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.

The belief that rabies is a bygone disease for which an adequate vaccine exists is incorrect. Global rabies mortality is c. 59,000/year. Existing control measures are inadequate: current human vaccines are too expensive for mass use, and canine vaccination is challenging in many settings.

We have developed a replication-deficient simian adenovirus vaccine encoding rabies glycoprotein. In a non-human primate trial, this outperformed the current human rabies vaccine: a single dose protected 100% of animals challenged 22 months after vaccination. The immunogenicity of the vaccine is such that the dose required to protect primates is 50-fold less than typically used for other adenovirus-based vaccines in humans. Moreover, we have developed an inexpensive thermostabilisation process to facilitate vaccine distribution. The vaccine will thus be sufficiently cheap to permit mass pre-exposure vaccination in rabies endemic low/middle-income countries, dramatically reducing mortality.

Importantly, the project will provide clinical proof of concept for the thermostabilisation technology. The approach is applicable to other vaccines, out-performing lyophilisation and potentially enhancing reach and cost-efficacy by removing the need for expensive cold-chain distribution.

We propose a milestone-based approach comprising
1. Process development
2. GMP manufacture of adenovirus; pre-GMP thermostabilisation tech transfer
3. GMP manufacture of thermostable formulation; pre-trial preparation (QC, toxicology, regulatory & ethics)
4. Phase I trial comparing standard v. stabilised adenovirus v. existing rabies vaccine.

Post-DPFS development would piggyback upon trials of adenovirus-based malaria vaccines in children in Africa. Rabies vaccine licensure is based upon a surrogate of protection (in vitro virus neutralisation) and thus achievable without a large trial to directly demonstrate efficacy.

The application is accompanied by a letter of support from the WHO.

The main direct benefit of this project is intended to be the provision of a tool for reduction in global rabies mortality, and as such, the main direct beneficiaries would be the recipients of the vaccine we intend to develop. We anticipate that benefits would accrue both via the avoidance of the terrifying and fatal illness of rabies itself, and via a reduction in the costs associated with rabies prophylaxis (notably a reduction in the requirement for extremely expensive rabies immune globulin following animal bites). A realistic timescale for the delivery of this benefit- allowing for subsequent clinical trials and licensure- is c. 10 years from the initiation of the project.

As described in the downstream development sections of the Case for Support, later-stage development of the vaccine would be undertaken with commercial partners. The size of the potential market for rabies vaccines is large and we anticipate that such partners would be able to secure a commercial return. As well as this direct commercial benefit, the project will further promote the UK's strategic excellence in vaccine development, a major business area for UK-based pharmaceutical companies.

The cost-effectiveness of a thermo-stable rabies vaccine will be crucial to its eventual deployment in rabies-endemic areas, which are in low and middle income countries. This issue is addressed in more detail in section 5.1 of the Case for Support, where we conclude that cost equilibrium for PrEP and PEP (pre and post exposure prophylaxis respectively) would be reached if a PrEP vaccine cost less than USD 4 per course. Current calculations estimate the final cost of a thermo-stable ChAdOx2-RabGP vaccine to be less than USD 2 per dose (including GMP manufacture, and a vaccine storage and delivery device). If funded, we will work during the project with vaccine manufacturers and with economists at the Said Business School in Oxford to calculate more accurately the predicted cost of manufacture of thermo-stable ChAdOx2-RabGP produced at a large scale, suitable for mass immunisation campaigns.

Indirect academic beneficiaries are described in the separate section above and would include vaccine developers targeting other disease indications, who would benefit from the development of the ChAdOx2 and thermostabilisation platform technologies. Other economic beneficiaries are companies and/or manufacturing organisations producing thermo-stable vaccines in both the developed world and resource-poor countries, which would benefit from production of cheap, stable vaccines with reduced losses from vaccine instability during transport and storage.