Potent AMA1-specific human monoclonal antibody against Plasmodium vivax Pre-erythrocytic and Blood Stages
New therapeutics are necessary for preventing Plasmodium vivax malaria due to easy transmissibility and dormancy in the liver that increases the clinical burden due to recurrent relapse. In this manuscript we characterize 12 Pv Apical Membrane Antigen 1 (PvAMA1) specific human monoclonal antibodies from Peripheral Blood Mononuclear Cells of a Pv-exposed individual. PvAMA1 is essential for sporozoite and merozoite invasion, making it a unique therapeutic target. We show that humAb 826827 blocks the invasion of human reticulocytes using Pv clinical isolates and inhibits sporozoite invasion of human hepatocytes in vitro (IC<sub>50</sub> of 0.3 - 3.7 µg/mL). Inoculation of human liver transgenic (FRG-humHep) female mice with humAb 826827 significantly reduces liver infection in vivo. The crystal structure of rPvAMA1 bound to 826827 shows that 826827 partially occupies the highly conserved hydrophobic groove in PvAMA1 that binds its known receptor, RON2. We have isolated a potent humAb that is isolate-transcendent, blocks both pre-erythrocytic and blood stage infection, and could be a potential therapy for Pv.
Authors
- Melanie H. Dietrich (ORCID: https://orcid.org/0000-0002-2780-4389)
- Nastaran Rezakhani
- K B Nielson
- Alyssa Malachin
- Karli R. Redinger (ORCID: https://orcid.org/0009-0008-5073-0809)
- Christopher L. King (ORCID: https://orcid.org/0000-0003-3873-7860)
- Chiara Drago
- Jetsumon Sattabongkot (ORCID: https://orcid.org/0000-0002-3938-4588)
- Lionel Brice Feufack-Donfack (ORCID: https://orcid.org/0000-0003-1578-455X)
- Wai‐Hong Tham (ORCID: https://orcid.org/0000-0001-7950-8699)
- Lenore L. Carias
- Ágnes Orbán (ORCID: https://orcid.org/0000-0001-5865-2106)
- D. Herbert Opi (ORCID: https://orcid.org/0000-0002-4589-4365)
- Gigliola Zanghì (ORCID: https://orcid.org/0000-0002-9656-9642)
- Yelenna Skomorovska-Prokvolit
- Lee M. Yeoh (ORCID: https://orcid.org/0000-0001-7872-762X)
- Ashley M. Vaughan (ORCID: https://orcid.org/0000-0001-5815-756X)
- Wanlapa Roobsoong (ORCID: https://orcid.org/0000-0002-1789-0439)
- Jean Popovici (ORCID: https://orcid.org/0000-0002-3135-1175)
- James G. Beeson (ORCID: https://orcid.org/0000-0002-1018-7898)
- Brandon K. Wilder (ORCID: https://orcid.org/0000-0002-5577-7787)
- Jürgen Bosch (ORCID: https://orcid.org/0000-0002-2624-4105)
- Maya Aleshnick (ORCID: https://orcid.org/0000-0001-5471-4242)
- Payton Kirtley
- Léa Baldor
- Olivia S. McLaine
- Anna C. Winnicki
- Nicolai C Jung
Institutions
- Infectious Disease Research Institute (US)
- Burnet Institute (AU)
- Oregon Health & Science University (US)
- The University of Melbourne (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- University of Washington (US)
- Mahidol University (TH)
- Veterans Health Administration (US)
- Center for Global Health (US)
- Institut Pasteur du Cambodge (KH)
- Children's Cancer Therapy Development Institute (US)
- Monash University (AU)
- Case Western Reserve University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-12-04
- DOI
- https://doi.org/10.1038/s41467-024-53848-4
- Citations
- 4
- Primary Topic
- Malaria Research and Control
- Type
- article
- Field-Weighted Citation Impact
- 2.17
Funders
- U.S. Department of Veterans Affairs
- University of Washington
- Case Western Reserve University
- Australian Nuclear Science and Technology Organisation
- Case Comprehensive Cancer Center, Case Western Reserve University
- Burnet Institute
- School of Medicine, Case Western Reserve University
- Seattle Children's Research Institute
- Children’s Hospital of Wisconsin Research Institute
- Australian Cancer Research Foundation
- Australian Synchrotron
- Monash University
- University of Melbourne
- Mahidol University
- National Institutes of Health
- National Health and Medical Research Council
- Faculty of Tropical Medicine, Mahidol University