Human infection challenge vaccine (HIC-vac) network

Although vaccines save millions of lives around the globe every year, there are many infectious diseases that still kill large numbers of people that are still not preventable by vaccination. This is especially true in low and middle income countries (LMIC) where even basic hospital treatment is unavailable, and the only realistic option is to prevent infectious diseases by finding new and economically viable vaccines. For several hundred years the UK has led the world in making original scientific discoveries by human experimentation. Although there are clearly risks in infecting people with pathogens, these risks need to be balanced against the great advantage of being able to test vaccines experimentally without waiting for people to acquire infections naturally. Central to our network is a close collaboration with scientists in these LMIC to advocate for the value of these studies with regulators, policy makers and the public and then to support scientists to perform the studies.

Developing a new vaccine typically takes 20 years and costs over £1bn. Using experimental challenge studies, definitive results can be obtained showing that a vaccine works or does not work with only a few volunteers - perhaps 10 to 100. Conducting challenge studies in this way allows proof in principle of vaccine efficacy. By contrast, field studies that are needed to prove that a vaccine works can be vast, usually involving thousands of individuals and costing many times more than a human challenge study.

Ethically, the benefits of human challenge need to be weighed carefully against the intention to cause disease. This narrows the range of infections that can be tested to those where the disease is relatively mild or predictable and self-limiting, or diseases that can be easily and reliably treated by existing drugs or supportive care. Examples of human infection studies that are on-going in the United Kingdom include influenza, RSV, rhinovirus, typhoid, malaria, bacterial pneumonia and whooping cough. Although there are problems to be overcome, vaccine development for emerging viruses such as Zika, dengue and MERS would be greatly accelerated if human challenge could be performed.

The field of vaccines is entering a very exciting stage in that many immunological concepts that have emerged from studies in animals are now ready for testing in man. At present the groups around the UK, in London, Oxford, Liverpool, York, Nottingham and Southampton, face the ethical and regulatory challenges to mounting such studies without a structure to provide mutual support. We have a great deal to learn from one another regarding not only experimental techniques but also how to overcome the large but necessary burden of regulation and safe working practices. There are groups working on similar infections but not sharing reagents, tested pathogens or other resources between them. Our proposed network will bring together all of this expertise, build on the support that we have from the public in replacing animal experimentation with informative and well controlled human studies, bringing a unified voice from the human infection volunteer network and regulatory/ethical networks to reinforce the UK's position as the most permissive and supportive environment for vaccine development.

We will do this by uniting our efforts: holding regular meetings by phone, face to face and providing one another with practical support. We will form consortia within the Network to apply for funding to provide core materials and resources. In addition to accelerating vaccine development, HIC-Vac will collaborate to address fundamental scientific questions about human infection that can only be obtained from challenge studies both within the UK and internationally. All of this work is relevant to diseases that afflict LMIC; if funded, our proposed network will therefore contribute very substantially to improving global health.

Vaccines are amongst the most practical and cost-effective ways of mitigating the impact of infectious disease, especially in LMIC/resource-poor settings. Although they already prevent an enormous number of serious and lethal infections, new or improved vaccines are needed. Animal studies can be misleading and human field trials are both expensive and prone to failure. Human infection challenge (HIC) is an excellent way to expedite vaccine development, enabling vaccines to be tested at reduced cost while providing abundant information about disease pathogenesis and mechanisms of protection. Going back to the time of Edward Jenner, the UK has had a strong tradition of HIC and continues to have a relatively supportive legal, regulatory, ethical and reputational environment. Our network will draw upon the extensive HIC experience of the UK's many research groups using pathogens such as RSV, influenza, rhinovirus, typhoid/paratyphoid, malaria, Neisseria, pertussis, pneumococcus, BCG, leishmania and hookworm. It will draw together our collective experience and share best practice, supporting the development of new research initiatives in testing vaccine safety and efficacy. The network will bring in new investigators and will provide resources to promote the ethical, legally compliant and safe use of HIC. By distributing pump-priming funds, we will catalyse areas of study that extend the use of HIC, enabling substantial grant applications to be made. Most importantly, it will allow comparison of vaccine effects in UK volunteers with those in LMIC such as Malawi, India, Vietnam and Kenya. The network will work with commercial partners to promote the development and use of HIC in vaccine development, communicating the advantages of HIC to regulators, policy-makers and the public. Our network will thereby keep the UK at the forefront of global vaccine research.

In order to develop the best next generation vaccines, we need to understand more about how pathogens are controlled by the human immune response and human challenge is a key component of this understanding. Broadening interactions between individuals performing challenge studies affects multiple beneficiaries.

Who will benefit from this research?
1. Academic communities studying vaccinology and the pathogenesis of disease, and designing countermeasures, will benefit from this work.
2. Private sector vaccine developers. Vaccines, in order to be developed and produced commercially, have to be supported by private sector companies, both SME and larger pharmaceutical companies. Improved understanding about how the human immune response controls infections is critical for these organisations to develop effective vaccines.
3. Policy-makers. Through the effective use of human vaccine and challenge studies, it may be possible to assess the efficacy of vaccines, without recourse to phase III studies. This is of particular benefit when the infectious agent has a low strike rate in communities or when it is a pandemic agent that only occurs sporadically.
4. LMIC. The network will synergise the expertise and disease knowledge of LMIC partners with the experience of the network HIC studies to develop platforms to ensure vaccine success in LMIC settings.
5. Volunteers. Due to the nature of the studies, the public are a key constituency, altruistically taking part in the studies for no immediate benefits to themselves. Unified ethical and regulatory frameworks will ensure their continued safety.

How will they benefit from this research?
The Catalyst co-ordinator will have responsibility for external activities across the Network. They would assist the HIC-Vac PIs with industrial liaison and (together with the Network Manager), co-ordinate a series of "Ask the Experts" documents on logistics, ethics, regulatory, safety and legal aspects of conducting human challenge studies, culminating in a series of SOPs and Best Practice articles for external use.

1. Academic Community. By bringing together multiple partners with expertise with individual pathogens, synergies and overlaps will be highlighted.
2. Private sector. Developing solutions to complex problems requires a multidisciplinary approach, through links with industry, both large Pharma (e.g. GSK, Janssen, Medimmune-AZ) and SME (Mucosis, Humabs Biomed), the HIC-Vac network will accelerate work from the laboratory into actual products.
3. Policy makers. The drawing together of human challenge experts into this network will create an advocacy body to support the use of challenge to license vaccines.
4. LMIC. Cross fertilisation between scientists in LMIC and the UK will be supported benefit UK scientists by sharing disease expertise and LMIC scientists in cutting edge techniques in HIC.
5. Volunteers. The research will contribute to increase public awareness of scientific and clinical research. It will contribute to interactions between researchers and the public with an aim to increase public participation in clinical research.
Timescales for the benefits to be realised
The training, networking and advocacy benefits will be immediately realised from the initiation of the project. The impact on the private sector will take a bit longer as the information feeds into their clinical assessment strategies.
What research and professional skills will staff working on the project develop which they could apply in all employment sectors?
The lead applicants have many years of successful internationally renowned experience in the field of vaccines and challenge studies. This project will add to the continuation of their expertise as well as maintaining their training and development. The HIC-Vac network will provide an important experience for the wider community of academic staff associated with it, including students, postdoctoral scientists, and clinicical fellows.