PROJECT SUMMARY
Most pathogens enter the body at mucosal surfaces, yet, to date, the majority of licensed vaccines are injected
parenterally, predominantly intramuscularly. While excellent at eliciting systemic immunity, they do not always
induce the required mucosal immune responses. This highlights a gap in our understanding of how non-mucosal
immunization might be manipulated to elicit mucosal immune responses and how such knowledge could be
exploited to create better vaccines against mucosal pathogens. Defining the role that adjuvants play in this
response is key to developing such vaccines; however, the mechanisms that dictate adjuvant driven mucosal
antibody and cellular immune responses are not well understood. Our published work and preliminary
experiments using major histocompatibility complex class I (MHCI) and II (MHCII) and B cell tetramers to
examine mucosal immune responses after intradermal immunization with a novel detoxified bacterial ADP-
ribosylating enterotoxin, called dmLT, demonstrate that we can retarget the endogenous T and B cell immune
responses to the lung, intestinal mucosa, and female reproductive tract (FRT). When dmLT is combined with a
safe, bacterial-derived outer membrane vesicle (OMV) adjuvant, CD4 T cell numbers and vaccine-specific
antibodies and B cells are even further increased. Simultaneously, OMV adjuvant induces significant expansion
of vaccine-specific CD8 T cells. Furthermore, immunization with dmLT- or OMV-adjuvanted vaccines elicits
protection against bacterial infections in the lung and gut. These results lead us to hypothesize that intradermal
immunization with combined dmLT plus OMVs will drive antigen-specific B cells and T cells to the mucosa and
enhance vaccine protection against mucosal pathogens. We propose to: 1) determine how intradermal
immunization with dmLT combined with OMV adjuvant directs 1) T cells and 2) B cells to mucosal tissue and
whether these cells are bona fide tissue resident memory cells. In parallel, we will 3) examine if immunization
with dmLT-OMV adjuvanted vaccines is protective against mucosal viral and bacterial infections in the lung, gut
and FRT. This investigation will provide novel insights into how adjuvants regulate immunity at the mucosa and
allow us to guide the response in favor of pathogen elimination.