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Van Der Weken, H. Oral subunit vaccine design. Encyclopedia. Available online: (accessed on 22 June 2024).
Van Der Weken H. Oral subunit vaccine design. Encyclopedia. Available at: Accessed June 22, 2024.
Van Der Weken, Hans. "Oral subunit vaccine design" Encyclopedia, (accessed June 22, 2024).
Van Der Weken, H. (2021, January 11). Oral subunit vaccine design. In Encyclopedia.
Van Der Weken, Hans. "Oral subunit vaccine design." Encyclopedia. Web. 11 January, 2021.
Oral subunit vaccine design

Many pathogens invade the host at the intestinal surface. To protect against these enteropatho-gens, the induction of intestinal secretory IgA (SIgA) responses is paramount. While systemic vaccination provides strong systemic immune responses, oral vaccination is the most efficient way to trigger protective SIgA responses. However, the development of oral vaccines, especially oral subunit vaccines, is challenging due to mechanisms inherent to the gut. Oral vaccines need to survive the harsh environment in the gastrointestinal tract, characterized by low pH and intestinal proteases and need to reach the gut-associated lymphoid tissues, which are protected by chemical and physical barriers that prevent efficient uptake. Furthermore, they need to surmount default tolerogenic responses present in the gut, resulting in suppression of immunity or tolerance. Several strategies have been developed to tackle these hurdles, such as delivery systems that protect vaccine antigens from degradation, strong mucosal adjuvants that induce robust immune responses and targeting approaches that aim to selectively deliver vaccine antigens towards specific immune cell populations.

oral vaccination subunit vaccines mucosal immunity

1. Introduction

Vaccines play a crucial role in reducing the global burden of infectious diseases and are responsible for the elimination of diseases like polio, tetanus and pertussis and even the eradication of smallpox and rinderpest [1][2][3][4]. Furthermore, vaccines can aid in solving the current crisis regarding antimicrobial resistance by eliminating or reducing the need for antibiotics, especially in animal husbandry [5][6]. Most vaccines are administered via parenteral routes, generally leading to strong systemic immune responses. In contrast, most pathogens infect or invade the host at mucosal surfaces and systemic immunity generally does not provide sufficient protection against these types of pathogens. Local administration of vaccines to mucosal surfaces, such as via oral vaccination, provides much better protection against pathogens that colonize or invade these surfaces by inducing mucosal immunity, characterized by the local production of secretory IgA (SIgA) as well as a systemic immunity [7]. The production of SIgA is crucial because it shows improved stability in the gut via its secretory component and can prevent the colonization of the gut tissues by pathogens, such as enterotoxigenic Escherichia coli (ETEC), via a process called “immune exclusion”, characterized by agglutination, entrapment and clearance of the pathogen [8]. In addition to eliciting robust intestinal immune responses, oral vaccination has other advantages over parenteral vaccines, such as the reduced need for trained personnel, allowing self-administration, and a reduced risk of transmitting blood-borne diseases due to needle-free administration. They also increase patient compliance due to easier administration and often do not require refrigerated storage, which results in easier transport and delivery to remote places. For most oral vaccines, no expensive purification techniques or equipment are required, generally making it easier to get market approval. Finally, they also have a more cost-effective production, drastically reducing the cost of mass vaccination programs [9][10]. Currently, most oral vaccines consist of either inactivated or live-attenuated organisms. The latter have several risks attributed to them, such as uncontrolled replication, severe inflammatory reactions, the risk of infection in immunocompromised patients and the possibility of reversion to a virulent strain. In recent years, the focus for oral vaccination strategies has shifted to the use of safer subunit vaccines, but these still face many hurdles. Oral vaccine antigens have to survive the harsh environment of the gastrointestinal tract, characterized by a low gastric pH and degradation by gastric and small intestinal proteases. They also have to be able to reach the gut associated lymphoid tissue (GALT), which is protected by an epithelial barrier that has evolved to regulate nutrient absorption as well as to provide protection against foreign invaders [9]. Furthermore, under normal circumstances, antigens that enter via the oral route are treated as dietary components. If a vaccine does not induce the appropriate danger signals, then the gut tissues will recognize it as non-pathogenic, resulting in suppression of immunity or tolerance [11][12]. Compared to parenteral immunizations, high dosages are generally required for successful immunization, but these larger doses also increase the risk of tolerance [13][14][15]. Because of this risk, inclusion of potent adjuvants is essential for promoting robust intestinal immune responses [16]. The limited residence time of vaccine antigens in the gut is also an important factor to consider as it can prevent their effective uptake [17]. All these obstacles generally lead to poor immune responses to oral vaccination and are the main reasons so few effective oral vaccines exist. Finally, the microbiota might also impinge on the efficacy of oral vaccines. Currently, this aspect of oral vaccination is not yet well understood it certainly requires further research [18][19].

