GMP manufacture and Phase I clinical trial of a thermostable single-dose rabies vaccine for pre-exposure prophylaxis for children in endemic areas

Although rabies is one of the first diseases for which effective vaccines were developed, it still kills more than 50,000 people every year- mostly children in developing countries in South Asia and Africa who are bitten by rabid dogs. The disease is unique among human viral infections in that it has a 100% fatality rate: infected people suffer a slow and terrifying death. The reason that the problem persists on this scale is that currently available rabies control tools have major shortcomings. Current vaccines, based upon killed rabies viruses, have changed relatively little from the first rabies vaccine administered by Pasteur in 1885. They are too expensive to be given to whole populations as part of routine childhood vaccination packages, partly because they require refrigeration and need multiple doses to achieve protection. The combination of vaccine and antibody treatment needed if an unvaccinated child is bitten by a dog which might be rabid is even more expensive and not reliably available- so many people are forced to take the risk of going without treatment. Vaccinating dogs can be very effective, but in many areas, there is a lack of veterinary health infrastructure or the behaviour patterns of dogs make them difficult to reach. This project aims to test in humans a new rabies vaccine which we have produced using modern techniques. This new vaccine will be considerably cheaper than current vaccines, will not require refrigeration, and will only require a single dose. As such, it should be suitable for mass vaccination of all children at risk of rabies. Our vaccine consists of a version of a common cold virus which cannot grow in the human body but exposes the body's immune system to the major protein building block of the rabies virus' coat. By doing this, it stimulates the immune system to produce antibodies that are capable of killing the rabies virus. We have shown in studies in experimental animals that a small dose of our vaccine is sufficient to protect the animals against infection with rabies for nearly two years. The other key part of this project involves the stabilisation of the vaccine by drying it in a defined sugar solution on a paper-like membrane- a technique inspired by the ability of certain sugar-containing plants to survive in hot, dry conditions. The dried vaccine is able to withstand high temperatures, instead of needing refrigeration or freezing. This will make the distribution of vaccine to low-resource areas considerably cheaper and more reliable. Importantly, the drying technique is very straightforward and could be applied to many other vaccines- our intention is that this study, using our new rabies vaccine, will provide a proof-of-concept encouraging the technique to be adopted for other vaccines. We have already manufactured the vaccine in the laboratory and (as stated above) have shown that it is highly effective in animals. This project will allow us to manufacture the vaccine to the stricter standards known as 'Good Manufacturing Practice', which are needed in order to make a 'pharmaceutical-grade' product which can be tested in human trials. We will produce 'pharmaceutical-grade' versions of the vaccine in both conventional liquid form and the dried, thermostable form. The final part of the project will be to test the vaccines carefully for safety in a clinical trial in healthy British adult volunteers. This will also allow us to compare the two forms of our vaccine with each other and with an existing rabies vaccine for their ability to induce anti-rabies antibodies. Good results in this trial will allow the vaccine to progress into further trials in children in countries which have major rabies problems.