Principles of Immunotherapeutic Drug Discovery for Severe Infections Using Extreme Phenotypes

Therapeutically modifying host responses in severe infection is an unmet need in critical care, either to augment pathogen clearance or limit immunopathology. Drug discovery in this space is impeded by the complexity of immune responses during infection. Identifying and studying extreme infection phenotypes is an emerging approach to negotiate this problem: by amplifying biological signal over noise, this can expedite the discovery of host determinants of severe disease or protection. Examples discussed in this article include critical Covid-19, HIV elite controllers, inborn errors of interferon gamma immunity, hypervirulent pathogen variants, and sepsis hyper-inflammatory and immunoparalysis subphenotypes.