Table of Contents
Summary
Infectious diseases account for 7% of deaths in the UK, with an economic cost of £30 billion each year. They present a huge challenge for the NHS, and have knock-on effects on childcare, productivity, wellbeing, and life expectancy.
Human challenge trials (HCTs) are an effective and faster way to study the early-stage impact of pathogens, develop vaccines and medications, and design non-pharmacological interventions to prevent outbreaks and pandemics. HCTs involve deliberately infecting volunteers with pathogens in a controlled and safe environment.
The UK has the potential to become a global leader in HCTs, drawing on its success with COVID-19 trials and the Common Cold Unit, which was a permanent human challenge facility in Salisbury from 1946 to 1991. The UK hosted the first and only COVID-19 HCTs, advancing understanding of SARS-CoV-2 transmission, testing, and immune response. UK challenge studies have also been essential for the development of malaria, RSV, and typhoid vaccines.
Several existing UK universities (Oxford, Imperial and Liverpool, among others), and the private company hVIVO, carry out HCTs on an extensive range of pathogens, including seasonal influenza.
Challenge trials support UK public health, reducing the strain on the NHS. Existing commercial challenge trials attract global scientific talent to the UK and add £1.8 billion to the UK economy annually.
The UK should set up a centralised facility for challenge agent manufacturing and storage, a network of decentralised dedicated study wards, and a government body to oversee the two.
The network should be funded up to £115 million, becoming self-sustaining over the first five years. This would complement existing HCT facilities in Oxford, London and Liverpool, and cement the UK’s position as a world leader in challenge trials.
The Challenge
The COVID-19 pandemic highlighted the immense importance of defending against infectious diseases. Even outside of a pandemic, seasonal flu costs the UK economy more than £600m a year, ~£100m of which is borne by the NHS.
Despite this, our understanding of and treatments for infectious diseases are still lacking. Research is hampered by the need to study infected populations during natural outbreaks, which makes diseases harder to study and slows scientific progress.
Human challenge trials (HCTs) address this issue by exposing volunteers to pathogens in a controlled environment to provide a study population for research. This allows us to advance our understanding of disease spread and progression and evaluate new pharmaceutical or non-pharmacological interventions. The resulting research can reduce the burden of existing infectious diseases and better prepare us for future pandemics.
The UK has long been a global leader in HCTs. From 1946 to 1989 the Medical Research Council ran the Common Cold Unit, a remarkable HCT facility that helped us to understand the causes and transmission of the common cold. Almost 20,000 members of the British public volunteered to support this research. This collaborative, public mission helped shape modern infectious disease treatments. However, this critical research is now bottlenecked by a lack of infrastructure:
Challenge agent manufacturing
Challenge agent availability is a limiting factor for HCTs. To infect volunteers, studies require pathogens (challenge agents) manufactured to high clinical standards (generally Good Manufacturing Practice, referred to as GMP). Outside of HCTs there is no need to manufacture pathogens to pharmaceutical standards. This means there is limited laboratory capacity for this work.
Bed space
A significant bottleneck in conducting HCTs is the limited availability of dedicated bed space. Currently, only one in-patient dedicated HCT facility is in operation in the UK: a 50-bed private facility owned by hVIVO. An additional inpatient 12-bed public facility is planned in Liverpool, funded by a £4,753,151 NIHR grant. This means that challenge studies typically rely on the ad-hoc availability of NHS or academic sites, meaning finding facilities can be too expensive or too difficult.
The lack of manufacturing capacity and bed space can make studies hundreds of thousands of pounds more expensive and extend their duration by several months. This extra cost and complexity make human challenge studies less viable, especially for small businesses, potentially limiting the development of more innovative products.
The Opportunity
Investing in challenge agent manufacturing and expanding HCT bed space presents a significant opportunity to unlock commercial trial success, enhance UK public health, and better prepare for future pandemics. These investments offer both economic and societal benefits.
Support UK commercial activity
Commercial clinical trials are an important activity for the UK, adding £1.8 billion to the UK economy each year. A 2023 Government review of commercial clinical trials found 86% of industry executives believe that increasing commercial clinical trial activity in the UK is important or very important for the next government.
Human challenge trials can be an additional strategic commercial tool. HCTs can provide evidence of efficacy at a much earlier stage in a product’s development, for a much smaller sum than traditional clinical trials. HCTs therefore reduce product development risk allowing companies and investors to focus resources on more promising products. This can be particularly helpful for smaller biotechnology companies that cannot afford to make it to later-stage trials before collecting efficacy data.
