Development of a novel vaccine to protect against Q fever epidemics: late stage preclinical formulation and progression to clinical trial

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Development of a novel vaccine to protect against Q fever epidemics: late stage preclinical formulation and progression to clinical trial. This project aims to progress a novel vaccine against Q fever (Coxiella burnetii), developed during an Innovate UK stream 1 project, to clinical development, by identifying the minimal formulation required for protection, and includes production of the pre-GMP starting material in an approved GMP production facility. Our novel vaccine against Q fever uses a potent vaccine delivery technology suitable for outbreak situations in low-income countries. Q fever is a highly contagious bacterial disease, currently regarded as a global health concern and a potential outbreak pathogens by the UK government, the CDC and WHO for several reasons: 1. It causes a range of disease from acute to potentially fatal chronic infection. 2. Extensive and costly antibiotic use may be required during outbreaks. 3. Chronic Q fever is very difficult to treat. 4. The symptoms are non-specific and thus Q fever is difficult to diagnose. 5. Q fever has a worldwide distribution, particularly affecting low-income countries. The number of reported cases is likely an underestimation. A large epidemic occurred recently in the Netherlands (2007 to 2010) that led to several deaths and long-term illnesses. 6. The bacterium is unusually resistant to drying and to heat, it can survive for years, and extremely low infectious doses (down to a single bacterium) are sufficient to cause infection. It is therefore also a potential bioweapon. The inactivated whole cell vaccine licensed in Australia induces severe adverse effects, particularly in pre-exposed individuals (a phenomenon known as sensitization), and thus requires pre-vaccination screening, not suitable for extensive use particularly in low-income countries and for outbreaks. The protective efficacy of conventional vaccines based on proteins in adjuvant is very limited, in part due to the weakness of this formulation in inducing the cellular immune responses that have been linked to resolution of Q fever infection. Our novel vaccine is based on the judicious use of a highly immunogenic replication-incompetent viral vector, able to induce the desired T-cell responses without the side effects of the whole cell vaccine. The viral vaccine technology is currently used for developing new vaccines against several infectious diseases such as Ebola, malaria, influenza, HIV, TB, capsular group B meningococcus and plague. It is particularly suitable for diseases for which cellular immune responses are required for protection, as is the case for Q fever. We have created vectored Q fever vaccine candidates, and demonstrated that a single dose injection of three or five components induces strong T-cell immune responses. A combination of three antigens was able to reduce Q fever infection in a mouse model. In this follow on project, we will identify the minimal protective antigen composition responsible for the reduction of infection, design and produce the clinically relevant vector suitable for human use. The pre-GMP (good manufacturing practice) starting material will then be produced, ready for GMP production and phase I trial. Our group has expertise in progressing vectored based vaccines against bacterial pathogens to GMP production and phase I trial.