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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - MycoSynVac (Engineering of Mycoplasma pneumoniae as a broad-spectrum animal vaccine)

Teaser

Summary

Annually, infections caused by Mycoplasma species in poultry, cows, and pigs result in multimillion Euro losses in the USA and Europe. There is no effective vaccination against many Mycoplasmas that infect pets, humans and farm animals. Furthermore, most Mycoplasmas are difficult to grow, requiring a complex media that includes animal serum. Consequently, even in those cases for which effective vaccines are available (namely, M.hyopneumoniae in pigs and M.gallisepticum and M.synoviae in poultry), the production process of the vaccines is challenging.
The main aim of this project is to design a universal Mycoplasma chassis that can be deployed as single- or multi-vaccine in a range of animal hosts. Specifically in this project, we will target the development of attenuated and/or inactivated vaccine(s) against two Mycoplasma pathogens: M. hyopneumoniae (pigs) and M. bovis (cattle), and a combined one against M. hyopneumoniae and PRSSV virus (pigs).
To achieve this overarching goal, the MycoSynVac project has the following specific objectives: Vaccine Design, Chassis Engineering, and Optimization of Large-Scale Production, all this taking into account the future exploitation of the technology developed and facing ethical concerns that synthetic biology can awaken.

Work performed

Regarding the development of a whole-cell dynamic model of M. pneumoniae, a draft dynamic model of central metabolism was developed, parameterized and validated. Also genome scale models of metabolism for M. pneumoniae and M. hyopneumoniae have been updated and built. Quantitative experimental data have been determined and used to calibrate the models.
On the chassis design, we have listed the essential proteins, identified the genes responsible of pathogenicity and growth. We have also developed a first version of a defined medium that allows the growth of M. pneumoniae in the absence of serum.
Related to biosafety, we successfully demonstrated that 3 repressor systems function in Mycoplasma and developed a inducible gene expression system.
Regarding the implementation of genome transplantation for genome engineering, cloning M. pneumoniae genome in yeast has been achieved. Related to tools for genome engineering, we have developed a system for homologous recombination and a cre-lox system that allows removal of the antibiotic resistance. The genome engineering method based on GP-35 recombinase developed is now working very effectively and allows to inactivate known M. pneumoniae virulence factors, which is a successful first step towards the building of a vaccine chassis.
For the vaccine development, we have identified antigens and virulent factors, and a first list of epitopes have been established for M.hyopneumoniae and M.bovis thanks to the newly developed epitope-mapping strategy. Also, first experimental identification of surface proteins has been obtained for both organisms. Simultaneously, we have done preliminary studies on infection challenges in pigs and calves, demonstrating that we have suitable models for identifying virulence factors.
Since the project involves synthetic biology applied to animal health, we have also addressed the concerns that this may raise and its ethical implications. So far, after reviewing the literature we performed an study on sociological perception that was carried out in 5 European countries with focus groups of experts and lay-person, we are currently analyzing the results. Also a risk assessment study is on-going, in order to identify and anticipate any problems that may arise. Some internal ethics workshops have also been conducted.
An Innovation Board has been created with the aim to continuously monitor the project progress, identifying all exploitable results and being the responsible to envisage the commercial route for all of them. During the first 2 years, this board met 4 times. So far, some results, besides the vaccine which is the main result of the project, have been identified and discussions of how to take advantage of them has been initiated.
During these 2 years, partners have also made a big effort in dissemination. We have created our visual identity. For the time being we have organized 2 scientific cafes, the project has been presented in several international congresses and published 6 scientific articles, created a twitter account and continuously feed the different communication channels in order to make it available to the scientific community as well as to the general public. Market analysis and first research steps for the development of a science game, some related teaching material and a film have been taken and planning of the next steps in each of these endeavors is going on.

Final results

The MycoSynVac project is highly ambitious, as we are tackling a really disruptive approach to vaccine production: a universal chassis for vaccination based on M. pneumoniae able to grow efficiently and reproducibly in a defined serum-free medium.
The consortium brings together cutting-edge knowledge and resources on Mycoplasma, modeling, synthetic biology, antigen epitope determination and vaccine production and commercialization as well as other important areas such as dissemination and ethical aspects.
Overall, the activities performed during the first year of the project enabled us to lay the groundwork for a strong impact in several areas:
On the one hand, we are developing a new whole-cell model, which could be used to engineer the genome, define optimal medium and improve growth rates of different Mycoplasma species. An accurate whole-cell model capable of quantitative predictions will have a major impact in the systems and synthetic biology community.
We are engineering a bacterial cellular chassis. Based on a well-studied system such as M. pneumoniae, we are on the way to design a chassis that could be used not only as a vaccine but also for other therapeutic applications like lung infections, lung cancer or in cell reprogramming.
On the other hand, a Mycoplasma vaccine produced in a serum-free medium would be a breakthrough advance for MSD, helping them to maintain their leadership position. Similarly, validation of new technology based on the epitope screening system property of ATG, will help them to be a major players in the field.
The team is engaging society by including some activities in a wider setting than the restricted to biotechnology and veterinary research community. Indeed, we are highly conscious that the rise of synthetic biology has raised great concern, and for this reason we are undertaking different actions to publicize what SynBio really is and what contributions can make to society.
Finally, the project is promoting the collaboration between industry and academia. For dealing with such a complex problem, a strong collaboration is required and a continuous exchange of expertise and knowledge mandatory for the project success. In that sense, the strategic development plan of the project joins really challenging research developments carried out in academia and a commercial driven vision provided by the expertise of the industrial partners.