Public Funding for Oxford Simcell Limited

Leveraging live bacteria for vaccines and therapies has long been an appealing concept, offering a comprehensive approach to targeting the immune system. However, the challenge lies in controlling this method, as it poses potential fatal consequences. Addressing this issue, SimCell technology, pioneered at the University of Oxford, presents a groundbreaking solution by producing live bacterial cells devoid of genetic material (DNA), rendering them incapable of division. The creation of SimCells involves introducing a switch that, when triggered, destroys the bacteria's DNA, preventing further division. Despite this genetic alteration, the bacteria retain their structural integrity, preserving essential cell-surface features recognised by the immune system. In contrast to traditional methods of bacterial inactivation using heat, chemicals, or irradiation, which often damage cells and diminish their ability to elicit immune responses, SimCells offer a more controlled and effective alternative. The global challenge of antimicrobial resistance (AMR) underscores the urgency for innovative solutions, with approximately 700,000 deaths annually attributed to AMR. Projections suggest that by 2050, deaths from AMR infections could surpass 10 million, posing a grave threat to surgical procedures and the collapse of healthcare systems. Pseudomonas aeruginosa, categorised as a 'priority 1: critical' pathogen by the World Health Organization due to its high lethality (over 300,000 deaths per year globally) and extensive antibiotic resistance, remains a formidable challenge for which novel therapeutic approaches have yet to emerge despite two decades of research. Our previous study utilising P. aeruginosa SimCells as a whole-cell inactivated vaccine demonstrates both their safety and efficacy. Building on these results, the primary objective of the current project is to develop a lyophilised version of the human P. aeruginosa SimCell vaccine prototype. This formulation aims to exhibit long-term stability at room temperature while inducing immune and protective responses in in vitro models and animals, thereby safeguarding against subsequent infections. The pilot-scale production of lyophilised SimCell vaccines and the demonstration of safety and efficacy of the P. aeruginosa SimCell vaccine will serve as crucial milestones, accelerating the broader development of SimCell vaccines targeting other concerning pathogens.

Using live bacteria as vaccines and therapies for diseases has long been seen as an attractive idea, offering a way to target the immune system more comprehensively. Unfortunately, the approach is difficult to control, with potentially dangerous side-effects. SimCell technology, developed at the University of Oxford, solves this problem by producing bacterial cells that lack genetic material (DNA) and are therefore unable to divide. SimCells are made by introducing an engineered switch that can be triggered to destroy the bacteria's DNA so that it can no longer divide. The bacteria remain intact, retaining the important cell-surface features recognized by the immune system. This contrasts with existing methods of inactivating bacteria using heat, chemicals, or irradiation, which are harsh treatments that damage the cells and reduce their ability to induce immune responses. In this project, we will adopt synthetic biological methods to engineer Yersinia into SimCells. The key goal is to achieve tight regulation of the endonuclease expression system to ensure maximum efficiency of SimCell conversion and prevent the emergence of escape cells. This includes the use of rationally designed promoter systems combined with the application of a robotic platform to optimize the expression and working conditions of the endonuclease upon induction. A successful project outcome will serve as a proof-of-concept for developing a Yersinia SimCell vaccine candidate against plague and accelerate the development of other SimCell vaccine pipelines of Gram-negative bacteria. Ultimately, this project will result in the engineering of a bacterial vaccine prototype to address one of the most significant public health threats in the world.

Using live bacteria as vaccines and therapies for diseases like cancer has long been seen as an attractive idea, offering a way to target the immune system more comprehensively. Unfortunately, the approach is difficult to control, with potentially fatal consequences. SimCell technology, developed at the University of Oxford, solves this problem by producing live bacterial cells that lack genetic material (DNA) and are therefore unable to divide. SimCells are made by introducing a switch that can be triggered to destroy the bacteria's DNA so that it can no longer divide. The bacteria remain intact, retaining the important cell-surface features recognised by the immune system. Existing methods of inactivating bacteria for use as vaccines involve heat, chemicals, or irradiation. These are harsh treatments which damage the cells and reduce their ability to induce immune responses. The spread of antimicrobial resistance (AMR) is a major public health challenge, causing some 700,000 deaths per year worldwide. By 2050 deaths from AMR infection could rise to more than 10 million, making all surgical procedures life-threatening and causing health systems to collapse. E coli is a World Health Organization (WHO) Priority 1 Critical Pathogen on the antimicrobial resistant (AMR) list for which countermeasures are urgently needed. Multidrug-resistant E coli has so far been winning the fight against novel antibiotics, including carbapenems, which are the last line of defense against most Gram-negative bacteria infections. This project aims to characterize the safety and immunogenicity of an E. coli SimCell vaccine candidate using mass spectrometry and the monocyte activation test. The key goal is to identify immunogenic surface biomarkers or antigens on E. coli SimCells and assess the safety of E. coli SimCells within humans, by stimulating the first stages of the human immune system in blood. The success of this project will advance OSC's E. coli SimCells into a leading vaccine candidate for urinary tract infection (UTI), ultimately contributing to the reduction of inappropriate antibiotic use and positively impacting the health of 50% of all women worldwide.