Today, the UK has a base of academic institutions that conduct HCTs—Liverpool School of Tropical Medicine, Imperial College London, Oxford University—and the world’s only private HCT company (hVIVO). UK regulators are uniquely experienced in evaluating and approving HCTs. The HRA, in collaboration with WHO, is leveraging the insights gained from COVID-19 studies by investing in training ethics committee members to better address emerging pathogen outbreaks. The success with COVID-19 has led to calls for the UK to return to the forefront of HCTs and build a focused research field to advance infectious disease study. However, this opportunity is currently not being taken advantage of due to a lack of infrastructure for HCTs.
The UK has the potential to become the global leader in challenge trials, attracting substantial investment in pharmaceutical development, expanding clinical trial activities, and pioneering novel infectious diseases research. Investment in challenge agent manufacturing and increasing HCT bed capacity would allow the UK to capitalise on its uniquely robust regulatory framework and its long-standing history of successful HCTs.
Support public health
Investments in HCTs are also investments to improve public health. Seasonal influenza costs the UK >£500 million annually, RSV £80 million, and infectious diseases in total cost the UK £30 billion.
If HCTs were just to be used to develop approaches that reduce seasonal influenza in hospitals, this would more than justify an investment into HCT facilities. In the 1980s a successful common cold model was used by two teams in the United States. The pandemic has reignited interest in this work, with the FDA funding a US follow-up study to the only other modern study, which was completed in the UK in 2010.
Government investment in HCT facilities would allow for a sustained focus on researching public health-focused projects which, due to the lack of obvious profit motive, would not be possible in the private sector. This provides a compelling economic and social justification for government intervention.
Prepare for pandemics
COVID-19 not only inflicted an enormous humanitarian toll but also cost the UK government at least £310 billion to £410 billion. The pandemic highlighted the urgent need for robust preparedness strategies to protect us from future threats.
Ready-to-go HCT infrastructure can speed up clinical trials in a pandemic, reducing the risk and—potentially—time of vaccine development. This supports the UK’s goal of becoming resilient to a spectrum of biological threats by 2030 and the global 100 day vaccine goal. Infrastructure for clinical studies has already been highlighted as a medium to long-term priority in the Government’s biosecurity review. Similarly, advances into reducing disease transmission and broader-spectrum risk may be an important part of reducing future pandemic risk.
Plan of Action
To establish the UK as a global leader in HCTs, the government should implement the following initiatives:
Establish a Centralised Facility for Challenge Agent Manufacturing and Storage:
Establish a central facility compliant with Good Manufacturing Practice (GMP) and Biosafety Level 3 (BSL-3) standards, addressing a critical gap in the UK’s biosecurity preparedness. The UK government should aim to establish the facility within one year.
Allocate £15-25 million to create a 10,000-20,000 square foot laboratory capable of producing human-grade pathogen samples. This facility's running costs are estimated at £10-15 million per year, with a development cost of £2.5 million per new agent.
Fund a Decentralised Network of Dedicated Study Wards:
Fund the establishment of a decentralised network of dedicated HCT wards across multiple sites, ensuring flexibility while maintaining a sufficient number of high-biosafety-level beds for emerging health situations or pandemics.
Allocate £20-40 million over five years to establish 50-70 beds across several academic sites.
Create a Government Oversight Body:
Create a governmental oversight body to coordinate these efforts and develop a comprehensive UK HCT strategy.
This body should manage the central laboratory capacity, plan and design agent production strategies, and ensure swift decision-making during health emergencies.
Aim to commercialise parts of the research to make the facility self-sustaining within five years, while reinvesting profits to maintain public health and preparedness goals.
To deliver on this plan, in the first 1-3 months, the Secretary of State for Science, Innovation and Technology should:
Commission a team within DSIT, in collaboration with the Department of Health, to:
Scope out use cases for a centralised UK Challenge Centre.
Conduct market research on the business case and commercial applications.
Evaluate existing challenge models/agents for potential inclusion in the central facility.
Engage with academic institutions to assess current agent stocks and requirements for further manufacturing.
Review past studies and establish knowledge-sharing mechanisms.
Allocate initial funding of £15-25 million for setting up the central laboratory space.
Create the governmental oversight body.
From 3-12 months, the newly established government oversight body should:
Open the centralised facility for challenge agent manufacturing and storage.
Gather agent stocks from academic laboratories, and create a knowledge-sharing structure to allow new teams to use these agents for their own studies
Design a strategy for new agent manufacture
Newly manufactured agents could be designed to create commercial value or public health benefit. These decisions should be taken by the new oversight body.
Create a framework for pandemic challenge agent manufacture.
Create a framework that encompasses funding, ethical guidelines, and technical procedures to enable the rapid production of challenge agents in response to emergencies. This framework should also include a streamlined process for quickly delivering regulatory decisions on the acceptability of challenge studies. The goal is to either expedite study timelines or release agents for research if the studies are deemed unacceptable.
