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

Periodic Reporting for period 2 - BoVLP-BVD (Tagged (DIVA) polyantigenic vaccine against Bovine Viral Diarrhea virus (BVDv) based on virus-Like-Particles)

Reporting period: 2020-05-01 to 2022-01-31

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-BVD project, Aquilón developed one vaccine to TRL8 stage, demonstrating the commercial-scale manufacturing, safety, efficacy and DIVA attributes in cattle.
For this purpose, the overall objectives of BoVLP-BVD project were vaccine batches produced under specifications and its selection in animal tests and analytical and diagnostics methods development and license agreement.
Aquilón aimed 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 is intended to 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 structure is manufactured by an expression platform (Pichia pastoris). After previous testing of the most reactive particles by in vitro tests against positive sera of BVD vaccinated animals, candidates have been produced at 1L scale. 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 in: first trial in calves tested enhancement of an in vivo immune-response, which gave very promising results in terms of safety, DIVA confirmation and detection of antibody against BVD; first experiment in a model species (rabbit to determine differences between reactivity of the prototypes) required for prototype selection and composition of a solid patent application.
Further in vivo trials were performed: second experiment in rabbits showed the safety of different vaccine formulations including purified and non-purified extracts and the last experiment in this species tested a maximal concentration of the active substance in a dose-response trial based on the final vaccine formulation. Furthermore, a new experiment in calves testing humoral response and neutralizing antibody activity was performed. Regarding ex vivo trials, all combinations between potential adjuvants and active substance were tested in cytotoxicity and immune response assays in order to facilitate the determination of a final formulation.
Besides, 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 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 EMA, giving us a preliminary overview of the registration process to be followed.

A Target Product Profile has been stablished since safety and efficacy data were achieved through in vivo and ex vivo trials performance. IP was managed by the application for an EU Patent (nº EP21382933.6) which protects the selected peptide sequences used for the vaccine formulations from BVD-E2 protein. Lastly, dissemination and communication activities to share technical results of the project were addressed to professionals and general public. It is worthy to mention that, due to the COVID global situation, online events such as webinars or social networks updating have been prioritized.
Although promising results were achieved during the first period, many tasks remained to be performed in the second project period. New results and outputs of day-to-day project tasks were analyzed constantly to adapt the following steps to a coherent and consistent vaccine development design, which led the project to awake the interest of industrial partners for project license agreement.
Development of diagnostic and analytical methods for BVD, antigenic determinants and DIVA tagging confirmation 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 was explored for the best candidate and a cost-effective industrial manufacturing process able to be transferred to a potential GMP manufacturer within the veterinary industry sector was stablished.
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 is the most common viral disease, delivering such a vaccine will cause a significant economic and environmental impact in EU agriculture.
Project outcome has resulted for Aquilón in an important active for the company, which will lead to potential 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 hired a high-profile researcher and received interest from local investors which reacted proactively after knowing about the project and its support by the EU. So, the efforts made for project dissemination through web page, social networks, participation in events, press appearances and organization of workshops to share the project ongoing and final results led to a positive outcome.
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