Magnitude and durability of ProC6C-AlOH/Matrix-M ^tm vaccine-induced malaria transmission-blocking antibodies in Burkinabe adults from a Phase 1 randomized trial

Article

Author: Addo Ofori, Ebenezer ; Plieskatt, Jordan ; Miura, Kazutoyo ; Theisen, Michael ; Tiono, Alfred B. ; Sagara, Issaka ; Long, Carole ; Naghizadeh, Mohammad

ProC6C is a multi-stage malaria vaccine designed to disrupt parasite transmission and prevent infection by incorporating three parasite proteins (Pfs230-Pro, Pfs48/45-6C, and CSP) in a single vaccine antigen. The Phase 1 clinical trial (PACTR202201848463189) conducted in Burkina Faso, showed ProC6C-AlOH/Matrix-M was safe, well tolerated, immunogenic and generated a functional antibody response to all three constituent antigens at the primary output (D70). As magnitude and durability are central to an efficacious malaria vaccine, analysis was expanded past the initial endpoint, to determine transmission-blocking antibodies (anti-Pfs230 and anti-Pfs48/45-6C) present through D180. Analysis of transmission-reducing activity (TRA) showed 7/20 samples remained biologically active at D180. To identify immune biomarkers for high levels of TRA, the Pfs48/45-6C IgG concentration (calculated relative to the transmission-blocking mAb TB31F) was compared among TRA positive and negative individuals. The magnitude of anti-Pfs48/45-6C IgG had an excellent predictive accuracy (area under the receiver operating curve [ROC AUC] >0.8) with a threshold of 8.7 μg/ml for significant TRA. Additionally, there was significant correlation of TRA and anti-Pfs48/45 epitope I IgG concentration but not significant correlation for anti-Pfs230-Pro IgG, suggesting that vaccine-induced anti-Pfs48/45-6C IgG is the main predictor of TRA. This finding was corroborated by the observation that complement had no effect on TRA in the standard membrane feeding assay (SMFA). Collectively, these efforts confirm the transmission-blocking attributes of ProC6C and suggest that an alternative dosing regimen be evaluated in future clinical trials to improve longevity of functional transmission-reducing antibodies.

01 Mar 2024·Vaccine

Clinical formulation development of Plasmodium falciparum malaria vaccine candidates based on Pfs48/45, Pfs230, and PfCSP

Article

Author: Singh, Susheel K ; Plieskatt, Jordan ; Theisen, Michael ; Naghizadeh, Mohammad ; Jore, Matthijs M ; Wood, Grith Krøyer ; Bang, Peter

Two malaria transmission-blocking vaccine (TBV) candidates, R0.6C and ProC6C, have completed preclinical development including the selection of adjuvants, Alhydrogel® with or without the saponin based adjuvant Matrix-M™. Here, we report on the final drug product (formulation) design of R0.6C and ProC6C and evaluate their safety and biochemical stability in preparation for preclinical and clinical pharmacy handling. The point-of-injection stability studies demonstrated that both the R0.6C and ProC6C antigens are stable on Alhydrogel in the presence or absence of Matrix-M for up to 24 h at room temperature. As this is the first study to combine Alhydrogel and Matrix-M for clinical use, we also evaluated their potential interactions. Matrix-M adsorbs to Alhydrogel, while not displacing the > 95 % adsorbed protein. The R0.6C and ProC6C formulations were found to be safe and well tolerated in repeated dose toxicity studies in rabbits generating high levels of functional antibodies that blocked infection of mosquitoes. Further, the R0.6C and ProC6C drug products were found to be stable for minimally 24 months when stored at 2-8 °C, with studies ongoing through 36 months. Together, this data demonstrates the safety and suitability of the L. lactis expression system as well as supports the clinical testing of the R0.6C and ProC6C malaria vaccine candidates in First-In-Human clinical trials.

npj VaccinesQ1 · MEDICINE

Preclinical development of a Pfs230-Pfs48/45 chimeric malaria transmission-blocking vaccine

Q1 · MEDICINE

ArticleOA

Author: van Daalen, Renate C ; van de Vegte-Bolmer, Marga ; Teelen, Karina ; Reimer, Jenny M ; Theisen, Michael ; Plieskatt, Jordan ; Singh, Susheel K ; Jore, Matthijs M ; Bengtsson, Karin Lövgren ; van Gemert, Geert-Jan ; Chourasia, Bishwanath K ; Singh, Vandana

AbstractThe Plasmodium falciparum Pfs230 and Pfs48/45 proteins are leading candidates for a malaria transmission-blocking vaccine (TBV). Previously, we showed that a Pfs230–Pfs48/45 fusion protein elicits higher levels of functional antibodies than the individual antigens, but low yields hampered progression to clinical evaluation. Here we identified a modified construct (ProC6C) with a circumsporozoite protein (CSP) repeat-linker sequence that enhances expression. A scalable and reproducible process in the Lactococcus lactis expression system was developed and ProC6C was successfully transferred for manufacturing under current Good Manufacturing Practices (cGMP). In addition, a panel of analytical assays for release and stability were developed. Intact mass spectrometry analysis and multiangle light scattering showed that the protein contained correct disulfide bonds and was monomeric. Immunogenicity studies in mice showed that the ProC6C adsorbed to Alhydrogel®, with or without Matrix-MTM, elicited functional antibodies that reduced transmission to mosquitoes and sporozoite invasion of human hepatocytes. Altogether, our data support manufacture and clinical evaluation of ProC6C as a multistage malaria-vaccine candidate.

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Indication	Highest Phase	Country/Location	Organization	Date
Malaria	Preclinical	Global	Statens Serum Institute	12 Oct 2021

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