Symptoms and adverse events in controlled human infection models

Karen Götz¹Poleta Luga^1,2Jörg Rengel¹Mei Masur¹Marcela Juárez-Hernández¹Isabelle Bekeredjian-Ding^1,2*

• ¹Paul-Ehrlich-Institut (PEI), Langen, Germany
• ²Institute of Medical Microbiology and Hospital Hygiene, University of Marburg, Marburg, Germany

The potential and positioning of controlled human infection models (CHIM) and human challenge trials (HCT) in the investigation of infectious pathogens and efficacy of new anti-infectives or vaccines is under evaluation. CHIM and HCT can provide supporting data for decision making in development of new medicines ("fast failure"). However, it is important to consider that, like in any phase 1 trial, CHIM volunteers have no direct health benefit. Approval by an ethics or regulatory board implies cautious evaluation of risk and potential safety issues. Here, we chose a syndromic approach to summarize CHIM and HCT adverse events (AE). AE were grouped by disease entities, e.g., enteric, respiratory, vector-borne and parasitic infections. The analysis concludes that severe AE are rare. It confirms that AE reflect symptoms of CHIM infections and are less prevalent in CHIM intended for induction of carriage. Furthermore, the number of subjects affected reflects the attack rate and individual predisposition. Rarely, AE affect the study subjects' daily activities, from impairing and preventing the daily routine to emergency room visits or hospitalizations. Nevertheless, while AE guide ethical and regulatory considerations, symptoms are needed as endpoints for evaluation of the efficacy of drugs or vaccines. Finally, we observe lack of harmonization on reporting and grading of AE. This reveals an eminent need for a reporting structure that allows accessibility and comparability of data sets.