UK SARS-CoV-2 Human Challenge Study Shows That Individuals Who Were Deliberately Infected With The Virus Only Displayed Mild Symptoms
: A British SARS-CoV-2 human challenge study led by Imperial College London and the commercial clinical-research organization hVIVO Services Ltd-UK that was also supported by researchers from various other hospitals and universities in the United Kingdom showed that young healthy individuals who were deliberately infected with the SARS-CoV-2 virus only displayed mild symptoms. https://clinicaltrials.gov/ct2/show/NCT04865237
In order 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.
The study findings showed that 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 viral load and symptoms, with high viral load even in asymptomatic infection, followed by the development of serum spike-specific and neutralizing 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.
Hence 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.
The SARS-CoV-2 Research
findings are useful in terms of determining the correct dosing when developing vaccines or other therapeutics.
The study findings were published on a preprint server: Research Square and are being peer reviewed for publication into the journal: Nature Reports.
In the study trial, healthy, young people who were intentionally exposed to the SARS-CoV-2 coronavirus developed mild symptoms but some remained asymptomatic in this first-of-its-kind COVID-19 human challenge study.
It should be noted that such clinical trials present a unique opportunity to study viral infections in detail from start to finish, but are controversial because of the risks they pose to participants.
The British study of 34 individuals, aged 18–30, shows that such trials can be done safely.
The researchers involved in the trial says that the trail lays
the precedence and groundwork for such more studies but involving more in-depth studies of vaccines, antivirals and immune responses to SARS-CoV-2 infection.
The study findings showed that nearly half of the participants who received a low dose of virus did not become infected, while some of those who became infected had no symptoms. Participants who did develop COVID reported mild to moderate symptoms, including sore throats, runny noses and loss of smell and taste.
Dr Miles Davenport, an immunologist at the University of New South Wales-Australia, who was not involved in the study commented, “Such a study presents a potentially important advance in how to assess future vaccine and drug efficacy. This opens a number of important possibilities to study immunity in a controlled environment.”
Some researchers and key members of the scientific community however questioned whether the insights yielded from such a research so far are significant enough to justify the risks to participants, including the potential for long-term side-effects.
Dr Seema Shah, a bioethicist at Lurie Children’s Hospital and Northwestern University in Chicago, Illinois told media, “In my mind, it’s still not entirely clear whether these studies are ethically justified, and I’m waiting to see what else they’ve found.”
Such human-challenge studies are however not new and have been used for decades to study influenza, malaria and numerous other infections.
While some scientists argued for conducting such trials with SARS-CoV-2 in the early months of the pandemic, as a way to accelerate development of COVID-19 vaccines, many saw challenge trials as too risky to justify, when so little was known about the pandemic virus and few, if any, effective treatments were available.
The first participants were exposed in early 2021 and volunteers received about US$6,200 for their participation, which involved at least two weeks of quarantine at a high-level isolation unit at the Royal Free Hospital in London.
The initial participants received a very low dose, roughly equivalent to the amount of virus in a single respiratory droplet, of a virus strain that circulated in the United Kingdom in early 2020.
hVIVO chief scientific officer Dr Andrew Catchpole said, “Many scientists initially thought that a higher dose would be needed to infect a majority of participants. But the starting dose successfully infected more than half of participants.”
He added, “Surprisingly the virus grew incredibly rapidly in those who became infected. Individuals in the study developed their first symptoms and tested positive, using sensitive PCR tests, less than two days after exposure, on average. That contrasts with the roughly five-day ‘incubation period’ that real-world epidemiological studies have documented between a probable exposure and symptoms. High viral levels persisted for an average of 9 days, and up to 12.”
The study findings showed that the most common symptoms were typical of other respiratory infections such as sore throats, runny noses and sneezing. Fever was less common, and no one developed the persistent cough that had been used as a hallmark of COVID-19.
However, about 70% of infected participants lost their senses of smell or taste which is a key COVID-19 signature, to varying degrees.
This loss of sense persisted for more than 6 months in five participants and more than 9 months in one.
Interestingly certain individuals in the study no symptoms at all, but had the same high viral levels in their upper airways that lasted as long as they did for others who exhibited symptoms.
The study team wants to understand why so many individuals did not become infected, despite being exposed to SARS-CoV-2.
According to Dr Christopher Chiu, a physician-scientist at Imperial College London, who led the study, “It was noted that some of these participants harbored very low levels of virus for short periods of time, suggesting that their immune systems were actively fighting the virus.”
The study team said that future studies of the challenge-trial participants will attempt to explain why.
Past studies have suggested that common-cold-causing coronaviruses might confer protection to COVID in some individuals.
Yet another possibility is that some people make potent ‘innate’ immune responses that don’t require a previous encounter with a pathogen or close relative.
Dr Chiu added, “We’re trying to understand the fundamentals of why people are protected even though they’ve not been exposed to a virus like this before.”
The study team plans to launch another challenge trial that will expose vaccinated individuals to the Delta SARS-CoV-2 variant.
That planned study will attempt to identify immune factors that protect individuals from ‘breakthrough’ infection after vaccination.
However, for the time being, SARS-CoV-2 challenge studies will likely enroll only individuals at very low risk of severe disease, says Dr Catchpole.
Dr Chiu added, “As scientists gain experience running COVID challenge trials safely, it may be possible to expand them to involve at-risk groups, such as older individuals.”
Dr Matt Memoli, an infectious-disease physician and virologist at the US National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland who was not involved in the study commented, “The study looked safe and well-conducted. It should make some people more comfortable with doing more SARS-CoV-2 challenge trials. Such trials could prove useful in the development of vaccines that protect against a broad range of coronaviruses, and not just SARS-CoV-2.”
“The study confirms insights gained from other COVID-19 studies, such as the swift rise in viral levels. But it has not eliminated her concerns about exposing people to a strain of SARS-CoV-2 that hasn’t been weakened. More than one-a quarter of participants who became infected had problems with smell or taste that lasted more than six months,” commented Dr Meagan Deming, a vaccine scientist and virologist at the University of Maryland in Baltimore.
Dr Shah, the bioethicist further commented, “Although mild symptoms and loss of sense sounds like they were the most serious risk that materialized, we do not know the long-term effects or long COVID conditions that might arise in the future.”
She added, “This is the one to keep an eye on. Moreover, do the insights gleaned from the study so far justify such risks. This study reads like a promissory note that ultimately, in conjunction with the other research they’re doing, there will eventually be substantial scientific and social benefits. But we’re not really seeing that yet.”
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