SARS-CoV-2/COVID-19 has already caused over 50,000 deaths, infected a million people worldwide, triggered massive economic disruption and changed how the entire world moves and interacts. The race to find a vaccine to prevent this disease is on.
To meet the dire need for vaccines, treatments and diagnostics, funders and the scientific community have stepped up rapidly. As of the 20th March there were 42 candidate vaccines being developed, with two already in Phase 1 clinical trials[1].
However, in order to go through the multiple stages needed to prove efficacy and safety we may not have a Coronavirus vaccine available for use in patients for up to 18 months, by which time the pandemic may already be waning. We need a Coronavirus vaccine now, human infection studies could help us get there much faster.
Human infection studies can be a valuable tool for some diseases in determining whether a vaccine is efficacious quickly, they involve healthy volunteers being infected with a well characterised and usually weakened version of the virus to allow testing of potential treatments and vaccines. Human infection studies can generate efficacy data within months and user fewer volunteers compared to Phase III trials. A Coronavirus human infection study could potentially allow for those vaccines currently being developed to be available to the public faster than traditional vaccine development, and some studies are already in development by researchers such as hVIVO.
However, there are many questions around whether these studies can and should go ahead in the current outbreak in a safe and ethical way.
1. Is it ethical to conduct a human infection study when natural infection is prevalent and vaccine efficacy could be determined through large phase III field trials instead? Even if this takes longer – traditionally years to complete?
2. Is it possible to safely establish a Coronavirus human infection study in time to be able to test the vaccine candidates that are in development now given that stocks of the virus for use in these studies needs to be made and tested and the optimal dose confirmed? With 42 vaccines potentially being available for clinical testing should the most promising vaccines be tested as a priority rather than first come first served?
3. Given that it won’t be possible to use the circulating COVID-19 strain, researchers have proposed using closely related strains to SARS-CoV-2 such as 229E and OC43. But, how relevant are these strains for use, is there confidence that any vaccine developed with these will protect against the circulating SARS-CoV-2 strain?
4. Will there be a sufficient number of validated antibody tests available to determine whether an individual has been previously infected with Coronavirus – usually human infection studies are performed with individuals who have not previously been infected or have little to no antibodies to the pathogen so that the immune response against a novel pathogen where the population does not have immunity can be determined. And so what impact might a second infection have in volunteers?
5. There are recent reports of healthy young adults who have succumbed to a severe infection and death following infection with Coronavirus, so are we aware of all the risk factors that might result in a severe outcome? How can we control for these as we would with a normal human infection study?
6. How can we make sure that volunteers have a detailed picture of the risks they are undertaking, with a virus we know so little about?
7. Is it ethical to take resources away from our already stretched health services at a time when in the UK at least the infection has not yet peaked? A coronavirus human infection study would require trained infectious disease staff, personal protective equipment and facilities.
Organising the structure that will regulate the studies is of importance for SARS-CoV-2 as so many unanswered questions around the virus remain.
1. We need an ethical framework for human infection studies to be established. The WHO are currently developing an ethical framework that will be applicable globally. Regulatory frameworks are available for those studies conducted in Europe and the USA however these guidelines may not be appropriate for a pandemic situation.
2. We need a global governance and regulatory structure for human infection studies which currently does not exist. Global guidance on the regulatory requirements for coronavirus human infection studies need to be issued by the WHO with input from national and regional regulators would enable these studies to be performed with a harmonised and aligned approach ensuring the safety of the study participants. It is critical that researchers interested in establishing a Coronavirus human infection study need to engage with their national regulator as early as possible to ensure that all parties are clear on the expectations.
3. We need the regulatory and ethical frameworks and guidance being developed to cover the following at a minimum: strain selection, requirements for the production of the challenge strain, guidelines on the volunteer population, containment facility requirements once volunteers have been challenged, long term health screening post study. 3rd party risk mitigations, serious adverse event reporting, data sharing to mention just a few.
This pandemic has highlighted the need for a global ethical and regulatory framework for human infections studies in general as well as the need for these frameworks to be established in endemic settings where diseases which are appropriate for use in these studies can be studied.
With many questions still to answer now is the time for WHO, national and regional regulators, ethicists, funders and scientists to come together and discuss how, when and why Coronavirus human infection studies should be conducted and how the data generated would accepted by the regulators to accelerate the vaccines being developed to prevent further unnecessary deaths. These discussions will certainly fuel the need for ethical and regulatory frameworks and guidance for human infection studies more widely.
[1] https://www.who.int/blueprint/priority-diseases/key-action/novel-coronavirus-landscape-ncov.pdf?ua=1
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