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expert reaction to human challenge studies to be explored in the UK

It has been announced that human challenge studies into COVID-19 are to be explored in the UK.

This Roundup accompanied an SMC Briefing.

 

Dr Claire Waddington, Clinical Lecturer in Infectious Diseases, University of Cambridge, said:

“Challenge studies are a well established mechanism for testing and improving vaccines, and have been developed for a range of pathogens, including bacteria, viruses and parasites.  These models have been successfully used to accelerate the development of vaccines against difficult pathogens such as Salmonella Typhi (the cause of typhoid fever), as well as providing us with detailed understanding of the different diseases.  They can also be used to develop and improve our understanding of diagnostic tests and treatments.

“Ensuring the safety of participants is always the absolute priority in these studies.  Using a very low initial dose of the virus, and only enrolling volunteers who are entirely healthy and unlikely to have anything other than mild symptoms are some of the ways that this can be done.  The more we learn about COVID-19, the better able we are to identify what the risk factors are for more severe disease, and we can use this knowledge to help ensure that only participants who can be safely challenged are enrolled.

 

“Characterising the response in participants challenged with the virus is the essential first step.  Initial volunteers are challenged at a very low dose; this is the safest way to do this as for most pathogens, the infection is more severe the more of the pathogen you’re exposed to.

“The announcement today is an exciting and positive development for the UK in tackling COVID.  Further increasing the national capacity for this sort of detailed study in the coming months will be crucial in facilitating the research that is needed to identify ways in which we can overcome COVID-19.”

 

Dr Charlie Weller, Head of Vaccines at Wellcome, said:

“Human infection studies have real potential to accelerate the development of Covid-19 vaccines in safe, controlled environments.  They are designed to complement Phase III vaccine trials by directly demonstrating vaccine efficacy in highly regulated studies.

“Collaboration between academic, clinical and industry partners is critical to innovation and will enable progress of these studies.  Therefore the announcement of a new partnership between the Department for BEIS, Imperial College London, hVIVO and the Royal Free Hospital to explore and establish a Covid-19 human infection study to begin in January is an encouraging and important first step.  In future, human infection studies could enable a wider assessment of efficacy in a number of promising vaccine candidates and could boost Covid-19 vaccines research by providing us with vital information on how this disease is transmitted, how our immune system mounts a response and how long immunity may last for.

“The safety of volunteers is paramount, and this study will require rigorous and strict assessment from safety and ethics regulators before it can go ahead.  We must consider every tool that could help us to find a safe and effective vaccine faster.  Not only can human infection studies speed up vaccine development, these findings will be crucial for research into promising Covid-19 treatments, ultimately helping communities around the world protect themselves against this disease and end this pandemic.”

 

 

Dr Ohid Yaqub, senior lecturer in the Science Policy Research Unit (SPRU) at the University of Sussex Business School, said:

“Controlled exposure to covid-19 in order to establish minimum threshold doses for infection would be very helpful.  However, there needs to be wider consultation about undertaking such studies, as specified in the WHO’s Key Criteria for Ethical Acceptability of Human Challenge Studies.

“The government’s press release notes that the study remains subject to approval by the regulator and ethics committee.  But the timeline leave little scope for a consultation before a planned January 2021 start.  The WHO’s guidance is clear (criterion number 3, page 10): “Public engagement at the local, national and international levels should begin immediately… Such consultations should seek considered public views on proposed research plans with engagement techniques that enable genuine dialogue in advance… Goals of public engagement should include assessing local acceptability of SARS-CoV-2 challenge studies, responding to community concerns, maximizing transparency, and understanding the potential impact of research on the community (especially in light of other social and public health disruptions related to the pandemic).”

“Selecting for only a small number of low-risk participants means that fatality, hospitalisation, or long-term symptoms are extremely unlikely scenarios.  Yet, even their remote possibility threatens trust in research and vaccines more than necessary, because public engagement on this issue has been limited.”

 

Katharine Wright, Assistant Director, Nuffield Council on Bioethics, said:

“Today’s announcement highlights an early stage of the human challenge trial process, and the study will require ethical approval before it goes ahead.  There are a number of issues for all those involved in study design and approval to consider.

“Engagement with the wider public is key, as it is important that public concerns are properly understood and addressed from the outset.

“There are significant challenges in ensuring volunteers thoroughly understand the risks of what they are being asked to do, and the uncertainty of any benefit.  The implications are significant as volunteers will be committing to stay within a biosecure facility until they are no longer infectious.

“Researchers and funders must consider how best to minimise and mitigate the risks involved, for example finding an appropriate dose of the challenge virus, determining which volunteers are unlikely to develop serious disease, ensuring suitable monitoring and access to the best possible care.”

 

Prof Dominic Wilkinson, Professor of Medical Ethics, Oxford Uehiro Centre for Practical Ethics, University of Oxford, said:

“Human challenge studies are an important and powerful research tool to help accelerate our understanding of infectious diseases and vaccine development.  They have been used for many years for a range of different infections.