2. Oral Vaccination Strategies

Several oral vaccination strategies have been developed in recent years to tackle the different hurdles associated with oral vaccination. Potent oral adjuvants have been developed that can stimulate the mucosal immune system and are capable of provoking robust mucosal immune responses. Different delivery systems have been designed that are able to protect vaccine antigens against the harsh gastrointestinal environment and release these antigens at the immune inductive sites to promote uptake by antigen presenting cells. Furthermore, by targeting specific receptors, selective delivery of vaccine antigens towards specific cell populations within the intestinal tissues can be achieved, further promoting robust intestinal immune responses. These oral vaccination strategies will be addressed in the next sections and are briefly summarized in Table 1.

Table 1. Overview of different oral vaccination strategies studied for oral administration.

Oral adjuvants

Toxin derivates

dmLT [20][21][22][23], mmCT [24]

PRR ligands

β-glucans [25][26], MPL [27], Flagellin [28][29], CpG [30][31]


α-galactosyl ceramide [32][33]

Delivery systems

Living delivery systems

Recombinant bacteria [34][35][36][37][38][39][40][41][42][43][44]

Viral vectors [45][46][47][48][49][50][51][52][53][54][55][56]

Non-living delivery systems

Virus-like particles [57]


Micro- and nanoparticles  [58][59][60]


Lipid-based delivery systems [61][62][63][64][65][66][67][68][69]


Nanogels [70]

Targeted delivery


Dectin-1 [71], GP2 [72], C5aR [73]


FcRn [74]

Aminopeptidase N [75][76][77][78][79]

2.1. Oral Adjuvants

As mentioned, most licensed oral vaccines make use of complete live-attenuated or inactivated organisms, which do not require potent adjuvants. These types of vaccines present an inherent adjuvanticity through the presence of conserved molecular patterns, such lipopolysaccharide (LPS), flagellin or cytosine-phosphate-guanine (CpG), which are recognized by pathogen recognition receptors (PRR)[80]. Since oral subunit vaccines generally do not possess any adjuvant functions, the addition of potent mucosal adjuvants is required to circumvent the default tolerogenic responses present in the gut and to allow the induction of robust intestinal immune responses [81][82]. Several types of adjuvants can be distinguished, and these can be broadly divided into two groups: the immunopotentiators and the delivery systems. Generally, immunopotentiators have the ability to enhance the immune response against otherwise weak immunogenic antigens and result in a broad and durable protection, while delivery systems improve the vaccine delivery to the targeted site or help protect the antigen from degradation. Often a combination of both these systems is used by including immunopotentiators in the delivery system or because the delivery system itself has inherent immune stimulating properties [83][84][85].

2.1.1. Toxin Derivates

One of the most important classes of immunopotentiators for oral vaccination is toxin derivates, such as the ADP-ribosyl transferase enterotoxins cholera toxin (CT) and heat-labile enterotoxin (LT). Due to their strong adjuvant properties and their ability to elicit SIgA, they are considered the gold standard for oral vaccination [86][87]. These toxins stimulate antigen-presenting cells, enhancing the expression of MHC class II and costimulatory molecules, and induce antigen-specific TH2 and TH17 cells to secrete IgA-promoting cytokines, further supporting the production of IgA [88][89]. It has been shown that oral delivery of CT to mice activates the canonical NF-ĸB pathway and mRNA expression of NF-ĸB-dependent pro-inflammatory cytokines in the mesenteric lymph nodes and Peyer’s patches [90]. Their effects are also thought to promote the permeation of antigens across the epithelial barrier and to promote intestinal stem cells to differentiate into M cells, an epithelial cell specialized in the uptake of macromolecules [91][92][93].

Although LT and CT are often used as potent oral adjuvants in animal models during preclinical research, unfortunately they display a high toxicity in humans, resulting in severe diarrhea at low doses and thus preventing their use as oral adjuvants in humans. Fortunately, modified versions of these toxins, such as the double mutant LT (dmLT) and multiple-mutated CT (mmCT), have been developed in recent years, resulting in a decreased toxicity, while retaining their potent adjuvant properties. In mice, dmLT has been shown to be an effective mucosal adjuvant when given orally together with several antigens from different pathogens, often providing protection against subsequent challenge infection. In humans, a live-attenuated ETEC vaccine (ACE527) was co-administered with dmLT, resulting in protection after subsequent ETEC challenge. The oral inactivated ETEC vaccine ETVAX also showed increased immune responses in children and infants, but not in adults when adjuvanted with dmLT.

