Table 2.

A comparison of the key factors for clinical trials that are reliant on natural exposure to, or a direct challenge with, SARS-CoV-2

	Natural field infection	Controlled human infection model
Infecting pathogen	Unknown	Sequenced SARS-CoV-2 made to good manufacturing practices
Infecting dose	Unknown	Predetermined and standardised
Timing of infection	Unknown	Predetermined
Risk to participant	No increased risk above population level	Potentially lower*
Numbers of participants required	High	Low
Participant involvement	Minimal	Likely to require an extended stay in study facility
Public health implications	NA	Risk of onward transmission
Confounders	Participant behaviour and risk factors; changes in public health policy; changes in transmission dynamics during the study	NA
Generalisability	Dependant on study size	Unclear, especially with reference to specific groups who are at high risk of severe disease

NA=not applicable. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2.

^*The risk of infection in a controlled human infection model trial could be lower than naturally acquired infection as individuals who are at low risk of severe disease can be selected (eg, aged 18–25 years), the minimum dose of virus needed to acquire infection can be administered, individuals can be carefully monitored, and rescue therapies can be given if needed.