Periodic Reporting for period 1 - CAPTIVATE (CorrelAtes of Protective immuniTy-driven Investigation of malaria VAccine combinaTion stratEgies)
Okres sprawozdawczy: 2023-11-01 do 2025-04-30
Malaria remains a serious health concern worldwide, with P. falciparum considered one of the deadliest human parasites. Yet, the currently approved vaccine against malaria (RTS,S/AS01) offers limited protection due to challenges in vaccine development. Using current advances made in understanding immunity to address some of the existing challenges, this proposal aims to develop a more efficacious vaccine against P. falciparum by targeting multiple developmental stages (sporozoite, liver and blood-stage). In this project, combinations of 1) highly promising whole parasite vaccination approach targeting the liver (late-arresting GAP), 2) RTS,S (provided by GSK) and 3) mRNA versions of clinically evaluated and partially protective blood stage vaccine candidates (Rh5, AMA1-DiCo [sporozoite and blood stage]) will be evaluated in preclinical and small-scale human trials to discern the optimal combination for further clinical investigations. To inform a rational design of future vaccine candidates, CAPTIVATE will analyse the vaccine-induced immune response to acquire a full understanding of malaria protective immunity and develop an advanced immunology in-silico platform. While immunity to blood stage malaria is relatively well understood, the mechanisms of adaptive protective immunity for pre-erythrocytic malaria vaccine candidates are less well-established. CAPTIVATE addresses this critical knowledge gap by combining state-of-the-art preclinical and clinical (CHMI) in vivo malaria vaccine efficacy models with an innovative in-silico platform comprising TCR/VDJ sequencing and artificial intelligence predictions, to identify such mechanisms. CAPTIVATE assembles a unique combination of European experts in their respective fields (malaria modelling in primates, clinical vaccine testing, in-silico modelling of immune responses, innovative omics approaches) in an integrated interdisciplinary approach aimed at bringing the next generation malaria vaccines to the clinic.
Metabolomics, lipidomics, and proteomics technologies will enable more comprehensive approach to biomarker discovery and the elucidation of malaria immune system mechanisms, understanding of the molecular pathways underlying protective adaptive immune responses to malaria vaccines.
By enabling more effective vaccination strategies, CAPTIVATE contributes to the long-term goal of reducing malaria’s global burden. Additionally, it strengthens healthcare systems through enhanced scientific capability and informs broader public health decision-making through improved understanding of immune protection. The outcomes are expected to benefit patients, healthcare providers, and policymakers by reducing disease risk and enhancing resilience against communicable diseases.
Metabolomics, lipidomics, and proteomics technologies will enable more comprehensive approach to biomarker discovery and the elucidation of malaria immune system mechanisms, understanding of the molecular pathways underlying protective adaptive immune responses to malaria vaccines.
By enabling more effective vaccination strategies, CAPTIVATE contributes to the long-term goal of reducing malaria’s global burden. Additionally, it strengthens healthcare systems through enhanced scientific capability and informs broader public health decision-making through improved understanding of immune protection. The outcomes are expected to benefit patients, healthcare providers, and policymakers by reducing disease risk and enhancing resilience against communicable diseases.
WP 1- Lead BRPC
A clonal Pk-LA GAP has been obtained in vitro which, after additional steps aimed at ensuring transmission, will allow the consortium to better understand the immunological mechanisms behind the efficacy of late-arresting GAP parasites using a NHP model (focusing on organs). This is essential knowledge necessary to the development of LA-GAPs as malaria vaccines.
Single immunization with GA2 parasites demonstrated an unprecedented 90% protective efficacy. To determine the optimal conditions for a combined vaccine trial with LA-GAP and RTS,S/AS01, an additional clinical trial was therefore required. Currently, the protocol synopsis for the combined vaccine trial is being written.
WP2 – Lead IMW
First steps toward development of the in silico platform were taken and applied to bulk TCR sequencing data samples obtained from a CHMI trial, enabling early identification of potential malaria-specific TCR clonotypes. A novel algorithm for annotating TCRs related to unseen epitopes was also developed, showing good predictive performance during internal testing but has not yet been applied to any of the consortium’s data.
