The unfulfilled potential of mucosal immunization

Abstract

Recent events involving the global coronavirus pandemic have focused attention on vaccination strategies. Although tremendous advances have been made in subcutaneous and intramuscular vaccines during this time, one area that has lagged in implementation is mucosal immunization. Mucosal immunization provides several potential advantages over subcutaneous and intramuscular routes, including protection from localized infection at the site of entry, clearance of organisms on mucosal surfaces, induction of long-term immunity through establishment of central and tissue-resident memory cells, and the ability to shape regulatory responses. Despite these advantages, significant barriers remain to achieving effective mucosal immunization. The epithelium itself provides many obstacles to immunization, and the activation of immune recognition and effector pathways that leads to mucosal immunity has been difficult to achieve. This review will highlight the potential advantages of mucosal immunity, define the barriers to mucosal immunization, examine the immune mechanisms that need to be activated on mucosal surfaces, and finally address recent developments in methods for mucosal vaccination that have shown promise in generating immunity on mucosal surfaces in human trials.

Keywords: Mucosal vaccines; barriers to mucosal immunization; innate lymphoid cells; respiratory infections; sterile immunity; tissue resident memory cells.

Fig 1

Barriers to mucosal immunization. There are several layers of barriers that uniquely challenge mucosal immunization. These barriers can be conceptualized as associated with different components of the epithelial anatomy. The barriers at each level of the mucosa are enumerated on the left side of the figure, with potential approaches to overcome each impediment presented on the right side. cDC, Conventional DC.

Fig 2

The optimal approach to activating mucosal-specific immune responses by vaccines. When a vaccine is placed on the mucosal surface, immune activation occurs through DC sampling and activation. This can occur either through direct antigen sampling by DCs across the epithelium, DC sampling of infected or dying epithelial cells, or through sampling of antigens passed across the epithelium by M cells. After that first step, activating of PAMPs, along with retinoic acid pathways, can activate DCs to induce specific, effector immunity (plus signs) involving cellular cytotoxicity and antibodies. In contrast to enhancing pathways for protective immunity, those inducing hypersensitivity reactions (minus signs) including ILC2 and T_H2 lymphocytes should be suppressed. α4β7, Alpha 4 beta 7 integrin; CCR9, chemokine CC receptor 9; NK, natural killer; RALDH, retinal dehydrogenase enzyme; TLR, Toll-like receptor.