Human challenge study gives insights into COVID-19

Findings from the UK’s world-leading human challenge study provide new insights into mild infections with SARS-CoV-2 in 36 healthy, young volunteers with no immunity to the virus. Those fitting the study demographic are believed to be major drivers of the pandemic and such studies, thought to be representative of ‘mild’ infection, allow detailed investigation of the factors responsible for infection and pandemic spread.

The Human Challenge Programme was a partnership between Imperial College London, the Vaccine Taskforce and Department of Health and Social Care (DHSC), and the Royal Free London NHS Foundation Trust, and Niche Science & Technology Ltd. was involved in managing the project. The 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.

The collaborative study was the first to provide detailed observations over the full course of COVID-19 infection, from the moment of first exposure to SARS-CoV-2, throughout the infection to the point when the virus is beaten by our immune system. 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.

Among the clinical insights derived from the observations, researchers noted that symptoms emerge quickly, about 2 days after virus contact (markedly sooner than existing estimates, of 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. Infectious virus peaked about 5 days into infection, when the virus is most abundant in the nose than the throat. The study highlighted how lateral flow tests (LFTs) are a good indicator of the presence of infectious virus, effectively whether an individual is likely to transmit the virus.

The study has yet to undergo peer-review, only having been published as a pre-print. However, one of the most important findings was that there were no severe symptoms or clinical concerns in with the challenge infection model investigating SARS-CoV-2. This is important as many had been concerned about the ethics of exposing healthy subjects to a virus with unknown health risks [see comments].

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, 13 infected volunteers reported losing their sense of smell, but this returned to normal within 90 days in all but three participants

The data reveals some interesting clinical insights, particularly around the short incubation period of the virus, extremely high viral shedding from the nose, and the utility of lateral flow tests, with potential implications for public health. High levels of viable (infectious) virus were still detectable up to 9 days after inoculation, extending out to 12 days for some, supporting the isolation periods advocated in most guidelines.

The authors highlight that while the model is a safe and effective approximation of real-world infection in young adults, the small sample size, reduced diversity of infected volunteers and limited follow up period may restrict the findings. The study used virus from very early in the pandemic, an older strain obtained from a hospitalized patient in the ISARIC4C study, prior to the emergence of the Alpha variant. 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.

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. However, LFT tests were less effective in picking up lower levels of virus at the very start and end of infection. According to the researchers, the data also underline the importance of wearing a face covering over the mouth and nose, in crowded, enclosed spaces.