A human monoclonal antibody blocks malaria transmission and defines a highly conserved neutralizing epitope on gametes

Camila H Coelho; Wai Kwan Tang; Martin Burkhardt; Jacob D Galson; Olga Muratova; Nichole D Salinas; Thiago Luiz Alves E Silva; Karine Reiter; Nicholas J MacDonald; Vu Nguyen; Raul Herrera; Richard Shimp; David L Narum; Miranda Byrne-Steele; Wenjing Pan; Xiaohong Hou; Brittany Brown; Mary Eisenhower; Jian Han; Bethany J Jenkins; Justin Y A Doritchamou; Margery G Smelkinson; Joel Vega-Rodríguez; Johannes Trück; Justin J Taylor; Issaka Sagara; Sara A Healy; Jonathan P Renn; Niraj H Tolia; Patrick E Duffy

doi:10.1038/s41467-021-21955-1

A human monoclonal antibody blocks malaria transmission and defines a highly conserved neutralizing epitope on gametes

Nat Commun. 2021 Mar 19;12(1):1750. doi: 10.1038/s41467-021-21955-1.

Authors

Camila H Coelho^#¹, Wai Kwan Tang^#², Martin Burkhardt³, Jacob D Galson^{4

5}, Olga Muratova³, Nichole D Salinas², Thiago Luiz Alves E Silva⁶, Karine Reiter³, Nicholas J MacDonald³, Vu Nguyen³, Raul Herrera³, Richard Shimp³, David L Narum³, Miranda Byrne-Steele⁷, Wenjing Pan⁷, Xiaohong Hou⁷, Brittany Brown⁷, Mary Eisenhower⁷, Jian Han⁷, Bethany J Jenkins¹, Justin Y A Doritchamou¹, Margery G Smelkinson⁸, Joel Vega-Rodríguez⁶, Johannes Trück⁴, Justin J Taylor⁹, Issaka Sagara¹⁰, Sara A Healy³, Jonathan P Renn³, Niraj H Tolia¹¹, Patrick E Duffy^{12

13}

Affiliations

¹ Pathogenesis and Immunity Section, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
² Host-Pathogen Interactions and Structural Vaccinology Section, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
³ Vaccine Development Unit, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁴ Division of Immunology and Children's Research Center, University Children's Hospital Zurich, University of Zurich (UZH), Zurich, Switzerland.
⁵ Alchemab Therapeutics Ltd, 55-56 Russell Square, London, UK.
⁶ Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
⁷ iRepertoire Inc., Huntsville, AL, USA.
⁸ Biological Imaging Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁹ Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
¹⁰ Malaria Research and Training Center, University of Sciences, Techniques, and Technology, Bamako, Mali.
¹¹ Host-Pathogen Interactions and Structural Vaccinology Section, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. [email protected].
¹² Pathogenesis and Immunity Section, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. [email protected].
¹³ Vaccine Development Unit, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. [email protected].

^# Contributed equally.

Abstract

Malaria elimination requires tools that interrupt parasite transmission. Here, we characterize B cell receptor responses among Malian adults vaccinated against the first domain of the cysteine-rich 230 kDa gamete surface protein Pfs230, a key protein in sexual stage development of P. falciparum parasites. Among nine Pfs230 human monoclonal antibodies (mAbs) that we generated, one potently blocks transmission to mosquitoes in a complement-dependent manner and reacts to the gamete surface; the other eight show only low or no blocking activity. The structure of the transmission-blocking mAb in complex with vaccine antigen reveals a large discontinuous conformational epitope, specific to domain 1 of Pfs230 and comprising six structural elements in the protein. The epitope is conserved, suggesting the transmission-blocking mAb is broadly functional. This study provides a rational basis to improve malaria vaccines and develop therapeutic antibodies for malaria elimination.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Animals
Antibodies, Monoclonal / immunology
Antibodies, Monoclonal / pharmacology*
Antibodies, Protozoan / immunology
Antibodies, Protozoan / pharmacology*
Antigens, Protozoan / chemistry
Antigens, Protozoan / immunology
Binding Sites
Cells, Cultured
Epitopes / chemistry
Epitopes / immunology*
Germ Cells / immunology*
Host-Parasite Interactions / drug effects
Host-Parasite Interactions / immunology
Humans
Malaria Vaccines / administration & dosage
Malaria Vaccines / immunology
Malaria, Falciparum / parasitology
Malaria, Falciparum / prevention & control*
Malaria, Falciparum / transmission
Mosquito Vectors / parasitology
Plasmodium falciparum / drug effects*
Plasmodium falciparum / immunology
Plasmodium falciparum / physiology
Protein Conformation
Protozoan Proteins / chemistry
Protozoan Proteins / immunology

Substances

Antibodies, Monoclonal
Antibodies, Protozoan
Antigens, Protozoan
Epitopes
Malaria Vaccines
Pfs230 antigen, Plasmodium falciparum
Protozoan Proteins