The world's first human COVID challenge trial has been given the green light by ethics and we at Niche are playing our part [1]. However, with significant numbers of the population now receiving their vaccinations, some have questioned the necessity for challenge trials and whether they are ethically justified [2].

In the case of the ground-breaking Imperial College study, volunteers will enter a clinical study unit where they will only have contact with people running the trial. After a period of stabilisation (baseline) a small syringe filled with live SARS-CoV-2 will be squirted up their nose. Subjects will be closely monitored after dosing. This is just the first of a range of studies aimed at addressing crucial scientific questions that are almost impossible to answer in a ‘real world ‘setting, such as:

• How much virus does it take to start an infection?
• How does the immune system mount its first defence?
• Can you tell which people will develop symptoms or not?

The answers will give us a better understanding of coronavirus and it is hoped that comparisons of rates of infection and infectiousness between vaccinated and control participants will eventually reveal how well our new vaccines block infection.

The Imperial study will be conducted in a young/healthy population who are believed to have relatively low vulnerability to the consequences of infection [3]. Nevertheless, clinicians will be on hand to deliver any supportive care. After at least 2 weeks, participants will be allowed home (if they are healthy and virus free) and they will continue to be followed up for a year after the trial [1].

Challenge studies, where subjects are deliberately exposed to infection under tightly controlled conditions, have a long history and there are many ways to use them. For example, it is possible to employ ‘control’ groups that receive a proven or experimental vaccine or a placebo. Although field trials have shown the available COVID vaccines to be safe (and most probably efficacious), encouraging many countries to roll out mass vaccination programmes, it remains important to test whether our vaccines block infection (still not yet confirmed) [3, 4], and how long any protection may last [5]. We also need to know whether next generation vaccines competitively prevent infection, especially potentially ‘better’ vaccines that aren’t restricted by low temperature requirements, repeat doses, limited availability or high production cost [6]. Human challenge trials will give us insight into all these aspects. They will also allow us to:

• Define the course of infection and testing strategies
• Test infection prevention efficacy
• Determine potential to prevent mucosal infection (a surrogate of infectiousness)
• Compare vaccine efficacies and weed out poor candidates
• Investigate different dosing regimens, e.g. half-doses, spaced out, etc.
• Test activity against viral variants
• Determine the duration and extent of vaccine immunity

It is difficult to test a vaccine’s effect on infectiousness in field trials and the challenge trial approach has been used previously to research vaccine candidates in malaria, cholera and flu. There is also the added complication with field trials that subjects are not necessarily young and fit individuals. Equally, it might be considered unethical for example to include a cohort that tests an experimental vaccine (or placebo) instead of a vaccine of known efficacy  [7-9]. Field trials also require greater numbers of subjects (possibly x100) to achieve statistical significance when testing vaccines for equivalence or superiority [10]. Denying protection (from a proven vaccine) to a cohort will likely pose a challenge to volunteer recruitment [7]. It is also certain that small Phase I-like studies can be completed in a much shorter time with lower resource burdens (and cost), two crucially important concerns during the burning heat of a pandemic. Information and understanding is achieved quickly and we know for certain that all participants were exposed to the virus (and we know when).

Unlike field trials, where it can be challenging to establish equivalence or superiority of one vaccine over another, challenge trials can assess comparative effectiveness efficiently, and can even compare challenges at different sites and from different trials (assuming similar methodology is employed such as the same dosage regimens via an agreed World Health Organisation protocol). This would facilitate a global approach to assessing different vaccines. It also introduces the possibility of reducing the need for studying ‘untreated’ patients by sharing data from a single small placebo group across trials—a scientific and an ethical merit that has often been discussed within the Association of Human Pharmacology in the Pharmaceutical Industry [11, 12]. Comparing data from field trials on the other hand is plagued with methodological and statistical challenges.