An alternative strategy to co-administration would be to conjugate or fuse these toxins to non-immunogenic antigens, allowing the binding of the B-subunit to intestinal epithelial cells, resulting in uptake and transport through the epithelium and improved immunogenicity. Examples of this strategy in the literature include fusion proteins, such as fimbriae-toxin multi-epitope fusion antigens (MEFA) [94][95][96][97][98][99]. Although these showed promising results in inducing protective immunity after i.m and s.c. administration in mice, the protective efficacy of this vaccination strategy still needs to be assessed after oral administration and challenge infection.

Besides LT and CT, the potential use of other toxin derivates, such as adenylate cyclase toxins, as an adjuvant for oral vaccination still has to be further investigated. In mice, nasal co-delivery of the anthrax edema toxin with ovalbumin resulted in high antigen-specific IgG and IgA serum responses and induced antigen-specific T-cell secretion of IFNγ, IL-5, IL-6 and IL-13 [100].

2.1.2. PRR Ligands

Pathogen recognition receptors play a crucial role in the recognition of pathogens and the induction of appropriate immune responses. They are expressed by many cell types, including intestinal epithelial cells and antigen presenting cells, such as dendritic cells and macrophages. In mice, the expression of some Toll-like receptors (TLR) by intestinal epithelial cells seemed to be age-dependent and differed along the length of the intestine, with the expression of TLR5 being restricted to Paneth cells in the small intestine and gradually decreased during the neonatal period [101]. PRR ligands have been intensively investigated for their adjuvanticity and can be subdivided in the membrane-bound TLRs and C-type lectin (CLR) receptors and the cytoplasmic RIG-I-like (RLR) and NOD-like (NLR) receptors (Table 2).

Table 2. Overview of pathogen recognition receptors, with their respective cellular localization and ligands.

Pathogen recognition receptor (PRR)

Cellular localization


Toll-like receptors (TLR) [102][103][104][105][106]


Plasma membrane



Plasma membrane






Plasma membrane



Plasma membrane



Plasma membrane










Unmethylated CpG




NOD-like receptors (NLR) *[107][108]









Cytosolic flagellin

C-type lectin receptors (CLR)[109]


Plasma membrane



Plasma membrane



Plasma membrane


Mannose receptor

Plasma membrane


RIG-I-like receptors (RLR)[110]







* Many more NLRs exist (NLRP1-14, NLRC1-5, NAIP, CIITA), but most of these have not been extensively researched [111]. ** Many different pathogen and damage associated molecular patterns are able to activate the NLRP3 inflammasome. This has been excellently reviewed by Kelley et al. [112].

The ligands of CLR, NLR and RLR have not been studied well as oral adjuvants. So far, only β-glucans have been shown to have immune stimulating properties after oral administration. The potential adjuvanticity of several TLR-ligands, such as monophosphoryl lipid A (MPL; TLR4), flagellin (TLR5) and CpG (TLR9) has been better studied [113][114]. MPL is a detoxified derivative of LPS [114]. Its interactions with TLR4 triggers the production of TNFα, IL-12 and IFNγ, promoting TH1 immune responses. In mice, pulmonary immunity against M. tuberculosis was obtained after oral administration of M. tuberculosis-derived antigens with MPL-based adjuvants . The TLR5 ligand flagellin is a highly abundant protein in flagellated bacteria and promotes the induction of pro-inflammatory cytokines and chemokines, the recruitment of B- and T-cells to secondary lymphoid tissues, the direct activation of T-cells and the activation of DC’s [115][116]. Flagellin produced in plants was shown to be a potent adjuvant after oral administration with ovalbumin in mice. Flagellin-coated ovalbumin-containing nanoparticles were found to enhance SIgA antibody responses to ovalbumin after oral administration in mice. In humans, an influenza-flagellin fusion vaccine (VAX125) provided strong systemic immune responses after intramuscular immunization [117][118]. CpG is a synthetic oligodeoxynucleotide composed of unmethylated CG motifs. Its binding to TLR9 triggers the secretion of pro-inflammatory and TH1-specific cytokines by DC’s, facilitating the induction of cell-mediated immunity. CpG also promotes the maturation and proliferation of NK cells, T-cells and monocytes/macrophages [119][120]. In mice, oral administration of purified hepatitis B surface antigen or tetanus toxin adjuvanted with CpG provided both systemic and mucosal immune responses. In piglets, oral vaccination with a live-attenuated pseudorabies virus, adjuvanted with CpG, resulted in significantly higher serum IgG and mucosal IgA responses compared to piglets that did not receive the adjuvant. Antigen-presenting cells have also been found to make a distinction between living or dead cells via TLR8-dependent detection of bacterial RNA, resulting in the differentiation of follicular T-helper cells. TLR8-agonists, such as CL075 or R848 showed similar responses and might hold promise as oral adjuvants [121].

