Accelerated development of a safe and easily manufactured Q fever vaccine

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Q fever is an important and highly contagious disease of worldwide importance affecting both livestock and humans caused by the intracellular Gram-negative bacterium, Coxiella burnetii. Infection of humans occurs following exposure to as few as 1-10 bacteria and can result in both acute and chronic forms of disease. Infections can result in death, especially in the elderly or immunocompromised. Livestock, in particular sheep and goats, are the major source of human infections where infection can cause abortion, stillbirth and delivery of weak offspring. The loss of lambs and kids can result in devastating economic losses to the livelihoods of farmers in Europe as well as LMIC countries, particularly during abortion storms where up to 35% losses can occur. Vaccines are currently considered the most effective way to control Q fever, and vaccines based on inactivated C. burnetii organisms are commercially available for use in both ruminants and humans. However, the safety of these vaccines is a major issue considering that severe local and systemic reactions occur post-vaccination in humans previously exposed to the bacteria and vaccination of ruminants is associated with significant production losses. Furthermore, manufacture of these vaccines involves culture of the organisms, which has both cost and safety issues. These issues have resulted in limited use of these vaccines. There is therefore an urgent need to develop safe, effective and easily manufactured vaccines to control Q fever in both humans and livestock species.To this end, attempts have been made to develop subunit vaccines targeting key C. burnettii proteins which would be safer to manufacture and could be engineered to induce fewer side effects following vaccination. However, current approaches to subunit vaccine development have been severely hampered by a lack of knowledge of the appropriate bacterial proteins to target.In this project, we will use novel peptide chip array technology to identify the key C. burnetii proteins recognised by antibodies from sheep and goats vaccinated with the current protective, but unsafe commercial vaccine in a high throughput and detailed manner. These antibody responses will be compared with those generated by a non-protective C. burnetii vaccine which is based on a different (non-virulent) form of the bacteria. By comparing antibody responses from protected and non-protective vaccines, bacterial proteins which are specifically targeted by the protective vaccine will be identified. Synthetic versions of these proteins will then be generated and subunit vaccines based on pools of these proteins will be tested in a sheep challenge model. This will provide preliminary safety and efficacy data to inform future Q fever vaccine development programmes.