A Potent Anti-Malarial Human Monoclonal Antibody Targets Circumsporozoite Protein Minor Repeats and Neutralizes Sporozoites in the Liver

Lawrence T Wang; Lais S Pereira; Yevel Flores-Garcia; James O'Connor; Barbara J Flynn; Arne Schön; Nicholas K Hurlburt; Marlon Dillon; Annie S P Yang; Amanda Fabra-García; Azza H Idris; Bryan T Mayer; Monica W Gerber; Raphael Gottardo; Rosemarie D Mason; Nicole Cavett; Reid B Ballard; Neville K Kisalu; Alvaro Molina-Cruz; Jorgen Nelson; Rachel Vistein; Carolina Barillas-Mury; Rogerio Amino; David Baker; Neil P King; Robert W Sauerwein; Marie Pancera; Ian A Cockburn; Fidel Zavala; Joseph R Francica; Robert A Seder

doi:10.1016/j.immuni.2020.08.014

A Potent Anti-Malarial Human Monoclonal Antibody Targets Circumsporozoite Protein Minor Repeats and Neutralizes Sporozoites in the Liver

Immunity. 2020 Oct 13;53(4):733-744.e8. doi: 10.1016/j.immuni.2020.08.014. Epub 2020 Sep 17.

Authors

Lawrence T Wang¹, Lais S Pereira¹, Yevel Flores-Garcia², James O'Connor³, Barbara J Flynn¹, Arne Schön⁴, Nicholas K Hurlburt⁵, Marlon Dillon¹, Annie S P Yang⁶, Amanda Fabra-García⁶, Azza H Idris¹, Bryan T Mayer⁵, Monica W Gerber⁵, Raphael Gottardo⁷, Rosemarie D Mason¹, Nicole Cavett¹, Reid B Ballard¹, Neville K Kisalu¹, Alvaro Molina-Cruz⁸, Jorgen Nelson⁹, Rachel Vistein¹, Carolina Barillas-Mury⁸, Rogerio Amino¹⁰, David Baker⁹, Neil P King⁹, Robert W Sauerwein⁶, Marie Pancera⁵, Ian A Cockburn¹¹, Fidel Zavala², Joseph R Francica¹, Robert A Seder¹²

Affiliations

¹ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
² Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
³ Department of Immunology and Infectious Diseases, John Curtin School of Medical Research, The Australian National University, Canberra, ACT 0200, Australia; The Australian National University Medical School, Canberra, ACT 2601, Australia.
⁴ Department of Biology, Johns Hopkins University, Baltimore, MD 21205, USA.
⁵ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
⁶ Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
⁷ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
⁸ Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
⁹ Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
¹⁰ Unit of Malaria Infection and Immunity, Institut Pasteur, 25-28 Rue du Dr Roux, 75015 Paris, France.
¹¹ Department of Immunology and Infectious Diseases, John Curtin School of Medical Research, The Australian National University, Canberra, ACT 0200, Australia.
¹² Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: [email protected].

Abstract

Discovering potent human monoclonal antibodies (mAbs) targeting the Plasmodium falciparum circumsporozoite protein (PfCSP) on sporozoites (SPZ) and elucidating their mechanisms of neutralization will facilitate translation for passive prophylaxis and aid next-generation vaccine development. Here, we isolated a neutralizing human mAb, L9 that preferentially bound NVDP minor repeats of PfCSP with high affinity while cross-reacting with NANP major repeats. L9 was more potent than six published neutralizing human PfCSP mAbs at mediating protection against mosquito bite challenge in mice. Isothermal titration calorimetry and multiphoton microscopy showed that L9 and the other most protective mAbs bound PfCSP with two binding events and mediated protection by killing SPZ in the liver and by preventing their egress from sinusoids and traversal of hepatocytes. This study defines the subdominant PfCSP minor repeats as neutralizing epitopes, identifies an in vitro biophysical correlate of SPZ neutralization, and demonstrates that the liver is an important site for antibodies to prevent malaria.

Keywords: Monoclonal antibodies; NVDP minor repeats; Plasmodium falciparum; circumsporozoite protein; malaria vaccines; passive transfer; sporozoites.

Publication types

Clinical Trial, Phase I
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Animals
Antibodies, Monoclonal / immunology*
Antibodies, Neutralizing / immunology*
Antibodies, Protozoan / immunology*
Antimalarials / immunology*
Cell Line
Cell Line, Tumor
Epitopes / immunology
Female
HEK293 Cells
Hepatocytes / immunology
Hepatocytes / parasitology
Humans
Liver / immunology
Liver / parasitology
Malaria / immunology
Malaria / parasitology
Malaria Vaccines / immunology
Male
Mice
Mice, Inbred C57BL
Middle Aged
Plasmodium falciparum / immunology*
Protozoan Proteins / immunology*
Sporozoites / immunology*
Young Adult

Substances

Antibodies, Monoclonal
Antibodies, Neutralizing
Antibodies, Protozoan
Antimalarials
Epitopes
Malaria Vaccines
Protozoan Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding