Coronavirus disease 2019 (COVID-19) is a complex clinical syndrome caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite extensive research into severe illness in hospitalized patients and many large studies leading to the approval of vaccines and antivirals, the global spread of SARS-CoV-2 continues and, in fact, is accelerating in many regions.
Infections are typically mild or asymptomatic in younger people, but are likely to drive community transmission and the detailed time course of infection and infectivity in this setting has not been fully elucidated.
Deliberate human infection of low-risk volunteers allows accurate longitudinal measurement of viral kinetics, immune responses, transmission dynamics, and duration of infectious shedding following a fixed dose of well-characterized virus.
Under these strictly controlled conditions , host factors leading to differences in clinical outcome can be tested and robustly inferred. While human infection challenge has been attempted during previous pandemics, none have been successfully established and there are no recent reports of human challenge by coronaviruses (including SARS-CoV-).
Summary
To establish a new model of human exposure to SARS-CoV-2, 36 volunteers aged 18 to 29 years without evidence of previous infection or vaccination were inoculated with 10 TCID50 of a wild-type virus (SARSCoV-2/human/GBR/ 484861/2020) intranasally.
Two participants were excluded from per-protocol analysis due to seroconversion between screening and inoculation.
Eighteen (~53%) became infected, and the viral load (VL) increased abruptly and peaked ~ 5 days after inoculation.
The virus was first detected in the throat, but increased 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 after inoculation, on average.
There were no serious adverse events. 16 (89%) infected people reported mild to moderate symptoms, starting 2 to 4 days after inoculation.
Anosmia/dysosmia developed more gradually in 12 (67%) participants.
No quantitative correlation was observed between VL and symptoms, with high VL even in asymptomatic infections, followed by the development of serum spike-specific and neutralizing antibodies.
However, the lateral flow results were strongly associated with viable virus and the model showed that twice-weekly rapid testing could diagnose infection before 70-80% of viable virus was generated.
Therefore, in this first human challenge study with SARS-CoV-2, no serious safety signals were detected and the detailed characteristics of early infection and its implications for public health were shown.
Discussion
Here we report the virological and clinical results of the first SARS-CoV-2 human challenge study. At a low inoculum dose of 10 TCID50, robust viral replication was observed in 53% of seronegative participants.
After an incubation period of <2 days, viral loads (VL) increased rapidly, reached high levels, and continued for more than a week.
Symptoms were present in 89% of infected individuals but, despite high VLs, were consistently mild to moderate, transient , and efficiently limited to the upper respiratory tract .
Anosmia /dysosmia was common, occurred later than other symptoms, and resolved without treatment in most participants within 90 days. In those with residual olfactory impairment, their sense of smell improved steadily over the follow-up period, consistent with the good long-term prognosis observed in community cases.
There was no evidence of lung disease in infected participants based on clinical and radiological evaluations.
Although these first human data do not exclude 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, without having caused serious consequences. unexpected and therefore support further development and expansion.
This first report focuses on safety, tolerability and virological responses, but the uniquely controlled nature of the model will also allow robust identification of host factors present at the time of inoculation and associated with protection in those individuals who resisted the infection.
Therefore, analysis of local and systemic immune markers (including antibodies, T cells, and potentially reactive soluble mediators) from this SARS-CoV-2 human exposure study that may explain these differences in susceptibility is ongoing.
Having demonstrated this approach using a prototypical wild-type strain , further challenge studies are now underway in which previously infected and vaccinated volunteers will be challenged with increasing doses of inoculum and/or viral variants to investigate the interaction between the virus and host factors that influence clinical outcome.
Together, these studies will optimize the platform for rapid evaluation of vaccines, antivirals, and diagnostics by generating efficacy data early during clinical development and avoiding the uncertainties of studies that require ongoing community transmission.
ClinicalTrials.gov identifier: NCT04865237.
