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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - CCHFVaccine (Crimean-Congo Haemorrhagic Fever Vaccine)

Teaser

Summary

Within this first reporting period, we have made significant progress in almost all Work Packages (WPs). In general, we have developed several key tools which will be used for validation and analysis. These include testing the efficiency of protein expression in different vaccine platforms and methods for the characterization of immune responses for animal and human samples. We have successfully sequenced a clinical isolate of CCHFV - strain Hoti. We have codon-optimized Hoti based sequence constructs and these have been used to develop vaccine candidate platforms (such as DNA, MVA, etc). We believe one of the most impressive achievements has been to establish a unique biobank of human clinical samples from CCHF patients collected from diverse endemic regions (Turkey, Tajikistan, and Bulgaria). The biobank, which will provide us access to samples for up to two years post onset of infection, will be key to our work in understanding the adaptive protective immunity against CCHFV in humans. We have also taken all necessary steps in regulatory compliance to support the obligatory criteria and requirements that our vaccine candidates should reach in order to even be considered for clinical testing. We have also developed a Target Product Profile (TPP), which will be used to focus our vaccine development efforts. In addition, we have considered and discussed the different steps involved in a clinical trial application and subsequent licensing of a vaccine by EMA. The CCHFVaccine project has also been presented to the WHO Blueprint roadmap for CCHFV. The coordinator of CCHFVaccine project moderated the discussion for the development of vaccines within this WHO meeting.

Work performed

The project is organised into seven work packages (WP): the first one, WP1, is dedicated to the management of the consortium and the organisation of annual and Executive Committee meetings. The Project Management Team has been acting as a helpdesk for all partners to answer their questions about the project, finances and reporting. Under WP7, the ethics deliverables required have been gathered and submitted to the EC. The other WPs are dedicated to the development of the scientific aspects of the project and its dissemination.
WP2: The overarching objective of this WP is to generate a wide range of modern vaccine candidates for CCHFV. Based on the sequences that were provided by partner 1Â´s linked third party (NIAID), participant 3 (JLU) designed cDNA constructs encoding codon-optimised proteins of CCHFV strain Hoti. The efficiency of codon-optimization has been evaluated and the plasmids have been distributed to all partners. Using these cDNAs or previously developed constructs, several vaccine platforms have been developed or are going to be developed and produced for immunization purposes.
WP3: The overarching objective of this WP is to evaluate the immunization and protective efficacy of CCHF vaccine candidates (developed by WP2 partners) in a wide range of animal models and develop an animal model road map. Within this WP we have established animal models using CCHFV Hoti strain including the widely-used laboratory strain (IbAr 10200).
WP4: The overarching objective of this WP is to establish a biobank and database to characterise the immune signature for protective immunity. During the first reporting period, the following work has been performed: (i) creation of a database to be shared amongst partners for recording clinical samples (this consists of anonymized patient information, clinical symptoms, biochemical results, etc.), (ii) development, standardization and dissemination of protocols for the collection of peripheral blood mononuclear cells (PBMCs), (ii) collection of patient samples, shipment and the creation of a biobank. Additionally, several immunological assays for characterization of immune responses against CCHFV have been developed.
WP5: The overarching objective of this WP is to establish protocols and to perform a small phase I clinical trial. During the first 18 months of the project, substantial headway has been made in understanding the limitations of what is possible to move into the clinic within the project timeframe; in particular in light of the Target Product Profile (TPP) for the vaccine developed within WP6. To date, we have discussed the possibility to use DNA/MVA/Adeno platforms for clinical trials. Thus, several key factors, together with the TPP are needed for consideration and selection of the final vaccine candidate(s). For evaluation of the clinical trial and to gain as much information as possible, WP5 has identified the absolute need for standardizing and validating the assays which will be used in preclinical development including assays that will be used for the evaluation of materials generated from the clinical trial. This has been highlighted as a clear priority.
In WP6 the objective is to widely publicise the project and its results to public health bodies, NGOs, outbreak management teams and develop an exploitation plan. Since the beginning of the project, we have held a workshop on regulatory requirements for human and veterinary vaccine development â€œNo translation without regulationâ€ at Paul-Ehrlich-Institut, where TPPs for different applications were drafted. The first training and exchange visits have been performed. An overview of the IP situation has been obtained, and awareness has been raised with all partners to ensure that newly generated IP is appropriately secured, and the development of a management plan for the different biobanks and databases has been started.

Final results

WP2: Within this reporting period, all milestones have been reached for CCHFV strain IbAr10200. The most efficient candidates produced by WP2 could form the basis for future veterinary and human vaccines.
WP3: The activities and obtained results in WP3 are without substantial delays and generally on time. It was possible based on experimental data to define the most suitable challenge strain, CCHFV Kosovo Hoiti. It was a great success that immunodeficient IFNAR-/- mice model by using CCHFV Kosovo Hoiti were set up. Recently scientist at NIAID/NIH has developed an NHP by using CCHFV Kosovo Hoiti (It should be highlighted that the development of NHP model for CCHFV was not done within the CCHFvaccine project). However, these models can be used in the further course of this project for the vaccine efficacy studies. These achievements within the consortium and also outside of the CCHFvaccine will benefit the long-term aims and major prerequisites for the development of CCHF vaccines.
WP4: As the CCHFVaccine biobank is augmented with further samples, it will provide the necessary repository of materials required to determine the immune signature of CCHF disease. Importantly, this will allow us to elucidate the adaptive immunity that vaccine candidates need to elicit.
WP5: The project in WP5 has identified the key hurdles that a vaccine against CCHF can encounter during clinical development. By identifying these hurdles, a safer path for clinical development can be taken.
WP6: A milestone has been reached by developing TPPs for different CCHF vaccine applications. These TPPs certainly have implications beyond the CCHFVaccine consortia, as they clearly identify key parameters needed in a functional CCHF vaccine. The work package is on track to reach its objectives.