WP3- Lead UQTM
The potency of individual mRNA-encoded variants of two preselected blood-stage antigens has been evaluated. For each candidate, two mRNA candidates were designed, manufactured and screened in vitro, mainly based on integrity and in vitro expression levels. The selected mRNA candidates were formulated with gold standard LNPs and used in a rabbit immunization study. High antibody titres against the respective proteins were observed, albeit slightly less high for one PfRH5 variant. Similarly high levels of growth inhibitory antibody levels were observed for all the tested vaccines, including the PfRH5-mRNA variant giving lower antibody titres. The highest inhibitory capacity was found for the PfRH5-immunized animals, higher than for the PfAMA1 DiCo1-immunized animals.
Phase 2 of the project will be dedicated to further optimize the mRNA vaccine candidates (potentially combining several antigens in one vaccine) and to evaluate them in combination with the liver-stage vaccine in a small-scale clinical study.
WP4- Lead LUMC
A Free Flow Electrophoresis apparatus has been bought and installed. Protocols for the isolation technique have been shared and training has been given. QC assays for yield, purity and viability of the FFE-purified sporozoites are being set up and optimised.
WP5- Lead BPRC
The objectives are scheduled to be reached for M36-M48; the overarching ethical clearance to conduct the experiments was obtained.
WP6- Lead EVI
The strategic, executive, and advisory bodies have been established and formalised, and the Coordinator is ensuring progress through effective monitoring, coordination, and reporting
A clonal Pk-LA GAP has been obtained in vitro which, after additional steps aimed at ensuring transmission, will allow the consortium to better understand the immunological mechanisms behind the efficacy of late-arresting GAP parasites using a NHP model (focusing on organs). This is essential knowledge necessary to the development of LA-GAPs as malaria vaccines.
Single immunization with GA2 parasites demonstrated an unprecedented 90% protective efficacy. To determine the optimal conditions for a combined vaccine trial with LA-GAP and RTS,S/AS01, an additional clinical trial was therefore required. Currently, the protocol synopsis for the combined vaccine trial is being written.
WP2 – Lead IMW
First steps toward development of the in silico platform were taken and applied to bulk TCR sequencing data samples obtained from a CHMI trial, enabling early identification of potential malaria-specific TCR clonotypes. A novel algorithm for annotating TCRs related to unseen epitopes was also developed, showing good predictive performance during internal testing but has not yet been applied to any of the consortium’s data.
WP3- Lead UQTM
The potency of individual mRNA-encoded variants of two preselected blood-stage antigens has been evaluated. For each candidate, two mRNA candidates were designed, manufactured and screened in vitro, mainly based on integrity and in vitro expression levels. The selected mRNA candidates were formulated with gold standard LNPs and used in a rabbit immunization study. High antibody titres against the respective proteins were observed, albeit slightly less high for one PfRH5 variant. Similarly high levels of growth inhibitory antibody levels were observed for all the tested vaccines, including the PfRH5-mRNA variant giving lower antibody titres. The highest inhibitory capacity was found for the PfRH5-immunized animals, higher than for the PfAMA1 DiCo1-immunized animals.
Phase 2 of the project will be dedicated to further optimize the mRNA vaccine candidates (potentially combining several antigens in one vaccine) and to evaluate them in combination with the liver-stage vaccine in a small-scale clinical study.
WP4- Lead LUMC
A Free Flow Electrophoresis apparatus has been bought and installed. Protocols for the isolation technique have been shared and training has been given. QC assays for yield, purity and viability of the FFE-purified sporozoites are being set up and optimised.
WP5- Lead BPRC
The objectives are scheduled to be reached for M36-M48; the overarching ethical clearance to conduct the experiments was obtained.
WP6- Lead EVI
The strategic, executive, and advisory bodies have been established and formalised, and the Coordinator is ensuring progress through effective monitoring, coordination, and reporting
Not applicable since there are no results in RP1