Public Funding for Chain Biotechnology Limited

CHAIN Biotechnology, a Nottingham-based biotech company and Dr Kelsey Jones, a Senior Research Fellow at University of Oxford plan to collaborate on a two-year project to develop a new type of vaccine to immunise against human rotavirus (HRV) infection. The vaccine should be highly effective for malnourished children susceptible to Childhood Diarrhoeal Disease (CDD). CDD is a global health problem affecting over 1.7 billion children every year and resulting in over 500,000 deaths, mainly in poorer countries. The most common cause of CDD is infection with human rotavirus (HRV). Vaccines that protect against HRV infection are available but relatively expensive, difficult to transport and administer in remote areas as they need to be kept cold. Also, they are ineffective in undernourished children. Consequently, it is much harder to prevent CDD in poorer countries. Existing HRV vaccines are based on oral ingestion of small doses of weakened virus and designed to trigger an immune response via immune tissue located in the small intestine. They interact with white blood cells present in the gut wall triggering the production of antibodies and memory cells that protect against future infection. However, these oral vaccines are not particularly effective in undernourished children. Dr Kelsey Jones has recently discovered that malnutrition destroys a branch of the immune system lining the small intestine required for vaccines to work. An unexpected finding was that the immune system in the large intestine (colon) remains largely unaffected. CHAIN has developed a way to deliver therapeutics including vaccines to the colon by genetic engineering a harmless microbe called Clostridium butyricum -- referred to as the CADD platform. CHAIN has engineered the bacterium to produce two key proteins from HRV. The bacteria are delivered orally, in a spore-form, and travel intact through the stomach and small intestine until they reach the colon where they germinate. The bacterial cells then grow and produce the HRV proteins necessary to trigger an immune response via the gut mucosa. The goal of this proposal is to test whether the CADD system can be used to bypass the immune defect present in under-nourished children. If successful, the results will be used to fast-track the development of a novel oral vaccine for HRV for clinical testing with the longer-term potential to transform the lives of millions of families across the world.

CHAIN Biotechnology, a Nottingham-based biotech company has developed a way to deliver therapeutics including vaccines to the colon by genetic engineering a harmless microbe called Clostridium butyricum – referred to as the CADD platform. CHAIN has engineered the bacterium to produce antigenic peptides. The bacteria are delivered orally, in a spore-form, and travel intact through the stomach and small intestine until they reach the colon where they germinate. The bacterial cells then grow and produce the antigens necessary to trigger an immune response via the gut mucosa. The goal of this project is to test whether the CADD system can be used to develop oral vaccine candidates for human rotavirus and cholera. If successful, the results will be used to fast-track the development of a novel oral vaccines for clinical testing with the longer-term potential to treat childhood diarrhoeal disease and transform the lives of millions across the world, especially in low- and middle-income countries. We have recently started work on an oral COVID vaccine. Building on developments in this project, we plan to include development of a COVID vaccine as part of the project scope. Given the pressing need of developing COVID booster vaccines and covering emerging variants of concern, our oral vaccine is therefore extremely timely given the need to maintain immunity in a vaccinated population. It is also a robust and low-cost solution making it ideally suited to global distribution without significant burdens on healthcare systems or personnel.

To incorporate specialist gut modelling expertise into the technology platform which delivers therapeutics directly to the gut thus accelerating time to market for a range of novel live biotherapeutic products.

"HPV is the most commonly sexually transmitted infection with over two-thirds of the population infected at some stage during life. Most infections are cleared without symptoms within a few months; however, infections with high risk types of HPV can lead to development of cancer in for example the cervix. Vaccination against these high-risk types is now available and these vaccines are being used in most high income countries and China to protect girls and women at risk of infection. While such interventions are recommended and have led to a decrease in cervical cancer incidence, the approach also has disadvantages. Stability of the vaccines is poor and the way in which the vaccines are given (by injection into muscle) does not give good protection at the sites where the virus normally enters the body. Critically, the high cost of these vaccines greatly limits their use in low income countries, where HPV infection is most prevalent. In this project, CHAIN Biotechnology Ltd, a microbiome company with expertise in developing _Clostridium_-based therapeutics, is collaborating with experienced immunological researchers from the University of Oxford to overcome limitations of currently available vaccines. The aim is to develop an oral vaccination approach to prevent HPV infection and also to treat people already affected by the virus. Delivery of vaccine directly to the mucosal surfaces of the gastrointestinal tract (GIT) via ingestion of harmless bacteria, overcomes the low pH and enzyme-enriched environment in the stomach that would destroy other oral vaccines. If successful, the approach provides a substantial improvement over the current vaccination strategies. It is non-invasive and would allow mass vaccination without the risk of spreading blood-borne infection by needle injuries, and administration could be performed by non-medical personnel. If the approach is successful, the project will give rise to the possibility of extending this technology to develop vaccines against other viral and bacterial infections that present challenges to global health such as for example HIV, Ebola or cholera. There is also the possibility to develop therapeutic vaccines that target the destruction of cancer cells."