An important observation that argues against the use of PRR ligands for oral vaccination is that the intestine already continuously encounters these ligands, which could result in hypo-responsiveness or the presence of a higher threshold for PRR ligand-mediated cellular activation.

2.1.3. Other Immune Modulating Molecules

Other immune modulating molecules that have been investigated as adjuvants include Natural Killer T (NKT) ligands and stimulator of interferon genes (STING) ligands. NKT ligands, such as the synthetic α-galactosyl ceramide, activate NKT-cells by binding to the CD1d receptor on antigen presenting cells. This α-galactosyl ceramide-CD1d complex is subsequently recognized by the NKT T-cell receptor. Mucosal tissues contain many NKT-cells that secrete both TH1, TH2 and TH17-specific cytokines upon stimulation. Alpha-galactosyl ceramide has been shown to be an effective adjuvant, inducing mucosal and systemic cell-mediated immunity after nasal or oral delivery with HIV peptide antigens in mice [122]. Addition of α-galactosyl ceramide to the oral cholera vaccine Dukoral® also strongly enhanced intestinal immune responses in mice.

STING ligands, such as cyclic dinucleotides of bacterial origin (2’,3’-cGAMP, 3’,3’-cGAMP, c-di-AMP and c-di-GMP), can stimulate robust type 1 interferon responses and proinflammatory cytokines, such as TNFα, IL-1β and IL-6, resulting in the activation of macrophages and dendritic cells. These primarily showed promising results with intranasal use and it would be interesting to assess their efficacy in oral vaccination [123][124].

2.1.4. Use of Adjuvants for the Induction of SIgA after Parenteral Administration

Two factors are crucial for inducing the production of SIgA at the induction sites. First, cytokines play an important role in driving the differentiation of T-helper cell populations, permitting intestinal immunity. Secondly, gut homing of effector cells, like plasma cells, towards the mucosal effector sites is another crucial step.

Gut homing is orchestrated by the expression of mucosal addressins, integrins, chemokine receptors and their ligands [125][126]. They allow the migration of activated lymphocytes and antibody-secreting cells towards specific regions in the gut. Both the integrin α4β7 and the chemokine receptor CCR9 are known to regulate gut homing of immune cells towards mucosal tissues in the gut [127][128]. The integrin α4β7 is present on activated T and B cells and allows binding to the mucosal vascular addressin cell adhesion molecule-1 (MAdCAM-1), expressed on endothelial cells in the high endothelial venules (HEV) of the small intestine and Peyer’s patches [129]. The chemokine receptor CCR9 is also present on T-cells and binds specifically to the chemokine CCL25, expressed within the crypts and lower villi of the small intestinal epithelium and on the surface of vascular endothelial cells in the small intestine [130][131][132]

Successful oral immunization should result in the activation of intestinal dendritic cells that produce high amounts of ATRA, leading to the generation of IgA-secreting cells capable of migrating towards the intestinal mucosa. Several factors influence the immune stimulating effects of ATRA, including IL-5, IL-6 and IL-21 or sphingosine 1-phosphate. Both IL-5 and IL-6 synergistically modulate the IgA producing effects of ATRA by modulating IgA class switching in a T-cell independent manner [135][136][137]. IL-21 production can be triggered by IL-6 and drives plasma cell differentiation. Expression of sphingosine 1-phosphate is regulated by ATRA signaling and is needed for the egression of immune cells from the lymphoid organs into the lymphatic vessels [138][139][140][141][142][143]. Besides gut homing and antibody-class switching, ATRA also promotes the generation of regulatory T cells and inhibits the differentiation of TH17 cells by enhancing TGFβ signaling [144][145].

Although ATRA is not necessarily considered as a mucosal adjuvant, its function could be important for the development of vaccines aiming at eliciting robust mucosal immune responses. Upon subcutaneous or intraperitoneal administration of ATRA together with vaccine antigens, increased α4β7 and CCR9 expression on lymphocytes and increased T-cell trafficking towards the gut were observed in mice and pigs [146][147][148]. More recently, a vaccine using two liposomal delivery systems that were subcutaneously administered to mice induced antigen-specific intestinal IgA responses. The first delivery system was designed to ensure fast drainage of ATRA towards the lymph nodes to precondition these for mucosal immune responses, while the second delivery system was optimized for slower, prolonged delivery of the antigen to these ATRA preconditioned lymph nodes via migrating antigen-presenting cells [149]. In the future, it would be interesting to see if similar results could be obtained in large animal models.



