Monoclonal antibodies block transmission of genetically diverse Plasmodium falciparum strains to mosquitoes
Abstract Malaria parasite transmission to mosquitoes relies on the uptake of sexual stage parasites during a blood meal and subsequent formation of oocysts on the mosquito midgut wall. Transmission-blocking vaccines (TBVs) and monoclonal antibodies (mAbs) target sexual stage antigens to interrupt hu...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2021-08-01
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| Series: | npj Vaccines |
| Online Access: | https://doi.org/10.1038/s41541-021-00366-9 |
| _version_ | 1797641285391089664 |
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| author | Roos M. de Jong Lisette Meerstein-Kessel Dari F. Da Sandrine Nsango Joseph D. Challenger Marga van de Vegte-Bolmer Geert-Jan van Gemert Elias Duarte Noam Teyssier Robert W. Sauerwein Thomas S. Churcher Roch K. Dabire Isabelle Morlais Emily Locke Martijn A. Huynen Teun Bousema Matthijs M. Jore |
| author_facet | Roos M. de Jong Lisette Meerstein-Kessel Dari F. Da Sandrine Nsango Joseph D. Challenger Marga van de Vegte-Bolmer Geert-Jan van Gemert Elias Duarte Noam Teyssier Robert W. Sauerwein Thomas S. Churcher Roch K. Dabire Isabelle Morlais Emily Locke Martijn A. Huynen Teun Bousema Matthijs M. Jore |
| author_sort | Roos M. de Jong |
| collection | DOAJ |
| description | Abstract Malaria parasite transmission to mosquitoes relies on the uptake of sexual stage parasites during a blood meal and subsequent formation of oocysts on the mosquito midgut wall. Transmission-blocking vaccines (TBVs) and monoclonal antibodies (mAbs) target sexual stage antigens to interrupt human-to-mosquito transmission and may form important tools for malaria elimination. Although most epitopes of these antigens are considered highly conserved, little is known about the impact of natural genetic diversity on the functional activity of transmission-blocking antibodies. Here we measured the efficacy of three mAbs against leading TBV candidates (Pfs48/45, Pfs25 and Pfs230) in transmission assays with parasites from naturally infected donors compared to their efficacy against the strain they were raised against (NF54). Transmission-reducing activity (TRA) was measured as reduction in mean oocyst intensity. mAb 45.1 (α-Pfs48/45) and mAb 4B7 (α-Pfs25) reduced transmission of field parasites from almost all donors with IC80 values similar to NF54. Sequencing of oocysts that survived high mAb concentrations did not suggest enrichment of escape genotypes. mAb 2A2 (α-Pfs230) only reduced transmission of parasites from a minority of the donors, suggesting that it targets a non-conserved epitope. Using six laboratory-adapted strains, we revealed that mutations in one Pfs230 domain correlate with mAb gamete surface binding and functional TRA. Our findings demonstrate that, despite the conserved nature of sexual stage antigens, minor sequence variation can significantly impact the efficacy of transmission-blocking mAbs. Since mAb 45.1 shows high potency against genetically diverse strains, our findings support its further clinical development and may inform Pfs48/45 vaccine design. |
| first_indexed | 2024-03-11T13:43:23Z |
| format | Article |
| id | doaj.art-852c3163e8664f10865e9f61f43db532 |
| institution | Directory Open Access Journal |
| issn | 2059-0105 |
| language | English |
| last_indexed | 2024-03-11T13:43:23Z |
| publishDate | 2021-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Vaccines |
| spelling | doaj.art-852c3163e8664f10865e9f61f43db5322023-11-02T11:14:38ZengNature Portfolionpj Vaccines2059-01052021-08-01611910.1038/s41541-021-00366-9Monoclonal antibodies block transmission of genetically diverse Plasmodium falciparum strains to mosquitoesRoos M. de Jong0Lisette Meerstein-Kessel1Dari F. Da2Sandrine Nsango3Joseph D. Challenger4Marga van de Vegte-Bolmer5Geert-Jan van Gemert6Elias Duarte7Noam Teyssier8Robert W. Sauerwein9Thomas S. Churcher10Roch K. Dabire11Isabelle Morlais12Emily Locke13Martijn A. Huynen14Teun Bousema15Matthijs M. Jore16Department of Medical Microbiology and Radboud Center for Infectious Diseases, Radboud University Medical CenterDepartment of Medical Microbiology and Radboud Center for Infectious Diseases, Radboud University Medical CenterInstitut de Recherche en Sciences de la Santé, Direction RégionaleMalaria Research