however , the re - activation of attenuated vaccine materials and the possible tumorigenicity of inactivated oncogenic viruses are important safety concerns . thus , non - pathogenic materials including inactivated toxins , synthetic peptides , and recombinant subunit proteins have been considered as vaccine materials . however , these antigens are poor in immunogenicity and must be given with supplemental materials to potentiate the vaccination capacity . such supplemental materials are termed adjuvants and can be divided into two classes depending on their mode of action : efficient delivery of vaccine materials and/or stimulation of the immune system ( tables 1 , 2 ) . adjuvants facilitating vaccine delivery include liposomes , nanogels , oil - in - water emulsions , and virosomes targeting the co - administered antigens to professional antigen - presenting cells ( apcs ) . adjuvants that stimulate the immune system include molecules binding to intracellular receptors including toll - like receptors ( tlrs ) , nod - like receptors , and rig - i  like receptors and to cytosolic dna sensors , all of which modulate the immune response . however , most adjuvants have been evaluated in the context of parenteral immunization ; thus , it is not clear how well the adjuvants function in the mucosal immune compartment . mucosal surfaces cover 400 m of the body including the gastrointestinal , urogenital , and respiratory tracts . the gastrointestinal mucosa is especially prone to the development of tolerogenic microenvironments , where luminal antigens may persist . the mucosal immune system has both inductive and effector sites differing in terms of their anatomical and functional characteristics . the major mucosal immune inductive sites include gut - associated lymphoid tissue ( galt ) and the nasopharyngeal - associated lymphoid tissue ( nalt ) . galt includes peyer 's patches , mesenteric lymph nodes , and isolated lymphoid follicles , while nalt includes tonsils / adenoids , inducible bronchus - associated lymphoid tissue , cervical lymph nodes , and hilar lymph nodes . mucosal immune inductive sites are covered by follicle - associated epithelium ( fae ) , which is composed of enterocytes and m cells . m cells can transfer antigens via transcytosis to apcs located in pockets within m cell clusters . dendritic cells that come in contact with antigens transcytosed through m cells enter the interfollicular t cell zone to activate nave t cells . finally , effector t cells move to the b cell follicles of germinal centers ( gcs ) and secrete cytokines capable of promoting iga class - switch recombination . in mucosal immune effector sites such as the lamina propria of the gut , the upper respiratory tract , and the female reproductive tract , iga plasma cells terminally differentiate to release secretory iga ( siga ) , the most important immune effector molecule in the mucosa . siga is transported across mucosal epithelial cells via a polymeric ig receptor ( pigr ) ( fig . 1 ) . siga is a major immune effector at mucosal surfaces that acts via three mechanisms : antigen excretion , immune exclusion , and intracellular antigen neutralization ( fig . 2 ) . antigen excretion by siga features the binding of siga to pathogen - derived antigens , thus inhibiting pathogen siga exerts immune exclusion by eliminating antigens via secretion of an iga  antigen complex , and invading pathogens can also be eliminated by complex formation with iga - joining ( j ) chain - pigr . siga inhibits the binding of pathogens and/or pathogenic antigens to specific receptors by neutralizing and eventually removing the pathogenic antigens . mucosal vaccination can induce antigen - specific humoral and cell - mediated immune responses in both the systemic and mucosal compartments . additionally , such vaccination efficiently induces long - lasting b- and t - cell memory . importantly , the characteristics of mucosal immune response induction depend on the vaccine delivery route chosen ( fig . 