  1. Plotkin, S. History of vaccination. Proc. Natl. Acad. Sci. USA 2014, 111, 12283–12287, doi:10.1073/pnas.1400472111.
  2. Greenwood, B. The contribution of vaccination to global health: Past, present and future. Philos. Trans. R. Soc. Lond. Ser. B Biol. Sci. 2014, 369, 20130433, doi:10.1098/rstb.2013.0433.
  3. Greene, S.A.; Ahmed, J.; Datta, S.D.; Burns, C.C.; Quddus, A.; Vertefeuille, J.F.; Wassilak, S.G.F. Progress toward Polio Eradication—Worldwide, January 2017-March 2019. MMWR Morb. Mortal. Wkly. Rep. 2019, 68, 458–462, doi:10.15585/mmwr.mm6820a3.
  4. Roeder, P.L. Rinderpest: The end of cattle plague. Prev. Vet. Med. 2011, 102, 98–106, doi:10.1016/j.prevetmed.2011.04.004.
  5. Hoelzer, K.; Bielke, L.; Blake, D.P.; Cox, E.; Cutting, S.M.; Devriendt, B.; Erlacher-Vindel, E.; Goossens, E.; Karaca, K.; Lemiere, S.; et al. Vaccines as alternatives to antibiotics for food producing animals. Part 2: New approaches and potential solutions. Vet. Res. 2018, 49, 70, doi:10.1186/s13567-018-0561-7.
  6. Hoelzer, K.; Bielke, L.; Blake, D.P.; Cox, E.; Cutting, S.M.; Devriendt, B.; Erlacher-Vindel, E.; Goossens, E.; Karaca, K.; Lemiere, S.; et al. Vaccines as alternatives to antibiotics for food producing animals. Part 1: Challenges and needs. Vet. Res. 2018, 49, 64, doi:10.1186/s13567-018-0560-8.
  7. Li, Y.; Jin, L.; Chen, T. The Effects of Secretory IgA in the Mucosal Immune System. Biomed Res. Int. 2020, 2020, 2032057, doi:10.1155/2020/2032057.
  8. Mantis, N.J.; Rol, N.; Corthesy, B. Secretory IgA’s complex roles in immunity and mucosal homeostasis in the gut. Mucosal Immunol. 2011, 4, 603–611, doi:10.1038/mi.2011.41.
  9. Vela Ramirez, J.E.; Sharpe, L.A.; Peppas, N.A. Current state and challenges in developing oral vaccines. Adv Drug Deliv. Rev 2017, 114, 116–131, doi:10.1016/j.addr.2017.04.008.
  10. Hutton, G.; Tediosi, F. The costs of introducing a malaria vaccine through the expanded program on immunization in Tanzania. Am. J. Trop. Med. Hyg. 2006, 75, 119–130, doi:10.4269/ajtmh.2006.75.119.
  11. Tordesillas, L.; Berin, M.C. Mechanisms of Oral Tolerance. Clin Rev Allergy Immunol. 2018, 55, 107–117, doi:10.1007/s12016-018-8680-5.
  12. Ebbo, M.; Crinier, A.; Vely, F.; Vivier, E. Innate lymphoid cells: Major players in inflammatory diseases. Nat. Rev. Immunol. 2017, 17, 665–678, doi:10.1038/nri.2017.86.
  13. Weiner, H.L.; da Cunha, A.P.; Quintana, F.; Wu, H. Oral tolerance. Immunol. Rev. 2011, 241, 241–259, doi:10.1111/j.1600-065X.2011.01017.x.
  14. Mestecky, J.; Russell, M.W.; Elson, C.O. Perspectives on mucosal vaccines: Is mucosal tolerance a barrier? J. Immunol. 2007, 179, 5633–5638, doi:10.4049/jimmunol.179.9.5633.
  15. Pavot, V.; Rochereau, N.; Genin, C.; Verrier, B.; Paul, S. New insights in mucosal vaccine development. Vaccine 2012, 30, 142–154, doi:10.1016/j.vaccine.2011.11.003.
  16. Subiza, J.L.; El-Qutob, D.; Fernandez-Caldas, E. New developments in oral vaccines and mucosal adjuvants. Recent Pat. Inflamm. Allergy Drug Discov. 2015, 9, 4–15, doi:10.2174/1872213x09666150211122313.
  17. Mudie, D.M.; Amidon, G.L.; Amidon, G.E. Physiological parameters for oral delivery and in vitro testing. Mol. Pharm. 2010, 7, 1388–1405, doi:10.1021/mp100149j.
  18. McDermott, A.J.; Huffnagle, G.B. The microbiome and regulation of mucosal immunity. Immunology 2014, 142, 24–31, doi:10.1111/imm.12231.
