journal July 2015
sciReptor: analysis of single-cell level immunoglobulin repertoires journal February 2016
The biological function of antibodies induced by the RTS,S/AS01 malaria vaccine candidate is determined by their fine specificity journal May 2016
A New Role of the Mosquito Complement-like Cascade in Male Fertility in Anopheles gambiae journal September 2015
Diversity of T Cell Epitopes in Plasmodium falciparum Circumsporozoite Protein Likely Due to Protein-Protein Interactions journal May 2013
Polymorphisms in Anopheles gambiae Immune Genes Associated with Natural Resistance to Plasmodium falciparum journal September 2010
Interrogating the Plasmodium Sporozoite Surface: Identification of Surface-Exposed Proteins and Demonstration of Glycosylation on CSP and TRAP by Mass Spectrometry-Based Proteomics journal April 2016
Protective effects of combining monoclonal antibodies and vaccines against the Plasmodium falciparum circumsporozoite protein journal December 2021
A novel CSP C-terminal epitope targeted by an antibody with protective activity against Plasmodium falciparum journal March 2022
Models of Somatic Hypermutation Targeting and Substitution Based on Synonymous Mutations from High-Throughput Immunoglobulin Sequencing Data journal January 2013
Establishment of a Human Hepatocyte line that Supports in Vitro Development of the Exo-Erythrocytic Stages of the Malaria Parasites Plasmodium Falciparum and p. Vivax journal May 2006
Next Generation Sequencing to Detect Variation in the Plasmodium falciparum Circumsporozoite Protein journal May 2012
The biological function of antibodies induced by the RTS,S/AS01 malaria vaccine candidate is determined by their fine specificity collection January 2016
Collaboration gets the most out of software journal September 2013

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