Recombinant yeast production of COVID-19 antigen to support clinical testing

This project aims to support a novel and vital alternative strategy to realise broad population immunity to the SARS-CoV-2 virus (the cause of COVID-19 disease) in the event that the adenoviral-based vaccines currently under development in the UK prove insufficiently efficacious, safe and/or cost-effective. It will show that yeast-based production of a key viral protein fragment (antigen), that has proven immunogenic in feasibility studies when linked to a novel Virus Like Particle (VLP), provides a rapidly scalable, highly cost-effective and versatile means to enable widespread vaccination of the UK and global population.

Crucially, whereas the VLP can be readily produced in the bacterium _E. coli,_ the viral protein fragment is unsuited to production in bacteria and has only been prepared in cultured human cells, a method that cannot be cost-effectively scaled-up for clinical trials and full scale manufacture. However, the yeast _Pichia pastoris_ can produce complex mammalian proteins efficiently, enabling rapid scale-up and highly cost effective production. Ingenza recently engineered _Pichia_ to prepare novel antibacterial proteins to high purity by optimising their production, purification, testing and yield from _Pichia_, using an innovative manufacturing platform called "visABLE" which enables selection of the most productive and stable _Pichia_ recombinants and recovery of their heterologous target protein.

In this project we will repurpose visABLE to deliver a recombinant _Pichia_ strain to rapidly prepare and supply the viral antigen, that will be combined with the novel VLP developed by researchers at Oxford University for efficacy testing. If comparably immunogenic, the _Pichia_ production system will permit rapidly scalable, highly cost-effective and cGMP-compliant manufacture of this vaccine component, thereby accelerating the development, testing and availability of a vital alternative to current COVID-19 vaccine production systems in development as well as providing a versatile and novel platform to enhance future UK viral responsiveness.

Effect of Extension for Impact funding 21-10-20:
This project successfully produced the intended SARS-CoV-2 spike-RBD antigen using the yeast P. pastoris. In rigorous immunogenicity testing by Oxford University in a validated mouse model of vaccine efficacy, the P. pastoris derived RBD proved to elicit at least as strong immunogenic efficacy as RBD produced using more expensive and less adaptable mammalian cell production systems. This critical demonstration underpins future work to realise anticipated major cost, adaptability and reusability benefits of the P. pastoris derived vaccine. Continued process optimisation and scale-up of the bio-manufacturing process by this team can ensure development of what could prove to be a vaccine platform of great importance in the fight against the on-going coronavirus pandemic and other major viral diseases.