Laboratory, OCEACMedical Research Council Centre for Global Infections Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College LondonDepartment of Medical Microbiology and Radboud Center for Infectious Diseases, Radboud University Medical CenterDepartment of Medical Microbiology and Radboud Center for Infectious Diseases, Radboud University Medical CenterEPPIcenter Research Program, Division of HIV, ID, and Global Medicine, Department of Medicine, University of CaliforniaEPPIcenter Research Program, Division of HIV, ID, and Global Medicine, Department of Medicine, University of CaliforniaDepartment of Medical Microbiology and Radboud Center for Infectious Diseases, Radboud University Medical CenterMedical Research Council Centre for Global Infections Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College LondonInstitut de Recherche en Sciences de la Santé, Direction RégionaleMalaria Research Laboratory, OCEACPATH’s Malaria Vaccine InitiativeCenter for Molecular and Biomolecular Informatics, Radboud University Medical CenterDepartment of Medical Microbiology and Radboud Center for Infectious Diseases, Radboud University Medical CenterDepartment of Medical Microbiology and Radboud Center for Infectious Diseases, Radboud University Medical CenterAbstract Malaria parasite transmission to mosquitoes relies on the uptake of sexual stage parasites during a blood meal and subsequent formation of oocysts on the mosquito midgut wall. Transmission-blocking vaccines (TBVs) and monoclonal antibodies (mAbs) target sexual stage antigens to interrupt human-to-mosquito transmission and may form important tools for malaria elimination. Although most epitopes of these antigens are considered highly conserved, little is known about the impact of natural genetic diversity on the functional activity of transmission-blocking antibodies. Here we measured the efficacy of three mAbs against leading TBV candidates (Pfs48/45, Pfs25 and Pfs230) in transmission assays with parasites from naturally infected donors compared to their efficacy against the strain they were raised against (NF54). Transmission-reducing activity (TRA) was measured as reduction in mean oocyst intensity. mAb 45.1 (α-Pfs48/45) and mAb 4B7 (α-Pfs25) reduced transmission of field parasites from almost all donors with IC80 values similar to NF54. Sequencing of oocysts that survived high mAb concentrations did not suggest enrichment of escape genotypes. mAb 2A2 (α-Pfs230) only reduced transmission of parasites from a minority of the donors, suggesting that it targets a non-conserved epitope. Using six laboratory-adapted strains, we revealed that mutations in one Pfs230 domain correlate with mAb gamete surface binding and functional TRA. Our findings demonstrate that, despite the conserved nature of sexual stage antigens, minor sequence variation can significantly impact the efficacy of transmission-blocking mAbs. Since mAb 45.1 shows high potency against genetically diverse strains, our findings support its further clinical development and may inform Pfs48/45 vaccine design.https://doi.org/10.1038/s41541-021-00366-9 |
| spellingShingle | Roos M. de Jong Lisette Meerstein-Kessel Dari F. Da Sandrine Nsango Joseph D. Challenger Marga van de Vegte-Bolmer Geert-Jan van Gemert Elias Duarte Noam Teyssier Robert W. Sauerwein Thomas S. Churcher Roch K. Dabire Isabelle Morlais Emily Locke Martijn A. Huynen Teun Bousema Matthijs M. Jore Monoclonal antibodies block transmission of genetically diverse Plasmodium falciparum strains to mosquitoes npj Vaccines |
| title | Monoclonal antibodies block transmission of genetically diverse Plasmodium falciparum strains to mosquitoes |
| title_full | Monoclonal antibodies block transmission of genetically diverse Plasmodium falciparum strains to mosquitoes |
| title_fullStr | Monoclonal antibodies block transmission of genetically diverse Plasmodium falciparum strains to mosquitoes |
| title_full_unstemmed | Monoclonal antibodies block transmission of genetically diverse Plasmodium falciparum strains to mosquitoes |
| title_short | Monoclonal antibodies block transmission of genetically diverse Plasmodium falciparum strains to mosquitoes |
| title_sort | monoclonal antibodies block transmission of genetically diverse plasmodium falciparum strains to mosquitoes |
| url | https://doi.org/10.1038/s41541-021-00366-9 |
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