Table 4. Risks associated with natural infection during trial period.

Risk	Inherent risk score		Total inherent risk	Controls	Residual risk score		Total risk post control
	Likelihood	Impact			Likelihood	Impact
Mixed sex infection in trial volunteers	Likely	Moderate *	12	1)  Avoidance of fresh water bodies during trial period 2)  Pilot survey to establish feasibility of fresh water avoidance 3)  Selection of trial volunteers with low risk of contracting natural infection 4)  Abrogation of infection as soon as the trial endpoint has been reached (e.g. CAA> 1 pg/mL) 5)  Displacement of volunteers to non-endemic setting with excellent water and sanitation facilities	Rare	Moderate	3
Mixed sex infection in trial volunteers leading to release of Puerto Rican strain into environment	Likely	Moderate	12	1)  Full clearance of infections before trial starts 2)  Continuous screening for egg production 3)  Abrogation of infection as soon as the trial endpoint has been reached (e.g. CAA> 1 pg/mL) 4)  Displacement of volunteers to non-endemic setting with excellent water and sanitation facilities.	Rare	Moderate	3

Likelihood was scored as almost certain/common, 5; likely, 4; possible, 3; unlikely, 2; rare, 1. Impact was scored as critical, 5; major, 4; moderate, 3; minor, 2; insignificant 1.

* The impact of natural co-infection on morbidity is classed as moderate (rather than major or critical) since volunteers who acquire such an infection would presumably be at risk of mixed-sex natural infections as a result of their usual behaviours and occupation. The risk of egg-related morbidity due to the presence of male worms from the CHI-S would therefore add little to the risk resulting from exposure to natural infection. CAA - circulating anodic antigen