Allocate £20-40 million over five years to establish 50-70 beds across several academic sites.
Design a strategy to use challenge studies for public health benefit.
This could include studies designed to assess the natural transmission of respiratory viruses or research on broader-spectrum products.
FAQs
What are human challenge studies, and are they safe?
Human challenge studies (HCTs) involve deliberately infecting volunteers with a pathogen in a controlled environment to study disease progression and test interventions. HCTs can be used to study a variety of diseases, both respiratory (such as influenza, COVID-19, RSV, and the common cold) and non-respiratory (such as malaria, gonorrhoea, and tuberculosis).
While there are inherent risks associated with HCTs, they can be minimised by carefully selecting volunteers of the right age and health, providing constant medical monitoring, and administering available therapies if volunteers become ill. Adverse events in human challenge studies have been found to be in line with those for standard medical studies. Surveys have shown broad public acceptance of HCTs.
All HCTs are approved in the same manner as any human research in the UK, requiring ethical approval from a Research Ethics Committee, and scientific approval from a competent regulatory body, either the Health Research Authority (HRA) or the Medicines and Healthcare Products Regulatory Agency (MHRA).
Furthermore, all HCTs take steps to minimise the risk of spreading disease to the community, including isolating volunteers, providing staff with PPE, and adhering to appropriate biosafety levels on wards, meaning the risk is very low. This small risk is factored into the decision of a Research Ethics Committee, so a study can only go ahead if the risk is deemed sufficiently low.
How are new HCTs developed and how do they fit into the drug development process?
The development of human challenge studies (HCTs) involves multiple steps before they can be used to test products. Initially, the pathogen to be used (the challenge agent) must be isolated and carefully grown, adhering to extensive regulatory requirements. An initial study is then conducted without any product to establish the minimum dose required to cause infection and to understand the behaviour of the model without treatment. This foundational knowledge is crucial for subsequent studies to investigate how treatments affect the course of infection.
HCTs generally fit into the drug development process as phase II studies. They are conducted after small-scale studies establish initial safety data, typically in healthy volunteers, but before large phase III studies, which assess safety and efficacy in the community with hundreds or thousands of volunteers. HCTs provide early efficacy data, allowing for more refined phase III studies. This early data helps determine the correct dose to maximise efficacy while minimising side effects, thus de-risking the later stages of product development and potentially accelerating the overall development timeline.
What precedence exists for HCTs?
The UK has a strong history and ongoing practice of conducting human challenge trials (HCTs). Leading institutions such as Oxford University, Imperial College London, and Liverpool School of Tropical Medicine routinely run HCTs. Pharmaceutical companies like Pfizer, GSK, and J&J also participate in these studies. Additionally, the UK hosts hVIVO, the only contract research organisation solely dedicated to human challenge studies.
Several successful products have emerged from HCTs, including the influenza antiviral Tamiflu, the R21 and RTS,S malaria vaccines, which are currently being deployed in Africa. Vaccines for other tropical diseases, such as typhoid and cholera, have also been tested using HCTs.
During the COVID-19 pandemic, the Vaccine Taskforce invested £80 million in HCTs, carried out by a consortium including Imperial College London, the Royal Free Hospital, and hVIVO. These studies were instrumental in several key findings:
Research conducted in the spring and summer of 2021 by a partnership between Imperial College London and hVIVO demonstrated that lateral flow devices detected infection at the onset of viral shedding, information that would have significantly contributed to the UK's mass testing strategy had it been available some months earlier.
The same study provided insights into the early immune response, identifying markers that distinguish between early and late stages of infection. Data on viral emissions revealed that a small number of volunteers were responsible for the majority of virus shedding, supporting the hypothesis of superspreaders.
A parallel study by Oxford University showed that a viral dose 10,000 times higher than normal failed to infect previously infected volunteers, while breakthrough infections, especially of the Omicron strain, were observed in the community. This provided unique insights into the natural immune response to SARS-CoV-2.
What applications are human challenge studies (HCTs) uniquely useful for?
Vaccine Development:
Vaccine development is notoriously risky, even for pharmaceutical products. The de-risking data provided by HCTs can be vital in making development viable. HCTs allow researchers to demonstrate a vaccine's efficacy in preventing infection under controlled conditions, which would otherwise require extensive field studies in high-infection areas. HCTs facilitate faster and more cost-effective experiments, quickly yielding statistically significant results.
In addition, the close monitoring allowed by HCTs can help scientists develop “correlates of protection”, biomarkers (e.g. antibodies or cells involved in the immune response) which demonstrate a product has worked effectively without requiring infection. This can accelerate the licensing process, as exemplified by the yearly influenza vaccines.
