Extending the range of Plasmodium falciparum transmission blocking antibodies

Lacy M Simons; Patricia Ferrer; Nita Gombakomba; Knashka Underwood; Raul Herrera; David L Narum; Gaspar Canepa; Festus Acquah; Linda Amoah; Patrick E Duffy; Carolina Barillas-Mury; Carole Long; Shwu-Maan Lee; Emily Locke; Kazutoyo Miura; Kim C Williamson

doi:10.1016/j.vaccine.2023.04.042

Extending the range of Plasmodium falciparum transmission blocking antibodies

Vaccine. 2023 May 16;41(21):3367-3379. doi: 10.1016/j.vaccine.2023.04.042. Epub 2023 Apr 24.

Authors

Affiliations

¹ Department of Biology, Loyola University Chicago, 1032 W Sheridan Rd, Chicago, IL 60660, USA.
² Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD, 20814, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, 6720A Rockledge Drive, Suite 100, Bethesda, USA.
³ Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD, 20814, USA.
⁴ Vaccine Development Unit, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD, 20892, USA.
⁵ Mosquito Immunity and Vector Competence Section Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 12735 Twinbrook Parkway, Rockville, MD 20852, USA.
⁶ Immunology Department, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana.
⁷ Malaria Immunology Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 12735 Twinbrook Parkway, Rockville, MD 20852, USA.
⁸ Center for Vaccine Innovation and Access, PATH, 455 Massachusetts Ave, NW, Suite 1000, Washington, DC, 20001, USA.
⁹ Department of Biology, Loyola University Chicago, 1032 W Sheridan Rd, Chicago, IL 60660, USA; Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD, 20814, USA. Electronic address: kim.williamson@usuhs.edu.

Abstract

Recent work demonstrating that asymptomatic carriers of P. falciparum parasites make up a large part of the infectious reservoir highlights the need for an effective malaria vaccine. Given the historical challenges of vaccine development, multiple parasite stages have been targeted, including the sexual stages required for transmission. Using flow cytometry to efficiently screen for P. falciparum gamete/zygote surface reactivity, we identified 82 antibodies that bound live P. falciparum gametes/zygotes. Ten antibodies had significant transmission-reducing activity (TRA) in a standard membrane feeding assay and were subcloned along with 9 nonTRA antibodies as comparators. After subcloning, only eight of the monoclonals obtained have significant TRA. These eight TRA mAbs do not recognize epitopes present in any of the current recombinant transmission-blocking vaccine candidates, Pfs230D1M, Pfs48/45.6C, Pf47 D2 and rPfs25. One TRA mAb immunoprecipitates two surface antigens, Pfs47 and Pfs230, that are expressed by both gametocytes and gametes/zygotes. These two proteins have not previously been reported to associate and the recognition of both by a single TRA mAb suggests the Pfs47/Pfs230 complex is a new vaccine target. In total, Pfs230 was the dominant target antigen, with five of the eight TRA mAbs and 8 of 11 nonTRA gamete/zygote surface reactive mAbs interacting with Pfs230. Of the three remaining TRA mAbs, two recognized non-reduced, parasite-produced Pfs25 and one bound non-reduced, parasite-produced Pfs48/45. None of the TRA mAbs bound protein on an immunoblot of reduced gamete/zygote extract and two TRA mAbs were immunoblot negative, indicating none of the new TRA epitopes are linear. The identification of eight new TRA mAbs that bind epitopes not included in any of the constructs currently under advancement as transmission-blocking vaccine candidates may provide new targets worthy of further study.

Keywords: Malaria transmission; Monoclonal antibody screen; Mosquito membrane feed; Plasmodium falciparum gametes; Vaccines.

Publication types

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

MeSH terms

Antibodies, Blocking
Antibodies, Monoclonal
Antibodies, Protozoan
Antigens, Protozoan
Epitopes
Humans
Malaria Vaccines*
Malaria, Falciparum*
Plasmodium falciparum
Protozoan Proteins

Substances

Antibodies, Blocking
Epitopes
Antibodies, Protozoan
Antibodies, Monoclonal
Malaria Vaccines
Protozoan Proteins
Antigens, Protozoan

Grants and funding

Z01 AI000947/ImNIH/Intramural NIH HHS/United States