Using live bacteria as vaccines and therapies for diseases like cancer has long been seen as an attractive idea, offering a way to target the immune system more comprehensively. Unfortunately the approach is difficult to control, with potentially fatal consequences. SimCell technology, developed at the University of Oxford, solves this problem by producing live bacterial cells that lack genetic material (DNA) and are therefore unable to divide. SimCells are made by introducing a switch that can be triggered to destroy the bacteria's DNA so that it can no longer divide. The bacteria remain intact, retaining the important cell-surface features recognised by the immune system. Existing methods of inactivating bacteria for use as vaccines involve heat, chemicals, or irradiation. These are harsh treatments which damage the cells and reduce their ability to induce immune responses. The spread of antimicrobial resistance (AMR) is a major public health challenge, causing some 700,000 deaths per year worldwide. By 2050 deaths from AMR infection could rise to more than 10 million, making all surgical procedures life-threatening and causing health systems to collapse. Pseudomonas aeruginosa is considered a 'priority 1: critical' pathogen by the World Health Organization, due to its lethality (over 300,000 deaths per year globally) and high level of antibiotic resistance. Despite over 20 years of research, no novel therapeutic approach to treatment of resistant P. aeruginosa has entered the market. In this project, we will apply SimCell technology to develop whole-cell inactivated vaccines against P. aeruginosa. The key goal is to develop a human P. aeruginosa vaccine, which induce immune responses in animals that protect against subsequent infection. Pilot-scale production in bioreactor and the demonstration of safety and efficacy of the P. aeruginosa SimCell vaccine will help us accelerate the development of SimCell vaccines against other pathogens of concern.

Using live bacteria as vaccines and therapies for diseases has long been seen as an attractive idea, offering a way to target the immune system more comprehensively. Unfortunately, the approach is difficult to control, with potentially dangerous side-effects. SimCell technology, developed at the University of Oxford, solves this problem by producing bacterial cells that lack genetic material (DNA) and are therefore unable to divide. SimCells are made by introducing an engineered switch that can be triggered to destroy the bacteria's DNA so that it can no longer divide. The bacteria remain intact, retaining the important cell-surface features recognised by the immune system. This contrasts with existing methods of inactivating bacteria using heat, chemicals, or irradiation are harsh treatments that damage the cells and reduce their ability to induce immune responses. In this project, we will adopt synthetic biological methods to engineer uro-pathogenic Escherichia coli (UPEC) into SimCells. The key goal is to achieve tight regulation of the endonuclease expression system to ensure maximum efficiency of SimCell conversion and prevent the emergence of escape cells. This includes the use of rationally designed promoter systems combined with the application of a robotic platform to optimize the expression and working conditions of the endonuclease upon induction. A successful project outcome will help us select a lead UTI SimCell vaccine candidate to enter the lead optimization stage and accelerate the development of other SimCell vaccine pipelines of Gram-negative bacteria. Ultimately, this project will result in the engineering of a bacterial vaccine prototype that could not only help reduce the inappropriate use of antibiotics but also positively impact the health of 50% of all women in the world.

Using live bacteria as vaccines and therapies for diseases has long been seen as an attractive idea, offering a way to target the immune system more comprehensively. Unfortunately, the approach is difficult to control, with potentially fatal consequences. SimCell technology, developed at the University of Oxford, solves this problem by producing live bacterial cells that lack genetic material (DNA) and are therefore unable to divide. SimCells are made by introducing a switch that can be triggered to destroy the bacteria's DNA so that it can no longer divide. The bacteria remain intact, retaining the important cell-surface features recognised by the immune system. Existing methods of inactivating bacteria for use as vaccines involve heat, chemicals, or irradiation. These are harsh treatments which damage the cells and reduce their ability to induce immune responses. The spread of antimicrobial resistance (AMR) is a major public health challenge, causing some 700,000 deaths per year worldwide. By 2050 deaths from AMR infection could rise to more than 10 million, making all surgical procedures life-threatening and causing health systems to collapse. S aureus is considered a high-priority pathogen by the World Health Organisation, due to its lethality of more than 3.6 million deaths worldwide annually attributable to a high level of antibiotic resistance. In some settings, up to 50% of hospital-acquired infections are caused by S aureus. In this project, we will apply SimCell technology to develop whole-cell inactivated vaccines against S aureus. The key goal is to extend the SimCell platform to S aureus, a Gram-positive bacterial species, and to demonstrate the safety of a human S aureus vaccine prototype in animal models. This is the first attempt to produce SimCells in Gram-positive bacteria. The successful project outcome will help us accelerate the development of SimCell vaccines against both Gram-negative and Gram-positive pathogens of concern for which countermeasures are urgently needed.