Cytotoxicity of human antibodies targeting the circumsporozoite protein is amplified by 3D substrate and correlates with protection
Manuela C. Aguirre-Botero,
Lawrence T. Wang,
Pauline Formaglio,
Eduardo Aliprandini,
Jean-Michel Thiberge,
Arne Schön,
Yevel Flores-Garcia,
Shamika Mathis-Torres,
Barbara J. Flynn,
Lais da Silva Pereira,
Yann Le Duff,
Mathew Hurley,
Adéla Nacer,
Paul W. Bowyer,
Fidel Zavala,
Azza H. Idris,
Joseph R. Francica,
Robert A. Seder,
Rogerio Amino
Affiliations
Manuela C. Aguirre-Botero
Institut Pasteur, Université Paris Cité, Malaria Infection and Immunity, BioSPC, F-75015, Paris, France
Lawrence T. Wang
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
Pauline Formaglio
Institut Pasteur, Université Paris Cité, Malaria Infection and Immunity, BioSPC, F-75015, Paris, France
Eduardo Aliprandini
Institut Pasteur, Université Paris Cité, Malaria Infection and Immunity, BioSPC, F-75015, Paris, France
Jean-Michel Thiberge
Institut Pasteur, Université Paris Cité, Malaria Infection and Immunity, BioSPC, F-75015, Paris, France
Arne Schön
Department of Biology, Johns Hopkins University, Baltimore, MD, 21218, USA
Yevel Flores-Garcia
Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA
Shamika Mathis-Torres
Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA
Barbara J. Flynn
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
Lais da Silva Pereira
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
Yann Le Duff
Centre for Aids Reagents, National Institute for Biological Standards and Control (NIBSC), Medicines and Healthcare products Regulatory Agency (MHRA), Blanche Lane, South Mimms, Potters Bar, EN6 3QG, UK
Mathew Hurley
Centre for Aids Reagents, National Institute for Biological Standards and Control (NIBSC), Medicines and Healthcare products Regulatory Agency (MHRA), Blanche Lane, South Mimms, Potters Bar, EN6 3QG, UK
Adéla Nacer
Division of Bacteriology, National Institute for Biological Standards and Control (NIBSC), Medicines and Healthcare products Regulatory Agency (MHRA), Blanche Lane, South Mimms, Potters Bar, EN6 3QG, UK
Paul W. Bowyer
Division of Bacteriology, National Institute for Biological Standards and Control (NIBSC), Medicines and Healthcare products Regulatory Agency (MHRA), Blanche Lane, South Mimms, Potters Bar, EN6 3QG, UK
Fidel Zavala
Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA
Azza H. Idris
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
Joseph R. Francica
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
Robert A. Seder
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA; Corresponding author
Rogerio Amino
Institut Pasteur, Université Paris Cité, Malaria Infection and Immunity, BioSPC, F-75015, Paris, France; Corresponding author
Summary: Human monoclonal antibodies (hmAbs) targeting the Plasmodium falciparum circumsporozoite protein (PfCSP) on the sporozoite surface are a promising tool for preventing malaria infection. However, their mechanisms of protection remain unclear. Here, using 13 distinctive PfCSP hmAbs, we provide a comprehensive view of how PfCSP hmAbs neutralize sporozoites in host tissues. Sporozoites are most vulnerable to hmAb-mediated neutralization in the skin. However, rare but potent hmAbs additionally neutralize sporozoites in the blood and liver. Efficient protection in tissues mainly associates with high-affinity and high-cytotoxicity hmAbs inducing rapid parasite loss-of-fitness in the absence of complement and host cells in vitro. A 3D-substrate assay greatly enhances hmAb cytotoxicity and mimics the skin-dependent protection, indicating that the physical stress imposed on motile sporozoites by the skin is crucial for unfolding the protective potential of hmAbs. This functional 3D cytotoxicity assay can thus be useful for downselecting potent anti-PfCSP hmAbs and vaccines.