  19. Ciabattini, A.; Olivieri, R.; Lazzeri, E.; Medaglini, D. Role of the Microbiota in the Modulation of Vaccine Immune Responses. Front. Microbiol. 2019, 10, 1305, doi:10.3389/fmicb.2019.01305.
  20. Clements, J.D.; Norton, E.B. The Mucosal Vaccine Adjuvant LT(R192G/L211A) or dmLT. mSphere 2018, 3, doi:10.1128/mSphere.00215-18.
  21. Harro, C.; Louis Bourgeois, A.; Sack, D.; Walker, R.; DeNearing, B.; Brubaker, J.; Maier, N.; Fix, A.; Dally, L.; Chakraborty, S.; et al. Live attenuated enterotoxigenic Escherichia coli (ETEC) vaccine with dmLT adjuvant protects human volunteers against virulent experimental ETEC challenge. Vaccine 2019, 37, 1978–1986, doi:10.1016/j.vaccine.2019.02.025.
  22. Qadri, F.; Akhtar, M.; Bhuiyan, T.R.; Chowdhury, M.I.; Ahmed, T.; Rafique, T.A.; Khan, A.; Rahman, S.I.A.; Khanam, F.; Lundgren, A.; et al. Safety and immunogenicity of the oral, inactivated, enterotoxigenic Escherichia coli vaccine ETVAX in Bangladeshi children and infants: A double-blind, randomised, placebo-controlled phase 1/2 trial. Lancet Infect. Dis. 2020, 20, 208–219, doi:10.1016/S1473-3099(19)30571-7.
  23. Akhtar, M.; Chowdhury, M.I.; Bhuiyan, T.R.; Kaim, J.; Ahmed, T.; Rafique, T.A.; Khan, A.; Rahman, S.I.A.; Khanam, F.; Begum, Y.A.; et al. Evaluation of the safety and immunogenicity of the oral inactivated multivalent enterotoxigenic Escherichia coli vaccine ETVAX in Bangladeshi adults in a double-blind, randomized, placebo-controlled Phase I trial using electrochemiluminescence and ELISA assays for immunogenicity analyses. Vaccine 2019, 37, 5645–5656, doi:10.1016/j.vaccine.2018.11.040.
  24. Lebens, M.; Terrinoni, M.; Karlsson, S.L.; Larena, M.; Gustafsson-Hedberg, T.; Kallgard, S.; Nygren, E.; Holmgren, J. Construction and preclinical evaluation of mmCT, a novel mutant cholera toxin adjuvant that can be efficiently produced in genetically manipulated Vibrio cholerae. Vaccine 2016, 34, 2121–2128, doi:10.1016/j.vaccine.2016.03.002.
  25. Vetvicka, V.; Vannucci, L.; Sima, P. beta-glucan as a new tool in vaccine development. Scand. J. Immunol. 2020, 91, e12833, doi:10.1111/sji.12833.
  26. Baert, K.; De Geest, B.G.; De Greve, H.; Cox, E.; Devriendt, B. Duality of beta-glucan microparticles: Antigen carrier and immunostimulants. Int. J. Nanomed. 2016, 11, 2463–2469, doi:10.2147/IJN.S101881.
  27. Doherty, T.M.; Olsen, A.W.; van Pinxteren, L.; Andersen, P. Oral vaccination with subunit vaccines protects animals against aerosol infection with Mycobacterium tuberculosis. Infect. Immun. 2002, 70, 3111–3121, doi:10.1128/iai.70.6.3111-3121.2002.
  28. Girard, A.; Saron, W.; Bergeron-Sandoval, L.P.; Sarhan, F.; Archambault, D. Flagellin produced in plants is a potent adjuvant for oral immunization. Vaccine 2011, 29, 6695–6703, doi:10.1016/j.vaccine.2011.06.092.
  29. Salman, H.H.; Irache, J.M.; Gamazo, C. Immunoadjuvant capacity of flagellin and mannosamine-coated poly(anhydride) nanoparticles in oral vaccination. Vaccine 2009, 27, 4784–4790, doi:10.1016/j.vaccine.2009.05.091.
  30. McCluskie, M.J.; Weeratna, R.D.; Krieg, A.M.; Davis, H.L. CpG DNA is an effective oral adjuvant to protein antigens in mice. Vaccine 2000, 19, 950–957, doi:10.1016/s0264-410x(00)00215-2.
  31. Linghua, Z.; Xingshan, T.; Fengzhen, Z. In vivo oral administration effects of various oligodeoxynucleotides containing synthetic immunostimulatory motifs in the immune response to pseudorabies attenuated virus vaccine in newborn piglets. Vaccine 2008, 26, 224–233, doi:10.1016/j.vaccine.2007.10.058.
