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Individuals exposed to SARS-CoV-2 became infectious after just 2 days, which is earlier than scientists originally estimated, according to results from the first human challenge trial investigating COVID-19.

In the study of 36 young and healthy subjects who were deliberately infected with SARS-CoV-2, viral shedding and symptoms began around 2 days post-inoculation, with viral load peaking at 5 days, reported Christopher Chiu, MD, of Imperial College London, and colleagues. The researchers published these findings, which have not yet been peer-reviewed, on the preprint server .

"Whilst the incubation period from the estimated time of natural exposure to perceived symptom onset has previously been estimated as ~5 days, this best aligns with peak symptoms and is longer than the true incubation period," the researchers wrote. They noted that because viable virus was still detectable at 10 days after exposure, the data support the idea that isolation periods should last at least 10 days after symptom onset.

Virus was first detected in the throat, but rose to significantly higher levels in the nose. The team did not observe a correlation between the level of viral load and symptoms.

Additionally, the majority of infected participants reported mild-to-moderate cold-like symptoms that were limited to the upper respiratory tract, including stuffy or runny nose, sneezing, and sore throat. Loss of smell was also common. The researchers did not report any major safety concerns or adverse events.

"Although these first-in-human data do not preclude rare adverse events that can only be detected in larger-scale studies, our results indicate that human challenge with SARS-CoV-2 is consistent with natural infection in healthy young adults, having caused no serious unexpected consequences and therefore supporting further development and expansion," Chiu and co-authors wrote.

In this trial, the team analyzed SARS-CoV-2 infections in 36 participants ages 18 to 29 (average 22 years). Two individuals were excluded due to seroconversion between screening and analysis. Participants were screened for known risk factors of severe COVID-19, including comorbidities, low or high body mass index, abnormal safety blood tests, spirometry, and chest radiography.

Of note, the researchers used the original SARS-CoV-2 strain (pre-Alpha) for their study.

"While there are differences in transmissibility due to the emergence of variants, such as Delta and Omicron, fundamentally, this is the same disease," Chiu said in a . "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."

All participants -- who had no previous immunity from vaccination or infection -- were inoculated with the virus via nasal drops. The virus was taken from someone with COVID-19 illness early on in the pandemic, before any notable variants had emerged. After inoculation, individuals were quarantined for at least 14 days, or until they met discharge criteria. The researchers said they plan to follow participants for 1 year to assess long-term symptoms.

Of the subjects inoculated with SARS-CoV-2, 18 became infected, as detected by PCR test.

The mean time from initial exposure to detection and early symptoms was 42 hours. On average, virus was detected in the throat after 40 hours, and in the nose after 58 hours, but viral load was higher in the nose at its peak (median ~8.87 log₁₀ copies/ml, 95% CI 8.41-9.53).

Among the infected participants, approximately 89% experienced mild-to-moderate cold-like symptoms, and 39% developed a fever. Some also had headaches, muscle aches, and fatigue. Peak symptoms occurred at around 5 days, which was aligned with peak viral load in the nose. But despite the temporal association between nasal viral load and symptoms, there was no correlation between the amount of viral shedding and symptom score, the researchers said.

Smell disturbance was common, occurring in two-thirds of the infected participants. Nine individuals experienced complete loss of smell, but nearly all of these participants improved by day-28 post-inoculation. Up to 180 days after exposure, five participants still had some smell disturbance, and only one had prolonged smell disturbance after this time.

In an analysis of testing, the researchers found that lateral flow tests were a good predictor of contagiousness, and "can be highly effective as a trigger for interventions to interrupt transmission." Modeling showed that rapid testing twice weekly can diagnose infection before 70-80% of viable virus has been generated.

Challenge trials allow researchers to assess immunological responses, transmission dynamics, and infectious shedding after exposure, but some have called attention to complex ethical considerations.

In addition to this study, the is also conducting a human challenge trial that is investigating reinfection among people who have already had COVID-19.

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