Novel vaccine development strategies for inducing mucosal immunity

Abstract

To develop protective immune responses against mucosal pathogens, the delivery route and adjuvants for vaccination are important. The host, however, strives to maintain mucosal homeostasis by responding to mucosal antigens with tolerance, instead of immune activation. Thus, induction of mucosal immunity through vaccination is a rather difficult task, and potent mucosal adjuvants, vectors or other special delivery systems are often used, especially in the elderly. By taking advantage of the common mucosal immune system, the targeting of mucosal dendritic cells and microfold epithelial cells may facilitate the induction of effective mucosal immunity. Thus, novel routes of immunization and antigen delivery systems also show great potential for the development of effective and safe mucosal vaccines against various pathogens. The purpose of this review is to introduce several recent approaches to induce mucosal immunity to vaccines, with an emphasis on mucosal tissue targeting, new immunization routes and delivery systems. Defining the mechanisms of mucosal vaccines is as important as their efficacy and safety, and in this article, examples of recent approaches, which will likely accelerate progress in mucosal vaccine development, are discussed.

Figure 1. Concept of mucosal inductive and effector sites: when mucosal immunization is initiated, Ags are taken up by mucosal inductive tissues (GALT, NALT and TALT)

This is an initial step for eliciting Ag-specific S-IgA Ab responses in mucosal effector tissues. DCs in mucosal inductive tissues play a major role as APCs for the activation of naive CD4⁺ T cells. In addition, ingested Ags activate IgA-committed B cells. Activated CD4⁺ T cells and IgA-committed B cells dispatch from mucosal inductive tissues and migrate into the mucosal effector tissues and subsequently interact for the terminal differentiation of IgA-committed B cells into IgA-producing plasma cells. In addition to the classical mucosal inductive tissues, the SL mucosa can initiate mucosal immune responses. Bα: IgA-committed B cell; GALT: Gut-associated lymphoreticular tissue; MALT: Mucosa-associated lymphoreticular tissue; NALT: Nasopharyngeal-associated lymphoreticular tissue; PC: Plasma cell; Th1: Type 1 helper CD4⁺ T cell; Th2: Type 2 helper CD4⁺ T cell; Te: Effector CD4⁺ T cell; Tn: Naive CD4⁺ T cell.

Figure 2. Nasal DC-targeting mucosal vaccines: nasal application of CpG ODN activates plasmacytoid DCs (pDC, B220⁺ DCs) for the induction of Th1-type cytokine responses

Thus, CMI and cytotoxic T lymphocyte (CTL) activity can be elicited in addition to Ag-specific S-IgA Ab responses. In contrast, pFL as nasal adjuvant preferentially expands the CD8⁺ DC subset and subsequently elicits Th2-type cytokine-mediated Ag-specific S-IgA Ab responses. Adenovirus expressing FL (Ad-FL) or a combination of CpG ODN and pFL induces a more balanced Th1- and Th2-type immune response. Ad-FL activates CD11b⁺ CD11c⁺ DCs, whereas a combined nasal CpG ODN and pFL stimulates both CD8⁺ DCs and pDCs for the induction of CMI and S-IgA Ab responses. Abs: Antibodies; Ag: Antigen; CMI: Common mucosal immune; CPG ODN: CpG oligodeoxynucleotides; DC: Dendritic cell; pDC: Plasmacytoid dendritic cell; pFL: Plasmid-expressing Flt3 ligand; S-IgA: Surface IgA.

Figure 3. Potential for an M cell-targeting strategy: mucosal M-cell targeting by M cell-specific monoclonal antibody or surface proteins can facilitate Ag delivery for the induction of Ag-specific S-IgA antibody responses to provide effective immunity at the entry site of pathogens

M-cell targeting is achieved by using the protein sigma-1 (pσ1) from reovirus, the ligand for M cell-specific peptide (Co1) or M cell-specific mAb. However, mucosal administration of genetically conjugated OVA protein with pσ1 in the absence of an adjuvant elicits mucosal tolerance. Ag: Antigen; DC: Dendritic cell; GAL: Gut-associated lymphoreticular; mAb: Monoclonal antibody; NALT: Nasopharyngeal-associated lymphoreticular tissue; S-IgA: Surface IgA; Th1: Type 1 helper CD4⁺ T cell; Th2: Type 2 helper CD4⁺ T cell; Th3: Type 3 helper CD4⁺ T cell; Treg: T regulatory cell.

Figure 4. Novel mucosal delivery systems: a plant-based MucoRice-CT-B vaccine effectively induces CT-B-specific protective immunity when orally administered

Because CT-B can be delivered to the small intestine in the rice protein body, MucoRice-CT-B effectively induced CT-B-specific Ab responses in the absence of the CT-A subunit or other potential adjuvants. The cationic nanogel-Hc-BoNT/A is retained for a longer period at the nasal epithelium for slow release of Ag when nasally administered. Thus, nasal APCs, including DCs, can more effectively take up Hc-BoNT/A to initiate Ag-specific immune responses. DC: Dendritic cell; GALT: Gut-associated lymphoreticular tissue; NALT: Nasopharyngeal-associated lymphoreticular tissue.