“The announcement of the UK Human Challenge Program is a vital step forward for the UK and the world in our shared objective of bringing the COVID-19 pandemic to an end.  With cases climbing across Europe, and more than 1.2 million deaths worldwide, there is an urgent ethical imperative to explore and establish COVID-19 challenge trials.

“All research needs ethical safeguards.  Challenge trials need to be carefully designed to ensure that those who take part are fully informed of the risks, and that the risks to volunteers are minimised.  Not everyone could take part in a challenge trial (only young, healthy volunteers are likely to be able to take part).  Not everyone would choose to take part.  But there are hundreds of young people in the UK and elsewhere who have already signed up to take part in COVID challenge studies.  They deserve our admiration, our support and our thanks.”

 

Prof Julian Savulescu, Uehiro Chair in Practical Ethics, and Director of the Oxford Uehiro Centre for Practical Ethics, and Co-Director of the Wellcome Centre for Ethics and Humanities, University of Oxford, said:

“In a pandemic, time is lives.  So far, over a million people have died.

“There is a moral imperative to develop to a safe and effective vaccine – and to do so as quickly as possible.  Challenge studies are one way of accelerating vaccine research.  They are ethical if the risks are fully disclosed and they are reasonable.  The chance of someone aged 20-30 dying of COVID-19 is about the same as the annual risk of dying in a car accident.  That is a reasonable risk to take, especially to save hundreds of thousands of lives.  It is surprising challenge studies were not done sooner.  Given the stakes, it is unethical not to do challenge studies.”

 

Dr Julian Tang, Honorary Associate Professor in Respiratory Sciences and Clinical Virologist, University of Leicester, said:

“Human viral challenge studies have been around for many years applied in both pathogenesis transmission studies in other respiratory viruses like rhinovirus and influenza (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5147828/; https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008704), and they have already been discussed in relation to COVID-19 earlier (https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30438-2/fulltext).

“Ethical issues are being overcome, and this is easier now that we know more about this virus, but we do now also have some therapeutic options for severely ill cases in remdesivir and dexamethasone, if needed.

“However, there are several key aspects on the practical side that are potentially limiting when compared to natural exposure.  The pre-existing antibodies to other common. cold coronaviruses may be potentially important and confounding – in how people respond to the COVID-19 vaccine – but also in how the seasonal common cold viruses will affect the vaccinees.  There is still a potential risk of antibody-enhancement which may make seasonal coronavirus infections or even COVID-19 reinfection more severe in vaccinees (https://www.nature.com/articles/s41564-020-00789-5).

“Pre-existing antibodies may also complicate the interpretation of the vaccine effect – as I outlined for this earlier influenza EMIT transmission study (https://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(12)70199-8.pdf) so it is unclear how the investigators will select their volunteers.  A mixture of COVID-naive (no antibodies) or experienced (antibody positive) volunteers would be useful to see how the vaccine reacts in both groups.

“For comparison, we vaccinate many people with the seasonal flu vaccine each year – regardless of whether they have pre-existing antibodies from previous seasons or not – and we don’t usually test to check for these.

“The problem with COVID-19 is that some cases either don’t develop antibodies or lose them very quickly – so the investigators may have to screen them for memory (anamnestic) B- and T-cell responses prior to recruitment.  Otherwise these variables may confound their antibody responses and result interpretation.

“The investigators also need to be careful how they administer the SARS-COV-2 infection to the volunteers as this may affect the way the infection/COVID-19 disease develops – which may differ from the natural infection/disease.

“This rather surprising finding has been demonstrated in an earlier study in influenza and may apply to SARS-COV-2, where large droplet inoculation may produce a different infection/disease than more natural aerosol inhalation (https://journals.sagepub.com/doi/abs/10.3181/00379727-122-31255) as discussed on our review article here: https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-019-3707-y#ref-CR58 and may explain partly why this large-scale influenza EMIT study failed to find any cases of the influenza transmission in its test subjects (https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008704) though this study did also used a lab strain of influenza that may not have been representative of how wildtype seasonal influenza transmits.

“Finally, perhaps the main limitation is that the challenge studies can ethically only select healthy adult volunteers – not children or the elderly, or those vulnerable groups with diabetes, hypertension, chronic heart, lung, kidney disease, or pregnant women or immunocompromised people – so the interpretation of such studies will, ironically, be only applicable to those who least need the protection.

“We know from influenza immunisation that the elderly and immunocompromised do not produce reliable or robust antibody responses to vaccination – hence why they are boosted with additional adjuvants (https://www.gov.uk/government/news/vaccine-for-older-adults-gives-significant-protection-against-flu).  So it is likely that some further work will be needed for any COVID-19 vaccine, in order to optimise the vaccine responses for this older population.”

 

Dr Doug Brown, Chief Executive of the British Society for Immunology, said:

“Human challenge trials are studies where healthy volunteers are deliberately infected with a bacteria or virus so that researchers can test the effectiveness of possible vaccines or therapeutics.  This type of study has well established protocols and has been used to successfully to test vaccines for other diseases such as malaria, cholera and influenza. These studies are always carried out under the strictest safety procedures with approval from the relevant authorities.