3 ) . for example , oral delivery ( a traditional form of mucosal vaccination ) can induce production of antigen - specific siga in the gastrointestinal tract , salivary glands , and mammary glands . currently , the licensed human live attenuated vaccines for rotavirus , poliovirus , salmonella typhi , and cholera are delivered orally ( table 3 ) . intranasal vaccines such as flumist , a live attenuated influenza virus vaccine , generate siga in the upper and lower respiratory , gastric , and genital tracts . upon sublingual vaccination , antigen - specific immune responses are induced in the gastrointestinal and the upper and lower respiratory tracts . although a few human mucosal vaccines are licensed , safety issues remain ; the current vaccines are live attenuated or non - living whole - cell vaccines ( table 3 ) . subunit vaccines lacking entire pathogens are considered to be safer next - generation vaccines . however , several issues must be addressed when developing subunit mucosal vaccines , including poor immunogenicity , degradation of vaccine materials in the harsh mucosal environment , delivery of vaccine materials to mucosal immune inductive tissue , and modulation of the mucosal immune environment such that oral tolerance does not develop . the mucosa is continuously exposed to various antigens and microbiota and tightly regulates the influx of luminal antigens . not only are the cells localized to the fae of mucosal immune inductive sites , but many apcs are located nearby and/or under pockets of m cells . although antigen uptake by m cells was previously thought to be non - specific , many recent studies have shown that a specific antigen delivery mechanism is involved . gp2 , a protein expressed specifically by m cells , drives transcytosis of fimh+ bacteria into such cells . therefore , m cell - specific markers can be utilized for antigen delivery to mucosal immune inductive sites   ( table 4 ) . for example , an m cell - specific antibody , nkm 16 - 2 - 4 , recognizes the (1,2)-fucose - containing carbohydrate moiety of m cells and can be used to enhance delivery of an associated antigen . additionally , an m cell - targeting ligand , co1 , also targets antigens to m cells by interacting with the complement 5a receptor , inducing an antigen - specific immune response . thus , m cell  targeting of vaccine materials will play a pivotal role in successful mucosal vaccination . in the tolerogenic mucosal environment , adjuvants with immunostimulatory capacities enhance immune induction ( table 5 ) . when tlr agonists such as pam3csk4 , poly(i : c ) , mpl , or cpg - odn were given either nasally or orally , in combination with vaccine materials , both systemic and mucosal antigen - specific immune responses were enhanced . cholera toxin ( ct ) is an effective mucosal vaccine adjuvant because it interacts with the gm1 ganglioside . thus , cta1-dd , which contains a mutant gm1 ganglioside - targeting a subunit of ct and the d - fragment of staphylococcus aureus protein a to activate follicular dendritic cells ( fdcs ) closely associated with gcs , has been developed . cta1-dd effectively promotes the induction of high - affinity b - cell clones and long - lived memory b cells and plasma cells . another mucosal vaccine adjuvant is the oil - in water emulsion mf59 , which is currently licensed for human use . although the mechanism of action remains unclear , mf59 not only enhances recruitment of innate immune cells via release of atp and antigen uptake , but it also increases the adjunctive capacities of b cells by enhancing gc actions via activation of follicular helper t cells . finally , cathelicidin ll-37 is an immunostimulatory adjuvant that targets antigens to m cells . ll-37 increases antigen delivery to such cells and activates fdcs by interacting with the formyl peptide receptor 2 . this enhances the induction of antigen - specific immune responses in both the systemic and mucosal compartments . such vaccines offer several advantages including safety , convenience of vaccination , economical production , induction of mucosal immune responses , and enhanced memory b- and t - cell induction . however , several hurdles must be overcome in the development of practical subunit mucosal vaccines , including poor immunogenicity , degradation of vaccine materials in a harsh mucosal environment , delivery of vaccine materials to mucosal immune inductive tissue , and modulation of the mucosal immune environment to ensure that oral tolerance does not develop . these obstacles will be overcome by developing effective mucosal adjuvants that target m cells and are immunostimulatory .
vaccination is the most successful immunological practice that improves the quality of human life and health . 
 vaccine materials include antigens of pathogens and adjuvants potentiating the effectiveness of vaccination . 
 vaccines are categorized using various criteria , including the vaccination material used and the method of administration . 
 traditionally , vaccines have been injected via needles . however , given that most pathogens first infect mucosal surfaces , there is increasing interest in the establishment of protective mucosal immunity , achieved by vaccination via mucosal routes . 
 this review summarizes recent developments in mucosal vaccines and their associated adjuvants .