Development of a novel vaccine to protect against Q fever epidemics

The aim of this project is to create an innovative vaccine against Q fever, caused by the bacterium Coxiella burnetii. We propose to use a potent vaccine delivery technology, highly suited to outbreak situations in low-income countries, and never tried for this disease. Q fever is highly contagious, often transmitted to humans by infected livestock. It is a global health concern, classified 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, and is particularly dangerous in pregnancy. 2. Extensive and costly antibiotic use may be required during outbreaks: while infections may be self-limited, antimicrobial therapy is effective in shortening illness duration and severity, but acute illness requires 14 days treatment. 3. Chronic Q fever is very difficult to treat, results in frequent relapses, causes severe symptoms and can be fatal despite treatment. 4. The symptoms are non-specific and thus Q fever is difficult to diagnose (there is no reliable diagnostic test). 5. Q fever has a worldwide distribution, particularly affecting low-income countries. The number of reported cases is likely an underestimation. In the US, around 3% of healthy adults, 10-20% of persons in high-risk occupations have been exposed. 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 licenced in Australia induces severe adverse effects, requires pre-vaccination screening and thus is 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, likely due to the weakness of this formulation in inducing the cellular immune responses that have been linked to resolution of Q fever infection. In this context, our proposed solution is to use viral vectors as a vaccine delivery platform. This technology is based on harmless replication-incompetent viruses, currently developed against numerous infectious diseases (Ebola, malaria, HIV…), but not yet investigated for Q fever. This technology is highly suitable when cellular immune responses are required for protection in addition to antibody responses, as it can induce both at remarkably high levels. This technology is suited to outbreaks in low-income countries: all vaccines developed for the recent Ebola outbreak were based on viral vectors. Importantly, this technology is perfectly suited to the challenge of antigen selection for Q fever vaccines: while the focus of the protective immune response is currently debated, the vectored technology allows the formulation and testing of multiple antigen targets and combinations, in a very short time frame, directly in the formulation that can progress to clinic. We will use Q fever proteins known to elicit immune responses and formulate them into our clinically relevant viral vaccine vectors. We will investigate the immune responses and levels of protection induced by the novel vaccines, and identify the most potent candidate. If successful, this project will provide a strong case for testing of this new Q fever vaccine in people.