“News that the team at Imperial College London are going to be looking into the feasibility of human challenge studies for COVID-19 is to be welcomed. The COVID-19 pandemic is the major medical challenge of our age and human challenge trials have enormous potential to increase our knowledge of the disease and accelerate our ability to develop successful vaccines and therapeutics. By carrying out this type of study in a controlled environment, researchers can learn at pace about the disease, which will ultimately increase our ability to control the pandemic and save lives.

“While human challenge studies have the potential to hugely increase our understanding of which treatments or vaccines may be effective against a disease, it’s important to remember that no studies of this type are completely free of risk. One aspect that will need to be taken into consideration with COVID-19 is that we don’t currently have many proven treatments to give to people who become very sick with the illness.  The research team will be acutely aware of this and there will be many stages to this project all aimed at minimising risk of harm to volunteers – this starts with finding out the minimum amount of virus needed to infect each individual. UK researchers are world leaders in carrying out this type of trial and will use all this experience to explore the possibility of human challenge studies for COVID-19.”

 

Prof Jonathan Ball, Professor of Molecular Virology, University of Nottingham, said

“Human challenge studies have been used throughout history and have provided a wealth of information about flu and cold viruses.  They also provide an opportunity to test out vaccine and treatments in a very controlled way; but only if you can ensure the safety of volunteers.

“And there’s the rub.  Any studies involving the novel coronavirus will focus on those most likely to experience a mild infection – young healthy volunteers.  Yet the people we need to protect against serious disease are more vulnerable elderly people, so what we learn from challenge studies might have limited wider relevance.”

 

Prof Gordon Dougan FMedSci FRS, Department of Medicine, University of Cambridge, said:

Can challenge trials help reduce the impact of infectious diseases?

“Challenge trials have been used for decades to assess both the infection itself or to develop preventative medicines such as vaccines.  In the past few years they have moved back onto the developmental and more importantly regulatory path for licensing vaccines.  This is in part because we are developing a strong ethical framework for managing such trials and also collecting detailed data from them.  They have been influential in developing vaccines for diseases such as cholera, malaria and typhoid.

What other diseases have challenge trials been used in?

“Many other diseases such as typhoid, cholera, dysentery, malaria.

How safe are virus characterisation studies?

“In any trial it is very important to risk assess the impact of the infection on the volunteer but also to have some form of rescue therapy if problems appear.  For bacteria, antibiotics can be used. For viruses, more challenging.

Is using the minimum dose required for infection a sensible way to minimise risk?

“Most studies will start with low numbers of people and the very lowest possible challenge dose.  Could also start with people already vaccinated (e.g. with Covid currently would have to use a non-licensed vaccine or an alternative route of infection).

Is only enrolling people with no known risk factors for COVID-19 a sensible way to minimise risk?

“They will normally start with fit people with no history of risk factors.

Can challenge trials help with vaccine development?

“Yes, see typhoid and cholera data (also malaria).

Can challenge trials help develop treatments?

“That is the aim.”

 

Dr Stephen Griffin, Associate Professor in the School of Medicine, University of Leeds, said:

“The perceived need for human challenge studies ought to be balanced against three critical issues.  The MHRA panel will have a difficult task.

“First and foremost, patient safety – whilst the study wisely aims to recruit volunteers from younger age groups, there are albeit rare cases of severe and/or long lasting disease in this group for which we have no clear explanation.  As an effective rescue therapy does not yet exist for SARS-CoV2, there is a serious ethical dilemma for the MHRA committee to address here.

“Second, given the nature of the cohort and the model that will be used – namely finding the minimal dose required for infection, it is possible that the relevance to clinical scenarios may be limited.

“Third, as we are seeing a worrying resurgence in cases, we must question whether direct challenge studies are necessary as vaccinees are increasingly likely to be exposed to infectious challenge in their natural environment.”

 

 

https://www.imperial.ac.uk/news/206893/uk-researchers-explore-human-challenge-studies/

https://www.gov.uk/government/news/expert-partnership-to-explore-and-establish-human-challenge-studies-of-covid-19-in-the-uk

http://www.ukcovidchallenge.com/

 

All our previous output on this subject can be seen at this weblink:

www.sciencemediacentre.org/tag/covid-19

 

Declared interests

Dr Charlie Weller: “Wellcome is not a partner of the study announced today but is a representative member of the UK Vaccines Taskforce, which is led by the Department of Business, Energy and Industrial Strategy.”

Prof Dominic Wilkinson: “I have no conflict of interest.”

Dr Julian Tang: “As a clinical virologist, I will need advise/recommend to GPs, clinical colleagues, and patients on the best choice of vaccine, and their likely effectiveness and complications of any COVID-19 vaccine that is eventually licensed – so I will need to follow these various vaccine trials with some keen personal and professional interest, in the coming months.”

Dr Doug Brown: “Dr Brown is a Trustee of the Association of Medical Research Charities (AMRC).”

Prof Jonathan Ball: “None.”

Prof Gordon Dougan: “I have been directly and indirectly involved in human challenge studies.  I have no conflicts.”

Dr Stephen Griffin: “No conflicts.”

None others received.

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