Clearly, the challenge trial approach comes with necessary compromises. For example, studies do not generally include older adults, children or people with comorbidities, groups within society who may have a different response to infection [13, 14]. Challenge trials are designed for speed rather than comprehensiveness. However, it is possible to conduct what we might call immune-bridging (and safety) studies in large high-risk populations at a later date [15]. It should also be noted that small studies give very little indication regarding the safety of any test vaccine [14, 16]. Challenge trials do not negate the need for formal safety and efficacy studies in the wider population.

In the age of social media, where any individual with an axe to grind, misplaced angst or conspiracy theory can broadcast their ‘meme’ to a world hungry for drama, there is the question of whether challenge trials and their associated risk of negative findings might destroy public trust in vaccines. The long-term damage this can have on public understanding and trust can still be felt following the Andrew Wakefield controversy concerning the MMR vaccine in 1998, something that could very well repeat itself [14, 17, 18]. It is difficult to speculate what ‘the internet’ will believe and even more difficult to determine whether empirical data will prevent malevolent misinterpretation. Results from limited surveys suggest that such trials are seen as proactive approaches to pandemic resolution and we might hope that most are likely to understand or appreciate the underlying scientific rationale [19, 20].

The beauty of challenge trials is their ability to be planned and executed at speed. When we look back at the ongoing pandemic and the lessons we have learned it might be hoped that future pandemics will see a more rapid and targeted response. This does however raise issues regarding whether volunteers taking part in such studies can be appropriately informed of the possible risks of participation. The currently planned challenge studies are only taking place after 16 months of pandemic experience where we have learned which subjects are at most risk of harm and how to manage more severe forms of the disease. It could be argued that it is impossible to provide study subjects with adequate disclosure concerning the risks for consenting purposes [14]. However, this is a challenge faced with almost every Phase I study and the ability to perform a high-quality consenting procedure is more likely in the setting of a small Phase I unit than ever can be expected in field studies that may involve thousands.

Is it fair to ask volunteers to take the risk with the promise, in some cases, of early exposure to new therapeutics [17] and the potential to develop more efficacious treatments when there remains no clearly defined rescue therapy for covid-19? Currently, if a volunteer experiences a severe reaction to infection all we have available to treat patients is a series of therapies that might relieve symptoms and a host of experience of managing patients in distress [11, 14]. Clearly it is easier in studies run under Phase I conditions to provide focused care. The best assurance of safety comes from our understanding of SARS-CoV-2 and how that can be applied to defining your inclusion and exclusion criteria for volunteer selection. Recent estimates place risk of death for a healthy volunteer with SARS-CoV-2 at a generally acceptable 0.00003 per volunteer [21], or 10 times below the risk of death associated with live kidney donation [22].

It must be acknowledged that young and healthy adults face the potential morbidities following infection that can take months to resolve and may even turn into long term disability or increased risk of mortality [14]. When considering the potential for harm it should be remembered that this possibility is just as high outside the clinic where medical support may not be as readily available. In challenge studies, like any Phase I study, investigators ensure access to lifelong care as necessary. And, although the greater good is often not a consideration when regulating clinical trials, many millions are facing suffering globally and caring for a limited number of study volunteers is easier than managing the consequences of a pandemic burning across the world. Similar questions might be posed at the early vaccine field trials for the different SARS-CoV-2 candidates—but options were limited considering the potential for world-wide death, morbidity and financial collapse.

Authorities rightly concluded that carefully conducted field trials were justified and ethical [23]. On balance, it is clear that, for SARS-CoV-2 infection, challenge studies offer a great opportunity for increasing our understanding. Even the most dunderheaded leaders have had the opportunity to observe the benefits of applying initiatives to limit the spread of disease and efficacious vaccines are becoming available. Consequently, it can only be recommended that medical science makes every effort to reap the benefits of challenge trials. However, there should be caution; such studies do not represent a shortcut to cure. In our current situation the proposed trials are taking place from a position of knowledge regarding SARSCoV-2 infection and how to manage it clinically. A serious consideration for any future pandemic.