Vaccine Strategies to Elicit Mucosal Immunity

Abstract

Vaccines are essential tools to prevent infection and control transmission of infectious diseases that threaten public health. Most infectious agents enter their hosts across mucosal surfaces, which make up key first lines of host defense against pathogens. Mucosal immune responses play critical roles in host immune defense to provide durable and better recall responses. Substantial attention has been focused on developing effective mucosal vaccines to elicit robust localized and systemic immune responses by administration via mucosal routes. Mucosal vaccines that elicit effective immune responses yield protection superior to parenterally delivered vaccines. Beyond their valuable immunogenicity, mucosal vaccines can be less expensive and easier to administer without a need for injection materials and more highly trained personnel. However, developing effective mucosal vaccines faces many challenges, and much effort has been directed at their development. In this article, we review the history of mucosal vaccine development and present an overview of mucosal compartment biology and the roles that mucosal immunity plays in defending against infection, knowledge that has helped inform mucosal vaccine development. We explore new progress in mucosal vaccine design and optimization and novel approaches created to improve the efficacy and safety of mucosal vaccines.

Keywords: mucosal adjuvant; mucosal barrier; mucosal immunity; mucosal vaccine; vaccine delivery; vaccine development.

Figure 1

Mucosa structures and immunity mechanisms. Mucosal immune responses are composed of multiple immune effector mechanisms with a complex network of innate and adaptive immune components and play critical roles in defending against invasive pathogens at host mucosal barriers. The first defense line of mucosal barriers is epithelial cells, which have tight cell junctions serving as physical barriers, together with microbiota and antimicrobial peptides in the lumen as biological and biochemical barriers, respectively. Ciliated cells in the respiratory tract epithelium are important for mucociliary clearance by propelling pathogens and particles out of the airways. Mucosal epithelium can be defined into different types: nonkeratinized epithelium, columnar epithelium, and squamous epithelium (the squamous epithelial cells in the respiratory tract and ends of the GI tract are omitted from the figure) according to their structures and functions. Pathogen surveillance is mediated by M cells (antigen transport) and DCs (antigen processing and transport) at mucosal barriers. Antigens are captured and processed by DCs and macrophages, leading to the activation and maturation of those antigen-presenting cells (APCs). Antigen-stimulated DCs later initiate downstream immune responses by migrating to lymph nodes to present antigens on MHC molecules to T-cells, which further mediate expansion of naïve T-cells into differentiated T helper subsets (Th1, Th2, Th17, Treg) via regulation of transcription factors and secretion of lineage-defining cytokines. Activated T helper subsets then perform their functions, including upregulation of polymeric Ig receptor (pIgR) expression and promotion of B-cell differentiation into plasma cells, with IgA class switching to produce secretory IgA (SIgA) to intercept the pathogens at the mucosa. Soluble factors (BAFF, APRIL) secreted by DCs, innate lymphoid cells (ILCs), and epithelial cells could also enhance IgA production by T-cell independent class switching. IgG, derived from local B-cells or from blood, is also present in mucosal tissues to directly neutralize pathogens or mediate cytotoxicity by recognition of Fc receptor expressed on nature killer (NK) cells. In addition, antigen-specific cytotoxic T-cells (CTLs) also enter the mucosa to kill those infected cells. (Figure created with BioRender.com).

Figure 2

Different types of mucosal epithelium structures and functions. The oral cavity, esophagus, vagina, and anus have nonkeratinized epithelium composed of several layers of cells. The columnar epithelium is found in the stomach, intestines, and respiratory tract, except for the alveoli and gallbladder, which are composed of tall, narrow cells that are tightly packed together. Squamous epithelium is a type of epithelium found in the lungs, blood vessels, and body cavities, which are composed of flat, scale-like cells that are tightly packed together. (Figure created with BioRender.com).