Development of Broad-Spectrum Products:
Human challenge studies allow for control over exactly which virus volunteers have, meaning it can be much simpler to test a product against multiple pathogens, or multiple strains of the same pathogen, even simultaneously. Testing a universal influenza vaccine without human challenge studies, for example, would require large and expensive studies in multiple different flu seasons to test against multiple strains, meaning development would take years and be extraordinarily financially risky, or simply unviable.
However, a human challenge study allows volunteers to be infected with various viral strains, providing evidence of broad-spectrum activity within months and at the early stages of development. This significantly reduces risk and accelerates future product development. Similarly, developing bacterial models can lead to more efficient testing of new antibiotics.
Understanding Disease Transmission:
Dedicated HCT facilities enable controlled studies on how diseases spread among individuals, providing valuable data for public health interventions. This is particularly crucial for respiratory diseases, which pose a significant threat to public health yet remain poorly understood in terms of transmission dynamics.
HCTs provide unique insights into the transmission dynamics of respiratory diseases. They enable close monitoring of the early stages of infection, especially when patients are most infectious but asymptomatic—a stage challenging to study in community settings.
For example, human challenge studies conducted in the UK in 2010 aimed to measure influenza transmission, though the studies generated inconclusive results that are only now being followed up in the United States. Additionally, COVID-19 challenge studies also generated useful data on disease transmission, enhancing our understanding of how the virus spreads and informing public health strategies.
How does the UK environment for HCTs compare internationally, and where is there opportunity to improve its standing?
The UK is a global leader in human challenge trials (HCTs), conducting a higher volume and having more extensive experience than any other country. The UK hosts the world’s only commercial challenge company, hVIVO, and benefits from highly experienced regulators. This robust regulatory framework is essential for enabling HCTs.
In contrast, other countries with HCT programs, such as the United States and the Netherlands, face challenges. For example, regulatory uncertainty and weaknesses in the existing research ecosystem in the Netherlands led to the abandonment of plans for a COVID-19 HCT, and the US faced a decades-long ban on influenza challenge studies due to a minor adverse event, only lifted during the 2011 swine flu pandemic. Additionally, several countries, especially in Africa, are currently developing HCT capacity.
Despite its leadership, the UK's HCT capacity is limited by infrastructure constraints. Enhancing physical infrastructure is critical for maintaining and improving the UK's standing in HCTs.
HCTs require both volunteer beds and laboratory space. Volunteer beds are often in short supply, especially those complying with the higher biosafety standards required for testing more dangerous pathogens, which can increase the duration and costs of HCTs—especially during severe disease outbreaks, during which such beds will inevitably be in high demand.
Laboratory space, meanwhile, is essential not only for analysing volunteer samples and data, but also for producing the pathogens required to infect volunteers. Currently, the UK completely lacks the facilities to manufacture biosafety level 3 pathogens (such as SARS-CoV-2) to the Good Manufacturing Practice standards required for HCTs, and general lack of lab space and experienced staff means the creation of agents is a very serious bottleneck, severely constraining the entire field.
How would carrying out commercial research help fund the facility?
Challenge studies can be highly valuable for drug developers, who often pay between £2-10 million to hVIVO, a commercial contract research organisation (CRO). Last year, hVIVO reported revenues exceeding £56 million from conducting 2-3 month long studies (varying based on size, pathogen, and data collected). Expanding the facility's capacity to handle these commercial studies could significantly increase revenue.
Additionally, the manufacturing of pathogen challenge agents is a complex process that many academic facilities are not equipped to handle. By offering these manufacturing services, the facility could attract additional commercial contracts, further boosting its funding.
Are there biosecurity risks from such a facility?
While facilities designed to manufacture pathogens do present biosecurity concerns, the risks are low in this project. The facility will focus on manufacturing and storing wild-type or attenuated pathogens which are safe enough to be given to consenting volunteers. Strict biosafety measures will prevent pathogens leaking from a laboratory, or from challenge studies.
Are there potential pitfalls to avoid?
Commercialising research may prove complex; a risk that can be mitigated by extensive market research and consultation with industry. Another difficulty of this proposal is the need to coordinate a number of different elements (laboratory facilities, bed space, and government bodies) to exploit the maximum benefits. Ensuring an overarching body has sufficient authority and a well-designed project management plan from the outset to ensure all the various elements of the proposal are well-coordinated will be essential to mitigate this risk.
Alastair is a research associate at 1DaySooner. Alastair is a former COVID-19 human challenge study volunteer. His research at 1Day Sooner focuses on indoor air quality and pandemic preparedness. He studies cancer biology at Imperial College London.