The first findings from a landmark study following healthy adults deliberately infected with SARS-CoV-2 have revealed new and unexpected insights into the earliest stages of COVID-19. The data indicates the virus’s incubation period is shorter than expected and rapid antigen tests are incredibly effective at identifying people when they are most infectious.
In what are known as “human challenge studies,” scientists have intentionally infected healthy adults with pathogens for well over a century. Although ethically controversial, human challenge studies have informed medical innovations for a number of viral infections, including cholera, typhoid and influenza.
Early in 2020, soon after the novel coronavirus SARS-CoV-2 emerged, some researchers began calling for human challenge studies to help accelerate insights into this new virus. Progress on SARS-CoV-2 challenge studies was slow as many were cautious to approve this kind of research. It wasn’t until the beginning of 2021 that the first human challenge trial commenced, and now one year later we are finally seeing preliminary data from those initial studies.
This first study covers 35 healthy volunteers aged between 18 and 29 with no history of previous SARS-CoV-2 infection. The trial utilized a sample of one of the first strains of SARS-CoV-2 taken from a patient early in the pandemic before more concerning variants emerged.
Because this was the first SARS-CoV-2 human challenge trial, an extremely low dose of the virus was tested. A single drop of viral material was administered nasally to all volunteers. The amount of virus used in the study was 10 times lower than the amount recommended by an independent advisory panel.
Despite the extraordinarily low dose administered, the researchers still saw 53 percent of the cohort developing a PCR-confirmed SARS-CoV-2 infection. Of the 18 positive infections in the study, only two presented with no symptoms.
However, those two asymptomatic subjects consistently displayed significant viral levels in their upper airways similar to those symptomatic subjects. This suggests asymptomatic infections can be as infectious as symptomatic infections.
Interestingly, the study found that the time from initial viral exposure to first symptoms was on average only 42 hours. This is significantly shorter than the three-to-five-day incubation period initially calculated for this original strain of SARS-CoV-2.
The virus was first detected in the throats of volunteers before moving up to the nose at around the three-day point after exposure. Viral levels were seen to peak at higher volumes in the nose compared to the throat, leading the researchers to indicate shedding from the nose to be a greater threat to others than shedding from the throat.
“With virus present at significantly higher titres in the nose than the throat, these data provide clear evidence that emphasizes the critical importance of wearing face coverings over the nose as well as mouth,” the researchers write in the study.
Of the 16 symptomatic subjects in the study, a variety of expected symptoms were detected, including headache, sore throat, malaise and rhinitis. Seven subjects developed fever and around half the symptomatic cohort experienced complete loss of smell.
Five symptomatic subjects experienced signs of long COVID, primarily a loss of smell that persisted for over six months. At a 12-month follow-up all symptoms had dissipated in all subjects.
One of the most immediately valuable findings in the study was the correlation between positive rapid antigen test results and high viral loads. Chief investigator on the trial Christopher Chiu says these tests, known as lateral flow tests in the United Kingdom, are very effective at identifying when a person is most infectious with this virus.
“We found that overall, lateral flow tests correlate very well with the presence of infectious virus,” said 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.”
Chiu pointed out that, although this study was conducted using the original strain of the virus, the findings still offer important insights into the nature of SARS-CoV-2 infections that will apply to more recently circulating variants.
“While there are differences in transmissibility due to the emergence of variants, such as Delta and Omicron, fundamentally, this is the same disease and the same factors will be responsible for protection against it,” said Chiu. “From the point of view of virus transmission related to the very high viral loads, we are likely if anything to be underestimating infectivity because we were using an older strain of the virus. With a newer strain, there might be differences in terms of size of response, but ultimately we expect our study to be fundamentally representative of this kind of infection.”
Moving forward, perhaps the biggest outcome from this first-of-its-kind study is the demonstration of how challenge studies with SARS-CoV-2 can be safely conducted. Doug Jones, from the British Society of Immunology, says these kinds of challenge studies will be increasingly important for the development of COVID-19 therapeutics and vaccines in the future.
“This is the first step in developing human challenge studies on COVID-19,” said Jones. “While the main aim of this study was to establish a safe and successful protocol to build on in the future, the significance of it should not be underestimated. In the longer-term, the hope is that these findings will now open up a new research avenue to develop a platform that will allow us to speed up the development of new vaccines, antivirals and diagnostics against COVID-19.”
The new study is yet to be peer-reviewed and published in a journal but it is available as a preprint on Research Square.