What Researchers Learned From Deliberately Giving People Covid

About half of the volunteers in the study became infected, but had relatively mild symptoms, detectable within 2 days, which lasted an average of 9 days. 25% of those infected had lingering problems with smell or taste that lasted 6 months or more. 

The strain used to infect them was from the UK in 2020, so not the milder omicron variant. What researchers now hope to learn is why some became infected and some didn't, the expectation being that some sort of natural immunity can be identified whose components can be isolated and perhaps turned into a vaccine or medical treatment. JL

Ewen Callaway reports in Nature:

Healthy, young people who were intentionally exposed to SARS-CoV-2 developed mild symptoms - if any at all. The first participants received a very low dose  - a single respiratory droplet from a UK variant in early 2020. The starting dose successfully infected more than half of participants. The virus grew incredibly rapidly in those who became infected; less than two days after exposure, on average. That contrasts with the five-day ‘incubation period’ real-world. Viral levels persisted for an average of 9 days. 25% who became infected had problems with smell or taste that lasted more than six months.

Healthy, young people who were intentionally exposed to the SARS-CoV-2 coronavirus developed mild symptoms — if any at all — finds a first-of-its-kind COVID-19 human challenge study. Such 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 UK study of 34 individuals, aged 18–30, shows that such trials can be done safely, say scientists, and lays the groundwork for more in-depth studies of vaccines, antivirals and immune responses to SARS-CoV-2 infection. The results were posted¹ on 2 February to the Research Square preprint server and have not been peer-reviewed.

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.

“It presents a potentially important advance in how to assess future vaccine and drug efficacy,” says Miles Davenport, an immunologist at the University of New South Wales in Sydney, Australia, who was not involved in the study. “This opens a number of important possibilities to study immunity in a controlled environment.”

However, some researchers question whether the insights yielded from the study so far are significant enough to justify the risks to participants, including the potential for long-term side-effects. “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,” says Seema Shah, a bioethicist at Lurie Children’s Hospital and Northwestern University in Chicago, Illinois.

Finding the dose

Human-challenge studies have been used for decades to study influenza, malaria and numerous other infections. Some researchers 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. But others 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 challenge trial was conducted in London.Credit: hVIVO

The UK trial, led by researchers at Imperial College London and a Dublin-based commercial clinical-research organization called Open Orphan and its subsidiary hVIVO, was announced in October 2020, and the first participants were exposed in early 2021. Volunteers received £4,565 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 first 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. Researchers anticipated a higher dose would be needed to infect a majority of participants, says hVIVO chief scientific officer Andrew Catchpole. But the starting dose successfully infected more than half of participants.

The virus grew incredibly rapidly in those who became infected. People 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 most common symptoms were typical of other respiratory infections: 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, says Catchpole. 70% of infected participants lost their senses of smell or taste — another COVID-19 signature — to varying degrees. Such problems persisted for more than 6 months in five participants and more than 9 months in one. Some people developed 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.

Researchers involved in the study want to understand why so many people did not become infected, despite being exposed to SARS-CoV-2. Some of these participants harboured very low levels of virus for short periods of time, suggesting that their immune systems were actively fighting the virus, says Christopher Chiu, a physician-scientist at Imperial College London, who led the study.

Future studies of the challenge-trial participants will attempt to explain why. Previous research has suggested that common-cold-causing coronaviruses might confer protection to COVID in some people. Another possibility is that some people make potent ‘innate’ immune responses that don’t require a previous encounter with a pathogen or close relative. “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,” Chiu adds.

A micrograph of SARS-CoV-2 virus particles (gold).Credit: NIAID (CC BY 2.0)

His team plans to launch another challenge trial that will expose vaccinated people to the Delta SARS-CoV-2 variant. That study will attempt to identify immune factors that protect people from ‘breakthrough’ infection after vaccination. For the time being, SARS-CoV-2 challenge studies will likely enroll only people at very low risk of severe disease, says Catchpole. But as researchers gain experience running COVID challenge trials safely, it may be possible to expand them to involve at-risk groups, such as older people, Chiu adds.

Concerns linger

The study looked safe and well-conducted, says Matt Memoli, an infectious-disease physician and virologist at the US National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland.

It should make some people more comfortable with doing more SARS-CoV-2 challenge trials, he adds. Such trials could prove useful in the development of vaccines that protect against a broad range of coronaviruses, and not just SARS-CoV-2, he adds.

Meagan Deming, a vaccine scientist and virologist at the University of Maryland in Baltimore, says 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, she notes.

“It sounds like this is the most serious risk that materialized. This is the one to keep an eye on,” adds Shah. Moreover, she questions whether 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.”