2 February 2022
The world’s first COVID-19 human challenge study – carried out at the Royal Free Hospital – has provided researchers with new insights into the virus and paved the way for future studies to test new vaccines and medicines.
The collaborative study is the first in the world to infect healthy, young volunteers with the virus that causes COVID-19 (known as SARS-CoV-2) and perform detailed monitoring from the moment a person first encounters SARS-CoV-2, throughout the infection to the point at which the virus is apparently eliminated.
Among several key clinical insights, researchers found that symptoms start to develop quickly, on average about two days after contact with the virus. The infection first appears in the throat; infectious virus peaks about five days into infection and, at that stage, is significantly more abundant in the nose than the throat. They also found that lateral flow tests are a reassuringly reliable indicator of whether infectious virus is present (i.e. whether they are a likely to be able to transmit virus to other people).
The Human Challenge Programme is a partnership between Imperial College London, the Vaccine Taskforce and Department of Health and Social Care (DHSC), hVIVO (part of Open Orphan plc), and the Royal Free London NHS Foundation Trust.
The findings, published on a pre-print server and which have not yet been peer-reviewed, detail the outcomes in 36 healthy, young participants with no immunity to the virus. This landmark study, which took place at a specialist unit at the Royal Free Hospital, shows that experimental infection of volunteers is reproducible and resulted in no severe symptoms in healthy young adult participants, laying the groundwork for future studies to test new vaccines and medicines against COVID-19.
Dr Sir Michael Jacobs, consultant in infectious diseases at the Royal Free London, said: “We have vast experience of safely managing highly transmissible infections at the Royal Free Hospital and we are really pleased to have been able to play our part in this landmark study.
“The trial has already provided some fascinating new insights into SARS-CoV2 infection, but perhaps its greatest contribution is to open up a new way to study the infection and the immune responses to it in great detail and help test new vaccines and treatments.”
Professor Christopher Chiu, Professor of Infectious Diseases from the Institute of Infection at Imperial College London and Chief Investigator on the trial, said: “First and foremost, there were no severe symptoms or clinical concerns in our challenge infection model of healthy young adult participants. People in this age group are believed to be major drivers of the pandemic and these studies, which are representative of mild infection, allow detailed investigation of the factors responsible for infection and pandemic spread.
“Our study reveals some very interesting clinical insights, particularly around the short incubation period of the virus, extremely high viral shedding from the nose, as well as the utility of lateral flow tests, with potential implications for public health.”
In the trial, healthy male and female volunteers aged 18-30 years, unvaccinated against COVID-19 and with no prior infection with SARS-CoV-2 were given a low dose of the virus – introduced via drops up the nose – and then carefully monitored by clinical staff in a controlled environment over a two-week period. The study used virus from very early in the pandemic obtained from a hospitalised patient, prior to the emergence of the Alpha variant.
Eighteen of the volunteers became infected, 16 of whom went on to develop mild-to-moderate cold-like symptoms, including a stuffy or runny nose, sneezing, and a sore throat. Some experienced headaches, muscle/joint aches, tiredness and fever. None developed serious symptoms. Two participants were excluded from the final analysis after developing antibodies between initial screening and inoculation.
Thirteen infected volunteers reported temporarily losing their sense of smell (anosmia), but this returned to normal within 90 days in all but three participants – the remainder continue to show improvement after three months. There were no changes seen in their lungs, or any serious adverse events in any participant. All participants will be followed up for 12 months after leaving the clinical facility to monitor for any potential long-term effects.
Participants were exposed to the lowest possible dose of virus found to cause infection, roughly equivalent to the amount found in a single droplet of nasal fluid when participants were at their most infectious.
Professor Sir Jonathan Van-Tam, Deputy Chief Medical Officer, said: “Human challenge studies have been performed using other pathogens for decades, including flu and Respiratory Syncytial Virus (RSV). They need full independent ethical review and very careful planning – as has been the case this time. Every precaution is taken to minimise risk.
“Scientifically these studies offer real advantage because the timing of exposure to the virus is always known exactly, therefore things like the interval between exposure and the profile of virus shedding can be accurately described.
“This important study has provided further key data on COVID-19 and how it spreads, which is invaluable in learning more about this novel virus, so we can fine-tune our response. Challenge studies could still prove to be important in the future to speed the development of ‘next-generation’ Covid-19 vaccines and antiviral drugs.
“This data underline just how useful a tool lateral flow tests can be to pick up people when infectious and the importance of wearing a face covering in crowded, enclosed spaces.”
Dr Andrew Catchpole, Co-investigator on the study and Chief Scientific Officer of hVIVO (part of Open Orphan plc), said: “The SARS-CoV-2 characterisation study has provided invaluable insights into the progression of COVID-19 infection in healthy young adults. Importantly the study demonstrated that SARS-CoV-2 challenge studies are safe and well tolerated by the volunteers with no serious symptoms and no Serious Adverse Events (SAEs).
“The study’s results have provided useful insights which could be used to inform public health decisions on COVID-19 symptoms and virus detection going forward, including isolation periods for infectious individuals, the use of LFTs, and establishing the human challenge platform to investigate further aspects of COVID-19.
“While the characterisation study was focused on the original SARS-CoV-2 strain, and there are differences in transmissibility between it and the other variants, the same factors will be responsible for protection against it, meaning the findings remain valuable for variants such as Delta or Omicron. These data provide a clear platform to now utilise the human challenge model to expedite product efficacy testing for new vaccines or antivirals”
Professor Peter Openshaw, co-investigator on the study and Professor of Experimental Medicine at Imperial College London, said: “The UK is able to provide a very good legal and ethical environment for human challenge studies and has invested substantially in studies of this sort for many years. I am especially pleased that this study has been made possible by the MRC investment in the Human Infection Challenge consortium (HIC-Vac) that we established in 2017. The information that we have been able to discover about the immune response to SARS-CoV-2 infection in this study is extraordinary.”
Safety, tolerability and viral kinetics during SARS-CoV-2 human challenge’ by Killingley, B. et al. is available on the Research Square pre-print server and has been submitted for peer-review.