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COVID-19 human challenge study reveals detailed insights into infection
by Ryan O'Hare
02 February 2022
Findings from the UK’s world-leading human challenge study provide new insights into mild infections with SARS-CoV-2 in healthy young adults.
The collaborative study is the first in the world to perform detailed monitoring over the full course of COVID-19, from the moment a person first encounters SARS-CoV-2, throughout the infection to the point at which the virus is apparently eliminated.
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.
Among several key clinical insights, researchers found that symptoms start to develop very fast, 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 (LFTs) 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The findings, published on a pre-print server and which have not yet been peer-reviewed, detail the outcomes in 36 healthy, young participants with no immunity to the virus.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 in London, 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.
Professor Christopher Chiu, from the Department of Infectious Disease and 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.”
Clinical insights
In the trial, 36 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 hospitalized patient in the ISARIC4C study, 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.
Accurate timeline of infection
The study has also revealed some unique insights into the timeline of COVID-19, particularly during the very early period after virus exposure that cannot be looked at in other types of study, where patients are not identified until symptoms are noticed.
Among the 18 infected participants, the average time from first exposure to the virus to viral detection and early symptoms (incubation period) was 42 hours, significantly shorter than existing estimates, which put the average incubation period at 5-6 days.
Following this period there was a steep rise in the amount of virus (viral load) found in swabs taken from participants’ nose or throat.
These levels peaked at around five days into infection on average, but high levels of viable (infectious) virus were still picked up in lab tests up to nine days after inoculation on average, and up to a maximum of 12 days for some, supporting the isolation periods advocated in most guidelines.
There were also differences in where the most virus was found. While the virus was detected first in the throat, significantly earlier than in the nose (40 hours in the throat compared to 58 hours in the nose), levels were lower and peaked sooner in the throat.
Peak levels of virus were significantly higher in the nose than in the throat, indicating a potentially greater risk of virus being shed from the nose than the mouth. This highlights the importance of proper facemask use to cover both the mouth and nose.
Lateral flow tests
Importantly, lateral flow tests (LFTs) were shown to be a good indicator of whether someone was harbouring viable virus. Positive LFTs correlated well with lab-confirmed detection of virus from swabs throughout the course of infection, including in those who were asymptomatic. However, the tests were less effective in picking up lower levels of virus at the very start and end of infection.
This is the first study that has been able to provide detailed data on the early phase of infection, before and during the appearance of symptoms. While there is a possibility of missing infectious virus early in the course of infection, particularly if only the nose is tested, the researchers say these findings overall support continued use of LFTs to identify people likely to be infectious.
The study provides supportive evidence that LFTs can reliably predict when someone is unlikely to infect others and can come out of isolation, and that twice-weekly rapid tests would allow diagnosis before 70-80% of viable virus was generated during the course of infection.
“We found that overall, lateral flow tests correlate very well with the presence of infectious virus,” said Professor Chiu. “Even though in the first day or two they may be less sensitive, if you use them correctly and repeatedly, and act on them if they read positive, this will have a major impact on interrupting viral spread.”
...
‘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.
See the press release of this article
https://www.imperial.ac.uk/news/233514/covid-19-human-challenge-study-reveals-detailed/
---------------------------------------------------------------------------------
This preprint is under consideration at a Nature Portfolio Journal. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal...
Safety, tolerability and viral kinetics during SARS-CoV-2 human challenge
Ben Killingley, Alex Mann, Mariya Kalinova, Alison Boyers, Niluka Goonawardane, Jie Zhou, Kate Lindsell, Samanjit S. Hare, Jonathan Brown, Rebeeca Frise, Emma Smith, Claire Hopkins, Nicolas Noulin, Brandon Londt, Tom Wilkinson, Stephen Harden, Helen McShane, Mark Baillet, Anthony Gilbert, Michael Jacobs, Christine Charman, Priya Mande, Jonathan S. Nguyen-Van-Tam, Malcolm G. Semple, Robert C. Read, Neil M. Ferguson, Peter J. Openshaw, Garth Rapeport, Wendy S. Barclay, Andrew P. Catchpole, Christopher Chiu
DOI:
10.21203/rs.3.rs-1121993/v1
Download PDF
Abstract
To establish a novel SARS-CoV-2 human challenge model, 36 volunteers aged 18-29 years without evidence of previous infection or vaccination were inoculated with 10 TCID50 of a wild-type virus (SARS-CoV-2/human/GBR/484861/2020) intranasally. Two participants were excluded from per protocol analysis due to seroconversion between screening and inoculation. Eighteen (~53%) became infected, with viral load (VL) rising steeply and peaking at ~5 days post-inoculation. Virus was first detected in the throat but rose to significantly higher levels in the nose, peaking at ~8.87 log10 copies/ml (median, 95% CI [8.41,9.53). Viable virus was recoverable from the nose up to ~10 days post-inoculation, on average. There were no serious adverse events. Mild-to-moderate symptoms were reported by 16 (89%) infected individuals, beginning 2-4 days post-inoculation. Anosmia/dysosmia developed more gradually in 12 (67%) participants. No quantitative correlation was noted between VL and symptoms, with high VLs even in asymptomatic infection, followed by the development of serum spike-specific and neutralising antibodies. However, lateral flow results were strongly associated with viable virus and modelling showed that twice-weekly rapid tests could diagnose infection before 70-80% of viable virus had been generated. Thus, in this first SARS-CoV-2 human challenge study, no serious safety signals were detected and the detailed characteristics of early infection and their public health implications were shown. ClinicalTrials.gov identifier: NCT04865237.
