Uncovering immunological mechanisms of protection from infection and vaccination in humans

Vaccines are among the most effective medical interventions available. The development of vaccines is a complex undertaking, involving many steps, that typically unfolds over a period of several years before a candidate vaccine is licensed. Key issues that need to be addressed early in this process are the identification of possible immunological correlates of protection in humans and the persistence of effective memory and effector responses elicited by immunization in multiple age strata.

Mass cytometry offers an unparalleled ability to identify associations of defined specific immune responses with protection, due to its ability to simultaneously measure many parameters per cell (currently 50-plus) in millions of individual cells. This is a great advantage for addressing the complex interactions among the myriad cell types involved in immune responses, particularly when limited numbers of cells are available.

In this presentation I will use examples from work performed in my group over the past few years in which mass cytometry helped us advance the fields of vaccine development and pathogen-host interactions. To this end, I will focus this talk on studies with Salmonella typhi (S. typhi), the causative agent of typhoid fever, an infectious disease of great public health importance. I will discuss how we have successfully used mass cytometry to (1) identify the key role that T regulatory cells appear to play in the development of typhoid disease following an oral challenge with wild-type S. typhi in humans, (2) investigate in depth the differences observed in T cell mediated immunity elicited by oral immunization with the licensed Ty21a attenuated typhoid fever vaccine in children and adults, and (3) uncover early cell type-specific epigenetic modifications elicited in human gut cells following ex vivo exposure to S. typhi, which are likely to influence downstream immune responses in the gut mucosa microenvironment.