Parenteral Vaccination Can Be an Effective Means of Inducing Protective Mucosal Responses

Abstract

The current paradigm in vaccine development is that nonreplicating vaccines delivered parenterally fail to induce immune responses in mucosal tissues. However, both clinical and experimental data have challenged this concept, and numerous studies have shown that induction of mucosal immune responses after parenteral vaccination is not a rare occurrence and might, in fact, significantly contribute to the protection against mucosal infections afforded by parenteral vaccines. While the mechanisms underlying this phenomenon are not well understood, the realization that parenteral vaccination can be an effective means of inducing protective mucosal responses is paradigm-shifting and has potential to transform the way vaccines are designed and delivered.

FIG 1

Mucosal immunity. (A) Mucosal surfaces constitute the largest interface between the body and the external environment, including the respiratory (purple), gastrointestinal (green), and genital (blue) tracts. (B) Mucosal immunity plays a crucial role in defense against invading pathogens at the epithelial cell surface, involving a complex network of innate and adaptive immune components. Continuous pathogen surveillance is mediated by specialized antigen transport cells (M cells) and antigen processing cells (DCs) (step 1). Mucosal DCs are particularly important for initiating adaptive immune responses by migrating to the draining lymph node and mediating the expansion of antigen-specific naive T cells into T helper subsets (step 2), involving an upregulation of transcription factors (T-bet, GATA3, RORgt, or Foxp3) and lineage-defining cytokines (gamma interferon [IFN-γ], interleukin-4 [IL-4], IL-17, transforming growth factor β [TGF-β], IL-35, and IL-10). Expanded T-cell subsets home back to mucosal surfaces to perform their effector functions (step 3). Th17 cells and IL-17 expression can upregulate polymeric Ig (pIg) receptor expression and IgA class switching, enhancing IgA secretion (step 4). In addition, soluble factors (BAFF, APRIL) secreted by DCs and epithelial cells can promote T-cell-independent IgA class switching (step 5). Increased IgA production and translocation through epithelial cells hinder pathogen invasion and promote immunity at mucosal surfaces. (Republished from reference with permission of the publisher.)

FIG 2

Structure of LT. The amino acid backbone diagram shows partially active LT, with identification of subunits and locations of the two mutations (R192G and L211A) present in dmLT. (Republished from reference .)