  32. Courtney, A.N.; Nehete, P.N.; Nehete, B.P.; Thapa, P.; Zhou, D.; Sastry, K.J. Alpha-galactosylceramide is an effective mucosal adjuvant for repeated intranasal or oral delivery of HIV peptide antigens. Vaccine 2009, 27, 3335–3341, doi:10.1016/j.vaccine.2009.01.083.
  33. Davitt, C.J.H.; Longet, S.; Albutti, A.; Aversa, V.; Nordqvist, S.; Hackett, B.; McEntee, C.P.; Rosa, M.; Coulter, I.S.; Lebens, M.; et al. Alpha-galactosylceramide enhances mucosal immunity to oral whole-cell cholera vaccines. Mucosal Immunol. 2019, 12, 1055–1064, doi:10.1038/s41385-019-0159-z.
  34. Robinson, K.; Chamberlain, L.M.; Schofield, K.M.; Wells, J.M.; Le Page, R.W. Oral vaccination of mice against tetanus with recombinant Lactococcus lactis. Nat. Biotechnol. 1997, 15, 653–657, doi:10.1038/nbt0797-653.
  35. Li, X.; Xing, Y.; Guo, L.; Lv, X.; Song, H.; Xi, T. Oral immunization with recombinant Lactococcus lactis delivering a multi-epitope antigen CTB-UE attenuates Helicobacter pylori infection in mice. Pathog. Dis. 2014, 72, 78–86, doi:10.1111/2049-632X.12173.
  36. Lin, R.; Zhang, Y.; Long, B.; Li, Y.; Wu, Y.; Duan, S.; Zhu, B.; Wu, X.; Fan, H. Oral Immunization with Recombinant Lactobacillus acidophilus Expressing espA-Tir-M Confers Protection against Enterohemorrhagic Escherichia coli O157:H7 Challenge in Mice. Front. Microbiol. 2017, 8, 417, doi:10.3389/fmicb.2017.00417.
  37. Ahmed, B.; Loos, M.; Vanrompay, D.; Cox, E. Oral immunization with Lactococcus lactis-expressing EspB induces protective immune responses against Escherichia coli O157:H7 in a murine model of colonization. Vaccine 2014, 32, 3909–3916, doi:10.1016/j.vaccine.2014.05.054.
  38. Wen, L.J.; Hou, X.L.; Wang, G.H.; Yu, L.Y.; Wei, X.M.; Liu, J.K.; Liu, Q.; Wei, C.H. Immunization with recombinant Lactobacillus casei strains producing K99, K88 fimbrial protein protects mice against enterotoxigenic Escherichia coli. Vaccine 2012, 30, 3339–3349, doi:10.1016/j.vaccine.2011.08.036.
  39. Kajikawa, A.; Satoh, E.; Leer, R.J.; Yamamoto, S.; Igimi, S. Intragastric immunization with recombinant Lactobacillus casei expressing flagellar antigen confers antibody-independent protective immunity against Salmonella enterica serovar Enteritidis. Vaccine 2007, 25, 3599–3605, doi:10.1016/j.vaccine.2007.01.055.
  40. Marelli, B.; Perez, A.R.; Banchio, C.; de Mendoza, D.; Magni, C. Oral immunization with live Lactococcus lactis expressing rotavirus VP8 subunit induces specific immune response in mice. J. Virol. Methods 2011, 175, 28–37, doi:10.1016/j.jviromet.2011.04.011.
  41. Yang, W.T.; Yang, G.L.; Yang, X.; Shonyela, S.M.; Zhao, L.; Jiang, Y.L.; Huang, H.B.; Shi, C.W.; Wang, J.Z.; Wang, G.; et al. Recombinant Lactobacillus plantarum expressing HA2 antigen elicits protective immunity against H9N2 avian influenza virus in chickens. Appl. Microbiol. Biotechnol. 2017, 101, 8475–8484, doi:10.1007/s00253-017-8600-2.
  42. Zhang, Z.H.; Jiang, P.H.; Li, N.J.; Shi, M.; Huang, W. Oral vaccination of mice against rodent malaria with recombinant Lactococcus lactis expressing MSP-1(19). World J. Gastroenterol. 2005, 11, 6975–6980, doi:10.3748/wjg.v11.i44.6975.
  43. Chen, G.; Dai, Y.; Chen, J.; Wang, X.; Tang, B.; Zhu, Y.; Hua, Z. Oral delivery of the Sj23LHD-GST antigen by Salmonella typhimurium type III secretion system protects against Schistosoma japonicum infection in mice. PLoS Negl. Trop. Dis. 2011, 5, e1313, doi:10.1371/journal.pntd.0001313.
