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Tagged (DIVA) polyantigenic vaccine against Bovine Viral Diarrhea virus (BVDv) based on virus-Like-Particles

Periodic Reporting for period 1 - BoVLP-BVD (Tagged (DIVA) polyantigenic vaccine against Bovine Viral Diarrhea virus (BVDv) based on virus-Like-Particles)

Reporting period: 2019-05-01 to 2020-04-30

Development of new vaccines to prevent disease and avoid the use of antibiotics, to improve suboptimal available vaccines is now a European and industry priority. Bovine viral diarrhoea virus (BVDV) is an important infectious agent of cattle worldwide, endemic and very prevalent in countries where no systematic eradication and control programs have been established.
BVD infection has a major economic impact, estimated in hundreds of euros per animal for a European hut of around 80 million animals. Aquilón CyL, a leading biotech company, develops a new recombinant vaccine against BVD using a Virus-Like-Particle patented technology. Aquilón demonstrated the technical, commercial and regulatory feasibility by the SME instrument phase 1 project (nº 774994). After developing the vaccine to TRL6 stage (pre-industrial prototype with positive activity data), within BoVLP BVO project, Aquilón will develop one vaccine to TRL8 stage, demonstrating the commercial-scale manufacturing, vivo safety, efficacy and DIVA attributes in the target species.

For this purpose, the overall objectives of BoVLP-BVD project are:
1. Vaccine batches produced under specifications
2. Vaccine selection in animal tests
3. Analytical and diagnostics methods development
4. License agreement

Aquilón aims to develop a new and disruptive BVD vaccine with the following characteristics:
-Broad-spectrum vaccine (protection against all variants of the BVD virus)
-Tagged (differentiation between infected and vaccinated animals (DIVA)) and the development of new diagnostic tests.
-Safe and efficacious protecting animals against the disease and the foetal transmission of the virus.
-Cost-effective: simple scaling up and manufacturing process.

This vaccine candidate will be licensed to one or more veterinarian pharmaceutical company that will complete the final field studies required for commercialisation. Our business projections, based on agreements with Development milestones and commercial royalties, show prospects for a relevant tax-payer money multiplier with potential for more than 25% internal rate of return.
Manufacturing of BoVLP-BVD vaccine combines a high innovative concept based on empty viral capsids (VLPs or “virus-Like-Particles”), not containing DNA, which is covered by antigenic determinants of BVD virus. This “Chimeric” VLP-BVD structure is manufactured by an expression platform such us yeasts. After previous testing of the most reactive particles by in vitro tests against positive sera of BVD vaccinated animals, different VLP-BVD candidates have been produced at 1L scale in order to test the most suitable candidates for a future vaccine production. One of them was also tested in a 30 L fermentation as first approach to an industrial scaling of the process.

These vaccine prototypes have been used during the first project year in two trials in calves and rabbits, aimed to demonstrate basic attributes of this innovative technology. The first one consisted in demonstrating if it was able to enhance an in vivo immune-response in the target species (cattle), which gave very promising results in terms of safety, DIVA confirmation and detection of antibody against BVD, and in a model species (rabbit) suitable to improve a potency test for batch release control. Furthermore, results in the rabbit model allowed to determine differences between reactivity of the prototypes, required for prototype selection and composition of a solid patent application.

In order to test the immune-reaction of the animals after inoculation of the prototypes, different analytical methods were optimized. In this way, commercial ELISA tests have been adapted, implemented and validated, as well as in house developed tests to determine the reactivity against the antigenic determinants of the vaccine’s active substance (VLP-BVD).
Advice to focus the project development on an adequate regulatory frame was applied by means of an Innovation Task Force (ITF) meeting by the European Medicines Agency, giving us a preliminary overview of the registration process to be followed.

The project business and exploitation plan, foreseen for the last stage, will require experimental data support to define a Target Product Profile and feed-back obtained from potential partners. On the other hand, the Intellectual Property (IPR) management, will include a new patent with the generated data package. Lastly, dissemination and communication activities have been carried out during the first project year providing to all kind of audiences attractive information about technical results, patent strategy, analytic methods development and commercial interest of the company.
Promising results have been achieved during the first period, however, and according to the initial project plan, many tasks remain to be performed. New results and outputs of day-to-day project tasks are analyzed constantly to adapt the following steps to a coherent and consistent vaccine development design. Rabbit and claves trials will be performed to establish the best VLP-BVD candidate for and vaccine formulation, as well as an adequate adjuvant and active substance dose and posology. Ex vivo assays will allow to this selection and finally, a challenge study in the target specie will give us information about the safety and protective effect of the selected vaccine formulation, which will lead the project to awake the interest of industrial partners for project license agreement.

Meanwhile, further development of diagnostic and analytical methods for BVD, antigenic determinants and DIVA tagging confirmation will let us release new and optimized methods of antibody detection for the disease and positive tagging control of vaccinated animals, aimed to the use of this vaccine in BVD control and eradication programs.

Industrial scale-up at a 30L fermentation will be explored for the best candidate to stablish a cost-effective industrial manufacturing process able to be transferred to a potential GMP manufacturer within the veterinary industry sector.

Our Target Product Profile is a commercially-attractive and regulatory-acceptable, breakthrough recombinant vaccine against the Bovine Viral Diarrhoea virus (BVDv). This product profile goes well beyond the state of the art since no comparable vaccine exists at the moment. Considering that Bovine Viral Diarrhoea (BVD) is the most common viral disease, delivering such a vaccine will cause a significant economic and environmental impact in EU agriculture.

Given the potential high economic impact of the vaccine, if the project reaches its pending milestones during the final part of its implementation, it will be considered as a high valuable asset for the veterinarian industry worldwide. Positive outcome of this project will result for Aquilón in licensing or co-development agreements and trigger the interest of potential investors for the company. The impact of the project in our company so far has been very relevant. We have hired a high-profile researcher and we have received interest from local investors which reacted proactively after knowing about the project and its support by the EU. So, the efforts put in project dissemination through the web page, participation in seminars and round-tables and press appearances have led already to a positive outcome.
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