A Phase 1b, Age De-Escalation/Dose Escalation Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of MAM01 in Adults and Children in a Setting of Perennial Malaria Transmission

This study will test a new drug (MAM01) to find which doses are safe and could help prevent people from getting malaria for at least 4 months. The study will take place in parts of Africa where malaria is common. Part A is an open-label study conducted in healthy adults whereas Part B is double-blind study conducted in young children and infants. Both the parts will evaluate the safety, tolerability and pharmacokinetics of MAM01.

Start Date01 Jan 2025

Sponsor / Collaborator

Bill & Melinda Gates Medical Research InstituteStartup

PACTR202410517100221 / SuspendedPhase 2IIT

A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial to Assess the Safety, Tolerability, and Efficacy of the Anti-Malaria Monoclonal Antibody L9LS in Infants 10 Weeks of Age in Western Kenya and to Evaluate the Impact of L9LS on Subsequent Malaria Vaccine Immunogenicity

Start Date02 Dec 2024

Sponsor / Collaborator-

NCT06461026 / RecruitingPhase 1IIT

A Phase 1b, Randomized, Double-Blind, Placebo-Controlled Trial to Assess the Safety, Tolerability, and Pharmacokinetics of L9LS in Infants in Mali and to Evaluate the Impact of L9LS on Subsequent R21/Matrix-MTM Vaccine Immunogenicity

The purpose of this study is to assess the safety, tolerability, and pharmacokinetics of L9LS in infants in Mali and to evaluate the impact of L9LS on subsequent R21/Matrix-MTM vaccine immunogenicity.

Start Date19 Aug 2024

Sponsor / Collaborator

National Institute of Allergy & Infectious Diseases

[+4]

100 Clinical Results associated with PfCSP

100 Translational Medicine associated with PfCSP

0 Patents (Medical) associated with PfCSP

184

Literatures (Medical) associated with PfCSP

01 Dec 2024·Computational and Structural Biotechnology Journal

Mass spectrometry-complemented molecular modeling predicts the interaction interface for a camelid single-domain antibody targeting the Plasmodium falciparum circumsporozoite protein’s C-terminal domain

Article

Author: Geens, Rob ; Vocht, Line De ; Opuni, Kwabena F.M. ; Sterckx, Yann G.-J. ; Glocker, Michael O ; Opuni, Kwabena F M ; Glocker, Michael O. ; Ruß, Manuela ; Wielendaele, Pieter Van ; Debuy, Christophe ; Sterckx, Yann G-J

BackgroundBioanalytical methods that enable rapid and high-detail characterization of binding specificities and strengths of protein complexes with low sample consumption are highly desired. The interaction between a camelid single domain antibody (sdAbCSP1) and its target antigen (PfCSP-Cext) was selected as a model system to provide proof-of-principle for the here described methodology.Research design and methodsThe structure of the sdAbCSP1 - PfCSP-Cext complex was modeled using AlphaFold2. The recombinantly expressed proteins, sdAbCSP1, PfCSP-Cext, and the sdAbCSP1 - PfCSP-Cext complex, were subjected to limited proteolysis and mass spectrometric peptide analysis. ITEM MS (Intact Transition Epitope Mapping Mass Spectrometry) and ITC (Isothermal Titration Calorimetry) were applied to determine stoichiometry and binding strength.ResultsThe paratope of sdAbCSP1 mainly consists of its CDR3 (aa100-118). PfCSP-Cext's epitope is assembled from its α-helix (aa40-52) and opposing loop (aa83-90). PfCSP-Cext's GluC cleavage sites E46 and E58 were shielded by complex formation, confirming the predicted epitope. Likewise, sdAbCSP1's tryptic cleavage sites R105 and R108 were shielded by complex formation, confirming the predicted paratope. ITEM MS determined the 1:1 stoichiometry and the high complex binding strength, exemplified by the gas phase dissociation reaction enthalpy of 50.2 kJ/mol. The in-solution complex dissociation constant is 5 × 10^-10 M.ConclusionsCombining AlphaFold2 modeling with mass spectrometry/limited proteolysis generated a trustworthy model for the sdAbCSP1 - PfCSP-Cext complex interaction interface.

