Experimental SARS-CoV-2 human challenge in young adults

Rationale: To establish a novel SARS-CoV-2 human challenge model enabling controlled investigation of pathogenesis, correlates of protection and efficacy testing of interventions. Method(s): Thirty-six healthy 18-29-year-old subjects, without evidence of previous infection or vaccination, received 10 TCID50 of a wild-type virus (SARS-CoV-2/human/GBR/484861/2020) intranasally. Following inoculation, subjects resided in a high-containment quarantine, with 24-hour medical monitoring. The study's main objectives were to identify a virus dose that induced well-tolerated infection in >50% of subjects and assess virus and symptoms over time. AEs and longitudinal disease profiles are presented. Result(s): Eighteen of thirty-four evaluable (~53%) subjects became infected and developed serum antibodies. Viral load rose steeply and peaked ~5 days post-inoculation (PI). Virus was first detected in the throat but rose 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 PI, on average. Mild-to-moderate symptoms were reported by 16 (89%) infected subjects, beginning 2-4 days PI. Anosmia or dysosmia developed in 15 (83%) subjects. Results from lateral flow tests were associated with viable virus and modelling showed that twice-weekly rapid antigen tests could diagnose infection before 70-80% of viable virus had been generated. There were no overt lung function changes, CT abnormalities, or SAEs. Conclusion(s): This novel SARS-CoV-2 challenge of 18-29-year-olds was considered safe. Viral kinetics over the course of primary infection was established, with implications for public health recommendations and strategies to impact transmission.

A Brief History of Human Challenge Studies (1900-2021) Emphasising the Virology, Regulatory and Ethical Requirements, Raison D'etre, Ethnography, Selection of Volunteers and Unit Design.

Venetian quarantine 400 years ago was an important public health measure. Since 1900 this has been refined to include "challenge" or deliberate infection with pathogens be they viruses, bacteria, or parasites. Our focus is virology and ranges from the early experiments in Cuba with Yellow Fever Virus to the most widespread pathogen of our current times, COVID-19. The latter has so far caused over four million deaths worldwide and 190 million cases of the disease. Quarantine and challenge were also used to investigate the Spanish Influenza of 1918 which caused over 100 million deaths. We consider here the merits of the approach, that is the speeding up of knowledge in a practical sense leading to the more rapid licensing of vaccines and antimicrobials. At the core of quarantine and challenge initiatives is the design of the unit to allow safe confinement of the pathogen and protection of the staff. Most important though is the safety of volunteers. We can see now, as in 1900, that members of our society are prepared and willing to engage in these experiments for the public good. Our ethnology study, where the investigator observed the experiment from within the quarantine, gave us the first indication of changing attitudes amongst volunteers whilst in quarantine. These quarantine experiments, referred to as challenge studies, human infection studies, or "controlled human infection models" involve thousands of clinical samples taken over two to three weeks and can provide a wealth of immunological and molecular data on the infection itself and could allow the discovery of new targets for vaccines and therapeutics. The Yellow Fever studies from 121 years ago gave the impetus for development of a successful vaccine still used today whilst also uncovering the nature of the Yellow Fever agent, namely that it was a virus. We outline how carefully these experiments are approached and the necessity to have high quality units with self-contained air-flow along with extensive personal protective equipment for nursing and medical staff. Most important is the employment of highly trained scientific, medical and nursing staff. We face a future of emerging pathogens driven by the increasing global population, deforestation, climate change, antibiotic resistance and increased global travel. These emerging pathogens may be pathogens we currently are not aware of or have not caused outbreaks historically but could also be mutated forms of known pathogens including viruses such as influenza (H7N9, H5N1 etc.) and coronaviruses. This calls for challenge studies to be part of future pandemic preparedness as an additional tool to assist with the rapid development of broad-spectrum antimicrobials, immunomodulators and new vaccines.