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

211

Literatures (Medical) associated with PfCSP

03 Jan 2025·Science

Protective antibodies target cryptic epitope unmasked by cleavage of malaria sporozoite protein

Article

Author: Tan, Joshua ; Idris, Azza ; Wijayalath, Wathsala ; Molina-Cruz, Alvaro ; Traore, Boubacar ; Purser, Lauren ; Seder, Robert A. ; Oda, Kyosuke ; Edgar, Joshua M. ; Ongoiba, Aissata ; Bonilla, Brian ; Barillas-Mury, Carolina ; Wollenberg, Kurt ; Franco, Adriano ; Zavala, Fidel ; Aleshnick, Maya ; Li, Shanping ; Da Silva Pereira, Lais ; Petros, Samantha ; Crompton, Peter D. ; Pazzi, Joseph ; Skinner, Jeff ; Teng, Andy A. ; Swearingen, Kristian ; Kayentao, Kassoum ; Kanatani, Sachie ; Shears, Melanie J. ; Moskovitz, Re’em ; Sinnis, Photini ; Vaughan, Ashley ; Paez, Gonzalo Gonzalez ; Kirtley, Payton ; Ghosal, Suman ; Dacon, Cherrelle ; Doumbo, Safiatou ; Krymskaya, Ludmila ; Flynn, Barbara ; Wilder, Brandon K. ; Dillon, Marlon ; Gupta, Priya ; Flores-Garcia, Yevel ; Tucker, Courtney ; Belmonte, Arnel ; Campo, Joseph J. ; Traver, Maria ; Kritzberg, Jake ; Wilson, Ian A.

The most advanced monoclonal antibodies (mAbs) and vaccines against malaria target the central repeat region or closely related sequences within the Plasmodium falciparum circumsporozoite protein (PfCSP). Here, using an antigen-agnostic strategy to investigate human antibody responses to whole sporozoites, we identified a class of mAbs that target a cryptic PfCSP epitope that is only exposed after cleavage and subsequent pyroglutamylation (pGlu) of the newly formed N terminus. This pGlu-CSP epitope is not targeted by current anti-PfCSP mAbs and is not included in the licensed malaria vaccines. MAD21-101, the most potent mAb in this class, confers sterile protection against Pf infection in a human liver–chimeric mouse model. These findings reveal a site of vulnerability on the sporozoite surface that can be targeted by next-generation antimalarial interventions.

01 Jan 2025·The Lancet Microbe

R21 in Matrix-M adjuvant in UK malaria-naive adult men and non-pregnant women aged 18–45 years: an open-label, partially blinded, phase 1–2a controlled human malaria infection study

Article

Author: Bellamy, Duncan ; Mair, Catherine ; Baum, Jake ; Edwards, Nick J ; Datoo, Mehreen S ; Bowyer, Georgina ; Lewis, David J M ; Collins, Katharine A ; Berrie, Eleanor ; Brendish, Nathan ; Morter, Richard ; Fries, Louis ; Lopez, Fernando Ramos ; Angell-Manning, Philip ; Angus, Brian ; Stockdale, Lisa ; Silman, Daniel ; Minassian, Angela M ; Venkatraman, Navin ; Powlson, Jonathan ; Brod, Florian ; Griffiths, Oliver ; Blagborough, Andrew M ; Roberts, Rachel ; Glenn, Greg ; Folegatti, Pedro M ; Ewer, Katie J ; Poulton, Ian ; Hill, Adrian V S ; Faust, Saul N ; Lawrie, Alison M

BACKGROUNDR21 is a novel malaria vaccine, composed of a fusion protein of the malaria circumsporozoite protein and hepatitis B surface antigen. Following favourable safety and immunogenicity in a phase 1 study, we aimed to assess the efficacy of R21 administered with Matrix-M (R21/MM) against clinical malaria in adults from the UK who were malaria naive in a controlled human malaria infection study.METHODSIn this open-label, partially blinded, phase 1-2A controlled human malaria infection study undertaken in Oxford, Southampton, and London, UK, we tested five novel vaccination regimens of R21/MM. A standard three-dose regimen (groups 1 and 6) was compared with a reduced (fractional) third dose (groups 2 and 5) of R21/MM, concomitant administration with viral vectors ChAd63-MVA expressing ME-TRAP (group 3), and a two-dose R21/MM regimen (group 7). Controlled Human Malaria Infection (CHMI) was delivered by mosquito bite at Imperial College London, London, UK, 3-4 weeks after final vaccination (or 18 months after final vaccination for group 6) alongside unvaccinated controls (groups 4A and 4B). The primary outcome measures were to assess safety of the vaccines in healthy malaria-naive volunteers and the efficacy (occurrence of blood-stage malaria infection) of the different vaccine regimens compared with non-vaccinated controls after CHMI. The trial was registered with ClinicalTrials.gov (NCT02905019).FINDINGS66 volunteers were enrolled with 59 undergoing subsequent CHMI. All vaccination schedules were well tolerated. The highest level of protection against CHMI was observed in participants receiving the standard three-dose regimen of R21/MM (group 1, nine of 11 volunteers protected) with protection maintained in three of five volunteers re-challenged by CHMI 7·5 months later. Protection against malaria was also seen in group 2, group 3, and group 5 compared with unvaccinated control participants. Total IgG antibody responses to the NANP repeat region of circumsporozoite protein peaked after the third dose of R21/MM in all volunteers and were well maintained to 90 days after challenge. Reducing the third dose did not affect protection or antibody concentrations.INTERPRETATIONOur study shows that R21/MM elicits high-level efficacy against clinical malaria in a controlled human infection model of malaria in adults who are malaria naive. These data supported the evaluation of R21/MM in field efficacy trials in the target population of young children in malaria-endemic areas.FUNDINGEU Horizon 2020, the UK Medical Research Council, the European Commission, the UK National Institute of Health Research, the Imperial NIHR Clinical Research Facility, the Oxford NIHR Biomedical Research Centre, and the Wellcome Trust.

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.

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