Targeting myeloid cells for regulation of alum-based immunity

Alum is the most widely used adjuvant in current subunit vaccines against infectious agents. Mucosal tissues
represent the main portal of entry of pathogens. In contrast with the general bloodstream in the systemic
compartment, mucosal tissues contain a large number of IgA producing cells. This immunoglobulin isotype
contributes to the protection of exposed mucosal surfaces via a number of mechanisms including prevention of
pathogen binding to host cells (epithelial cells and dendritic cells), neutralization of toxins in the lumen, and
neutralization of viruses within epithelial cells. Injected vaccines can induce high levels of IgG responses in the
bloodstream, but they are not effective at inducing secretory IgA responses which are needed for optimal
protection of mucosal surfaces. In contrast with injected vaccines, mucosal vaccines delivered through the oral,
rectal, nasal or sublingual routes target Mucosal-Associated Lymphoid Tissues where they can induce innate
signals necessary for induction of secretory IgA responses. Despite decades of research on mucosal vaccines,
to date, only two oral vaccines and one intranasal vaccine are licensed for use in the US. This proposal will
address the overall hypothesis that the adjuvant alum triggers innate signals that restrict the breath of antibody
responses and prevent the production of IgA. Our newly generated data suggest that a family of molecules
produced by myeloid cells plays a central role in preventing IgA production by alum-based injected vaccines and
targeting those molecules will improve protection by increasing IgA production. Aim 1 will focus on the
mechanisms underlying innate suppression of IgA responses by myeloid cells in non-mucosal sites. Aim 2 will
identify the cells and signaling pathways targeted by pharmacological agents inhibiting this family of molecules
to regulate induction of systemic and mucosal immune responses after systemic immunization. Aim 3 will
establish whether strategies targeting the innate suppressors of IgA responses promote broad systemic and
mucosal immunity and can protect a relevant animal model against infection with an enteric virus.

Grant Number: 5R01AI145144-05
NIH Institute/Center: NIH
Principal Investigator: Prosper Boyaka