Mucosal immunology is the study of immune system responses occurring in any surface that is in contact with the external environment. The intestines, respiratory tract, and the urogenital tract all belong to the mucosal barrier. The mucosal immune system has three main functions. It serves as the body’s first line defense from antigens and infections and prevents systemic immune responses to commensal bacteria and food antigens. It also regulates appropriate immune responses to pathogens encountered on a daily basis.
The majority of infections occur after crossing one of the body’s numerous protective mucosal barriers. For example, potentially fatal diarrheal diseases are often caused by enteropathogens crossing the mucosal barrier of the GI tract after ingestion of contaminated water. The formation of an immunologically strong mucosal barrier would be an effective strategy to prevent infection at the point of contact between microbes and the host. However, the current standards of vaccine technology typically only address pathogens that have already surpassed a mucosal barrier. The majority of licensed vaccines are administered either by subcutaneous or intramuscular injection. The resulting immune response is generally limited to systemic humoral immunity (e.g. antibody production) against the pathogen or toxin, with limited cellular immunity (e.g. T cell-mediated), and only weak protection generated at the mucosal surfaces.
In contrast, the oral delivery (a traditional form of mucosal vaccination) successfully induces mucosal antibodies (IgA) and cell-mediated immune responses, while still producing a systemic antibody response (IgG). The intestine, one of organs making up the gastrointestinal (GI) tract, is the mucosal site that holds the highest number of immune cells in the body, and it is regulated by the gut-associated lymphoid tissue (GALT), that coordinates effector and inductive sites. Inductive sites in the GI tract involve the coordinated action of Peyer’s patches (PPs), lymphoid follicles and antigen presenting cells (APCs), while effector sites mainly include the lamina propria (LP) and surface epithelium. Following administration of oral vaccines, antigens travel through the GI tract. Upon entering the small intestine, M cells in the Peyer’s patches sample and transport the immunogens across to APCs. These materials are then taken up and processed by dendritic cells (DCs) that process antigen material and present antigenic fragments on their surface to activate naïve CD4+ T cells. These helper cells further interact with antigen-specific B cells that then undergo class switching to become immunoglobulin-secreting cells. Upon maturation, B cells travel from the PPs through the lymphatic system to reach the mesenteric lymph node before entering systemic circulation. When these cells reach distant effector sites, they differentiate and maturate into plasma cells. In parallel, DCs migrate to the lymph nodes to activate humoral and cellular responses by interacting with germinal centers. A further analysis of the characteristics of the most relevant immune sites in the GALT is necessary to understand the process of generating gut immunity.
Therefore, development of vaccines administered orally is preferable to traditional injection-based formulations for numerous reasons including improved safety and compliance, and easier manufacturing and administration though oral delivery is challenging, requiring formulations to overcome the harsh gastrointestinal (GI) environment and avoid tolerance induction to achieve effective protection.
Julia E. Vela Ramireza et al. 2017. Current state and challenges in developing oral vaccines. Adv Drug Deliv Rev. 114: 116–131
Sae-Hae Kim and Yong-Suk Jang. 2017. The development of mucosal vaccines for both mucosal and systemic immune induction and the roles played by adjuvants. Clin Exp Vaccine Res. 6(1):15-21
Coree LLC, U.S.A. Dr. Park, Sang Tae contribution