...
https://www.researchsquare.com/article/rs-1121993/v1
COVID-19 human challenge study reveals detailed insights into infection
by Ryan O'Hare
02 February 2022
Findings from the UK’s world-leading human challenge study provide new insights into mild infections with SARS-CoV-2 in healthy young adults.
The collaborative study is the first in the world to perform detailed monitoring over the full course of COVID-19, from the moment a person first encounters SARS-CoV-2, throughout the infection to the point at which the virus is apparently eliminated.
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.
Among several key clinical insights, researchers found that symptoms start to develop very fast, 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 (LFTs) 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 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 in London, 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.
Professor Christopher Chiu, from the Department of Infectious Disease and 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.”
Clinical insights
In the trial, 36 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 hospitalized patient in the ISARIC4C study, 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.
Accurate timeline of infection
The study has also revealed some unique insights into the timeline of COVID-19, particularly during the very early period after virus exposure that cannot be looked at in other types of study, where patients are not identified until symptoms are noticed.
Among the 18 infected participants, the average time from first exposure to the virus to viral detection and early symptoms (incubation period) was 42 hours, significantly shorter than existing estimates, which put the average incubation period at 5-6 days.
Following this period there was a steep rise in the amount of virus (viral load) found in swabs taken from participants’ nose or throat.
These levels peaked at around five days into infection on average, but high levels of viable (infectious) virus were still picked up in lab tests up to nine days after inoculation on average, and up to a maximum of 12 days for some, supporting the isolation periods advocated in most guidelines.
There were also differences in where the most virus was found. While the virus was detected first in the throat, significantly earlier than in the nose (40 hours in the throat compared to 58 hours in the nose), levels were lower and peaked sooner in the throat.
Peak levels of virus were significantly higher in the nose than in the throat, indicating a potentially greater risk of virus being shed from the nose than the mouth. This highlights the importance of proper facemask use to cover both the mouth and nose.
Lateral flow tests
Importantly, lateral flow tests (LFTs) were shown to be a good indicator of whether someone was harbouring viable virus. Positive LFTs correlated well with lab-confirmed detection of virus from swabs throughout the course of infection, including in those who were asymptomatic. However, the tests were less effective in picking up lower levels of virus at the very start and end of infection.
This is the first study that has been able to provide detailed data on the early phase of infection, before and during the appearance of symptoms. While there is a possibility of missing infectious virus early in the course of infection, particularly if only the nose is tested, the researchers say these findings overall support continued use of LFTs to identify people likely to be infectious.
The study provides supportive evidence that LFTs can reliably predict when someone is unlikely to infect others and can come out of isolation, and that twice-weekly rapid tests would allow diagnosis before 70-80% of viable virus was generated during the course of infection.
“We found that overall, lateral flow tests correlate very well with the presence of infectious virus,” said Professor Chiu. “Even though in the first day or two they may be less sensitive, if you use them correctly and repeatedly, and act on them if they read positive, this will have a major impact on interrupting viral spread.”
...
‘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.
See the press release of this article
https://www.imperial.ac.uk/news/233514/covid-19-human-challenge-study-reveals-detailed/
---------------------------------------------------------------------------------
This preprint is under consideration at a Nature Portfolio Journal. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal...
Safety, tolerability and viral kinetics during SARS-CoV-2 human challenge
Ben Killingley, Alex Mann, Mariya Kalinova, Alison Boyers, Niluka Goonawardane, Jie Zhou, Kate Lindsell, Samanjit S. Hare, Jonathan Brown, Rebeeca Frise, Emma Smith, Claire Hopkins, Nicolas Noulin, Brandon Londt, Tom Wilkinson, Stephen Harden, Helen McShane, Mark Baillet, Anthony Gilbert, Michael Jacobs, Christine Charman, Priya Mande, Jonathan S. Nguyen-Van-Tam, Malcolm G. Semple, Robert C. Read, Neil M. Ferguson, Peter J. Openshaw, Garth Rapeport, Wendy S. Barclay, Andrew P. Catchpole, Christopher Chiu
DOI:
10.21203/rs.3.rs-1121993/v1
Download PDF
Abstract
To establish a novel SARS-CoV-2 human challenge model, 36 volunteers aged 18-29 years without evidence of previous infection or vaccination were inoculated with 10 TCID50 of a wild-type virus (SARS-CoV-2/human/GBR/484861/2020) intranasally. Two participants were excluded from per protocol analysis due to seroconversion between screening and inoculation. Eighteen (~53%) became infected, with viral load (VL) rising steeply and peaking at ~5 days post-inoculation. Virus was first detected in the throat but rose to significantly higher levels in the nose, peaking at ~8.87 log10 copies/ml (median, 95% CI [8.41,9.53). Viable virus was recoverable from the nose up to ~10 days post-inoculation, on average. There were no serious adverse events. Mild-to-moderate symptoms were reported by 16 (89%) infected individuals, beginning 2-4 days post-inoculation. Anosmia/dysosmia developed more gradually in 12 (67%) participants. No quantitative correlation was noted between VL and symptoms, with high VLs even in asymptomatic infection, followed by the development of serum spike-specific and neutralising antibodies. However, lateral flow results were strongly associated with viable virus and modelling showed that twice-weekly rapid tests could diagnose infection before 70-80% of viable virus had been generated. Thus, in this first SARS-CoV-2 human challenge study, no serious safety signals were detected and the detailed characteristics of early infection and their public health implications were shown. ClinicalTrials.gov identifier: NCT04865237.
...
https://www.researchsquare.com/article/rs-1121993/v1
