Saskia C van der Boor1, Merel J Smit2, Stijn W van Beek3, Jordache Ramjith4, Karina Teelen1, Marga van de Vegte-Bolmer1, Geert-Jan van Gemert1, Peter Pickkers5, Yimin Wu6, Emily Locke6, Shwu-Maan Lee6, John Aponte6, C Richter King6, Ashley J Birkett6, Kazutoyo Miura7, Morolayo A Ayorinde8, Robert W Sauerwein9, Rob Ter Heine3, Christian F Ockenhouse6, Teun Bousema2, Matthijs M Jore1, Matthew B B McCall10. 1. Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands. 2. Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, Netherlands; Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, Netherlands. 3. Department of Pharmacy, Radboud University Medical Center, Nijmegen, Netherlands; Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, Netherlands. 4. Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, Netherlands; Department for Health Evidence, Biostatistics Section, Radboud University Medical Center, Nijmegen, Netherlands; Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, Netherlands. 5. Department of Intensive Care, Radboud University Medical Center, Nijmegen, Netherlands. 6. PATH's Malaria Vaccine Initiative, PATH, Seattle, WA, USA. 7. Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA. 8. Human Immunology Laboratory, Imperial College London, London, UK. 9. Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands; TropIQ Health Sciences, Nijmegen, Netherlands. 10. Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands; Institut für Tropenmedizin, Universitätsklinikum Tübingen, Tübingen, Germany; Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon. Electronic address: matthew.mccall@radboudumc.nl.
Abstract
BACKGROUND: Malaria elimination requires interruption of the highly efficient transmission of Plasmodium parasites by mosquitoes. TB31F is a humanised monoclonal antibody that binds the gamete surface protein Pfs48/45 and inhibits fertilisation, thereby preventing further parasite development in the mosquito midgut and onward transmission. We aimed to evaluate the safety and efficacy of TB31F in malaria-naive participants. METHODS: In this open-label, first-in-human, dose-escalation, phase 1 clinical trial, healthy, malaria-naive, adult participants were administered a single intravenous dose of 0·1, 1, 3, or 10 mg/kg TB31F or a subcutaneous dose of 100 mg TB31F, and monitored until day 84 after administration at a single centre in the Netherlands. The primary outcome was the frequency and magnitude of adverse events. Additionally, TB31F serum concentrations were measured by ELISA. Transmission-reducing activity (TRA) of participant sera was assessed by standard membrane feeding assays with Anopheles stephensi mosquitoes and cultured Plasmodium falciparum gametocytes. The trial is registered with Clinicaltrials.gov, NCT04238689. FINDINGS: Between Feb 17 and Dec 10, 2020, 25 participants were enrolled and sequentially assigned to each dose (n=5 per group). No serious or severe adverse events occurred. In total, 33 grade 1 and six grade 2 related adverse events occurred in 20 (80%) of 25 participants across all groups. Serum of all participants administered 1 mg/kg, 3 mg/kg, or 10 mg/kg TB31F intravenously had more than 80% TRA for 28 days or more, 56 days or more, and 84 days or more, respectively. The TB31F serum concentration reaching 80% TRA was 2·1 μg/mL (95% CI 1·9-2·3). Extrapolating the duration of TRA from antibody kinetics suggests more than 80% TRA is maintained for 160 days (95% CI 136-193) following a single intravenous 10 mg/kg dose. INTERPRETATION: TB31F is a well tolerated and highly potent monoclonal antibody capable of completely blocking transmission of P falciparum parasites from humans to mosquitoes. In areas of seasonal transmission, a single dose might cover an entire malaria season. FUNDING: PATH's Malaria Vaccine Initiative.
BACKGROUND: Malaria elimination requires interruption of the highly efficient transmission of Plasmodium parasites by mosquitoes. TB31F is a humanised monoclonal antibody that binds the gamete surface protein Pfs48/45 and inhibits fertilisation, thereby preventing further parasite development in the mosquito midgut and onward transmission. We aimed to evaluate the safety and efficacy of TB31F in malaria-naive participants. METHODS: In this open-label, first-in-human, dose-escalation, phase 1 clinical trial, healthy, malaria-naive, adult participants were administered a single intravenous dose of 0·1, 1, 3, or 10 mg/kg TB31F or a subcutaneous dose of 100 mg TB31F, and monitored until day 84 after administration at a single centre in the Netherlands. The primary outcome was the frequency and magnitude of adverse events. Additionally, TB31F serum concentrations were measured by ELISA. Transmission-reducing activity (TRA) of participant sera was assessed by standard membrane feeding assays with Anopheles stephensi mosquitoes and cultured Plasmodium falciparum gametocytes. The trial is registered with Clinicaltrials.gov, NCT04238689. FINDINGS: Between Feb 17 and Dec 10, 2020, 25 participants were enrolled and sequentially assigned to each dose (n=5 per group). No serious or severe adverse events occurred. In total, 33 grade 1 and six grade 2 related adverse events occurred in 20 (80%) of 25 participants across all groups. Serum of all participants administered 1 mg/kg, 3 mg/kg, or 10 mg/kg TB31F intravenously had more than 80% TRA for 28 days or more, 56 days or more, and 84 days or more, respectively. The TB31F serum concentration reaching 80% TRA was 2·1 μg/mL (95% CI 1·9-2·3). Extrapolating the duration of TRA from antibody kinetics suggests more than 80% TRA is maintained for 160 days (95% CI 136-193) following a single intravenous 10 mg/kg dose. INTERPRETATION: TB31F is a well tolerated and highly potent monoclonal antibody capable of completely blocking transmission of P falciparum parasites from humans to mosquitoes. In areas of seasonal transmission, a single dose might cover an entire malaria season. FUNDING: PATH's Malaria Vaccine Initiative.
Authors: C M de Korne; R van Schuijlenburg; J C Sijtsma; H M de Bes; E Baalbergen; S Azargoshasb; M N van Oosterom; M B B McCall; F W B van Leeuwen; M Roestenberg Journal: Sci Rep Date: 2022-10-13 Impact factor: 4.996