08 Oct 2024·JCI Insight

Identification of RTS,S/AS01 vaccine–induced humoral biomarkers predictive of protection against controlled human malaria infection

Article

Author: Seaton, Kelly E ; Shabbir, Siam ; Deal, Aaron W ; Li, Kan ; Seaton, Kelly E. ; Kisalu, Neville K ; Deal, Aaron W. ; King, C. Richter ; Hilliard, Sir’Tauria ; Spreng, Rachel L ; Mudrak, Sarah V ; Gregory, Scott ; Mudrak, Sarah V. ; King, C Richter ; Kisalu, Neville K. ; Carnacchi, Alexander J ; Horn, Gillian Q. ; Tomaras, Georgia D. ; Dennison, S Moses ; Tomaras, Georgia D ; Dennison, S. Moses ; Horn, Gillian Q ; Abraha, Milite ; Bekker, Valerie ; Mercer, Laina D ; Carnacchi, Alexander J. ; Lin, Lin ; Zhang, Lu ; Mercer, Laina D. ; Hilliard, Sir'Tauria ; Feeney, Elizabeth ; Wille-Reece, Ulrike ; Jongert, Erik ; Dutta, Sheetij ; Spreng, Rachel L.

BACKGROUNDThe mechanism(s) responsible for the efficacy of WHO-recommended malaria vaccine RTS,S/AS01 are not completely understood. We previously identified RTS,S vaccine-induced Plasmodium falciparum circumsporozoite protein-specific (PfCSP-specific) antibody measures associated with protection from controlled human malaria infection (CHMI). Here, we tested the protection-predicting capability of these measures in independent CHMI studies.METHODSVaccine-induced total serum antibody (immunoglobulins, Igs) and subclass antibody (IgG1 and IgG3) responses were measured by biolayer interferometry and the binding antibody multiplex assay, respectively. Immune responses were compared between protected and nonprotected vaccinees using univariate and multivariate logistic regression.RESULTSBlinded prediction analysis showed that 5 antibody binding measures, including magnitude-avidity composite of serum Ig specific for PfCSP, major NANP repeats and N-terminal junction, and PfCSP- and NANP-specific IgG1 subclass magnitude, had good prediction accuracy (area under the receiver operating characteristic curves [ROC AUC] > 0.7) in at least 1 trial. Furthermore, univariate analysis showed a significant association between these antibody measures and protection (odds ratios 2.6-3.1). Multivariate modeling of combined data from 3 RTS,S CHMI trials identified the combination of IgG1 NANP binding magnitude plus serum NANP and N-junction Ig binding magnitude-avidity composite as the best predictor of protection (95% confidence interval for ROC AUC 0.693-0.834).CONCLUSIONThese results reinforce our previous findings and provide a tool for predicting protection in future trials.TRIAL REGISTRATIONClinicalTrials.gov NCT03162614, NCT03824236, NCT01366534, and NCT01857869.FUNDINGThis study was supported by Bill & Melinda Gates Foundation's Global Health-Discovery Collaboratory grants (INV-008612 and INV-043419) to GDT.

13 Jun 2024·Clinical Microbiology Reviews

Vaccines and monoclonal antibodies: new tools for malaria control

Review

Author: Miura, Kazutoyo ; Zavala, Fidel ; Long, Carole A. ; Flores-Garcia, Yevel

SUMMARY Malaria remains one of the biggest health problems in the world. While significant reductions in malaria morbidity and mortality had been achieved from 2000 to 2015, the favorable trend has stalled, rather significant increases in malaria cases are seen in multiple areas. In 2022, there were 249 million estimated cases, and 608,000 malaria-related deaths, mostly in infants and children aged under 5 years, globally. Therefore, in addition to the expansion of existing anti-malarial control measures, it is critical to develop new tools, such as vaccines and monoclonal antibodies (mAbs), to fight malaria. In the last 2 years, the first and second malaria vaccines, both targeting Plasmodium falciparum circumsporozoite proteins (PfCSP), have been recommended by the World Health Organization to prevent P. falciparum malaria in children living in moderate to high transmission areas. While the approval of the two malaria vaccines is a considerable milestone in vaccine development, they have much room for improvement in efficacy and durability. In addition to the two approved vaccines, recent clinical trials with mAbs against PfCSP, blood-stage vaccines against P. falciparum or P. vivax , and transmission-blocking vaccine or mAb against P. falciparum have shown promising results. This review summarizes the development of the anti-PfCSP vaccines and mAbs, and recent topics in the blood- and transmission-blocking-stage vaccine candidates and mAbs. We further discuss issues of the current vaccines and the directions for the development of next-generation vaccines.

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