"The gut microbiome, the collection of bacteria, viruses and fungi inhabiting the human gastrointestinal tract, has a profound impact on the development and maintenance of a healthy immune system. From birth, the microbiome influences how the human immune system responds to resident and invading microbes, which in turn influences our susceptibility to common diseases and long-term health outcomes. Recent advances in microbiome research have highlighted the importance of a healthy gut in prevention of several diseases, ranging from irritable bowel syndrome, to inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, antibiotic associated diarrhoea (including _Clostridium difficile_ associated disease), autism, obesity and type 2 diabetes mellitus. The bacteria present in the gut communicate with the human host by making molecules that not only influence the gut lining but have widespread effects throughout the body. For example, molecules produced by the gut microbiome can have effects on the liver triggering a reduced production of lipids, and the brain by triggering production of serotonin in the gut. In this project, CHAIN Biotechnology Ltd will develop harmless gut bacteria to increase the production of naturally occurring molecules that are often lacking in patients who are suffering from or who are at risk of developing diseases such as type 2 diabetes (T2D) and colitis. Our first focus will be on T2D, which places a huge commercial and medical burden on the healthcare industry and can have devastating effects for sufferers such as amputations or loss of vision. Success in this project may lead to treatments for other conditions that have been associated with a disturbance of the microbiome and an inflammatory background such as inflammatory bowel disease, Huntington's disease and Alzheimer's disease."

"The gut microbiome is a pharmacologically active tissue controlling infection, inflammation, receptor signalling, hormone secretion and central nervous system signalling. These events have significant impacts on patient health and wellbeing (Nature Special Review, June 2012). The importance of the gut microbiome in both health and disease is now widely recognised resulting in an explosion in research, development and pharma investment in new therapeutics, based on live microbes, that can treat chronic gut related diseases. Clostridia are the most prevalent class of microbes in the human large intestine. CHAIN Biotech capitalises on its unique expertise with these bacteria to develop a novel live biotherapeutic for treating inflammatory bowel disease. This product has been validated in pre-clinical tests and we now seek a manufacturing partner that can produce spores for clinical trials. No such facility exists in the UK and this project seeks to address this bottleneck. More specifically, the partners will determine the costs and economic feasibility to build a bespoke spore manufacturing plant in the South East for CHAIN and other SME microbiome and biotech companies."

CHAIN Biotechnology Ltd. and the University of Nottingham are developing Clostridia bacteria for the healthcare market targeting C. difficile infections and chronic diseases like inflammatory bowel disease. The bug is a live biotherapeutic product. Success on the project will transform existing treatments for chronic gut-related diseases benefiting the lives of millions of sufferers around the world.

More than $4T of products are made currently by petrochemical (oil) derived chemical processes and only 5 % of these potentially “addressable markets” have been explored using biological approaches. There exists huge potential to reduce greenhouse gas emissions and oil dependency by further harnessing the power of Biology. Fermentation of engineered bacteria growing on sustainable feedstocks is one means to produce biochemicals. Much progress has been made but these efforts have concentrated on lab-friendly 'model organisms' which are relatively easy to genetically manipulate but which often do not scale up efficiently and economically to industrial processes. CHAIN Biotech focuses solely on microbes proven to be robust in industrial processes such as Clostridia bacteria. In this study we use new engineering tools to produce valuable chemicals called butanediols which are used widely in diverse array of applications including functional materials, pharmaceuticals and functional foods.

In this project, researchers from CHAIN and the University of Nottingham aim to develop process technology that utilises methanotrophic bacteria to ferment methane into valuable nutritional supplements (lipids) for animal feed. Methane is a low cost and sustainable feedstock that can be produced from fracking or from a variety of renewable sources, including anaerobic digestion which is prevalent in the UK and Europe. Using specialist synthetic biology tools, the partners plan to engineer methanotrophs to ferment methane to produce a fish oil replacement in high yield.

CHAIN Biotech aims to produce high value fine chemicals (3-hydroxbutyric acid and ethyl-3-hydroxybutyrate) at costs lower then current chemical sysnthesis methods. By using microbial fermentation and renewable feedstock we also address key environmental and sustainability concerns. CHAIN has identified a new nutracetical market opportunity with TS who require lower cost ethyl-3-hydroxybutyrate to bring their new food ingredient to market. The over reaching goal is to capitalise on recent developments for genetic manipulation of Clostridium species to re-engineer industrially proven strains to produce high value chemicals instead of low value bulk chemicals. Success on this project would enable us to exploit the full potential of Clostridium bacteria for a wide range of IB products and applications.

Certain molecules used within industrially manufactured products not only have to be highly purified but also be of a specific structural composition. ‘Chiral’ molecules exist in two forms (scientifically called enantiomers and referred to as the S or R form) that are mirror images of one another and although the same by atomic composition are not always the same by biological activity. Producing pure quantities of one form is often expensive and this prevents new innovative products from reaching the market. Current production methods can also involve harsh chemical treatments to separate mixtures which may result in unwanted by-products such as toxic heavy metals. This project tackles these issues by targeting high value chiral molecules in their R forms using a biological route of microbial fermentation. These molecules can be used in diverse applications such as antibiotics, pharmaceuticals, nutraceuticals and have non-medical uses such as liquid crystal displays.