  44. Tvinnereim, A.R.; Hamilton, S.E.; Harty, J.T. CD8(+)-T-cell response to secreted and nonsecreted antigens delivered by recombinant Listeria monocytogenes during secondary infection. Infect. Immun. 2002, 70, 153–162, doi:10.1128/iai.70.1.153-162.2002.
  45. Premanand, B.; Prabakaran, M.; Kiener, T.K.; Kwang, J. Recombinant baculovirus associated with bilosomes as an oral vaccine candidate against HEV71 infection in mice. PLoS ONE 2013, 8, e55536, doi:10.1371/journal.pone.0055536.
  46. Basak, S.; Chu, K.B.; Kang, H.J.; Kim, M.J.; Lee, S.H.; Yoon, K.W.; Jin, H.; Suh, J.W.; Moon, E.K.; Quan, F.S. Orally administered recombinant baculovirus vaccine elicits partial protection against avian influenza virus infection in mice. Microb. Pathog. 2020, 149, 104495, doi:10.1016/j.micpath.2020.104495.
  47. Stephenson, K.E.; Keefer, M.C.; Bunce, C.A.; Frances, D.; Abbink, P.; Maxfield, L.F.; Neubauer, G.H.; Nkolola, J.; Peter, L.; Lane, C.; et al. First-in-human randomized controlled trial of an oral, replicating adenovirus 26 vector vaccine for HIV-1. PLoS ONE 2018, 13, e0205139, doi:10.1371/journal.pone.0205139.
  48. Scallan, C.D.; Tingley, D.W.; Lindbloom, J.D.; Toomey, J.S.; Tucker, S.N. An adenovirus-based vaccine with a double-stranded RNA adjuvant protects mice and ferrets against H5N1 avian influenza in oral delivery models. Clin. Vaccine Immunol. 2013, 20, 85–94, doi:10.1128/CVI.00552-12.
  49. Kim, L.; Martinez, C.J.; Hodgson, K.A.; Trager, G.R.; Brandl, J.R.; Sandefer, E.P.; Doll, W.J.; Liebowitz, D.; Tucker, S.N. Systemic and mucosal immune responses following oral adenoviral delivery of influenza vaccine to the human intestine by radio controlled capsule. Sci. Rep. 2016, 6, 37295, doi:10.1038/srep37295.
  50. Gurwith, M.; Lock, M.; Taylor, E.M.; Ishioka, G.; Alexander, J.; Mayall, T.; Ervin, J.E.; Greenberg, R.N.; Strout, C.; Treanor, J.J.; et al. Safety and immunogenicity of an oral, replicating adenovirus serotype 4 vector vaccine for H5N1 influenza: A randomised, double-blind, placebo-controlled, phase 1 study. Lancet Infect. Dis. 2013, 13, 238–250, doi:10.1016/S1473-3099(12)70345-6.
  51. Liebowitz, D.; Gottlieb, K.; Kolhatkar, N.S.; Garg, S.J.; Asher, J.M.; Nazareno, J.; Kim, K.; McIlwain, D.R.; Tucker, S.N. Efficacy, immunogenicity, and safety of an oral influenza vaccine: A placebo-controlled and active-controlled phase 2 human challenge study. Lancet Infect. Dis. 2020, 20, 435–444, doi:10.1016/S1473-3099(19)30584-5.
  52. Joyce, C.; Scallan, C.D.; Mateo, R.; Belshe, R.B.; Tucker, S.N.; Moore, A.C. Orally administered adenoviral-based vaccine induces respiratory mucosal memory and protection against RSV infection in cotton rats. Vaccine 2018, 36, 4265–4277, doi:10.1016/j.vaccine.2018.05.112.
  53. Kim, L.; Liebowitz, D.; Lin, K.; Kasparek, K.; Pasetti, M.F.; Garg, S.J.; Gottlieb, K.; Trager, G.; Tucker, S.N. Safety and immunogenicity of an oral tablet norovirus vaccine, a phase I randomized, placebo-controlled trial. JCI Insight 2018, 3, doi:10.1172/jci.insight.121077.
  54. Berg, M.G.; Adams, R.J.; Gambhira, R.; Siracusa, M.C.; Scott, A.L.; Roden, R.B.; Ketner, G. Immune responses in macaques to a prototype recombinant adenovirus live oral human papillomavirus 16 vaccine. Clin. Vaccine Immunol. 2014, 21, 1224–1231, doi:10.1128/CVI.00197-14.
  55. Henderson, H.; Jackson, F.; Bean, K.; Panasuk, B.; Niezgoda, M.; Slate, D.; Li, J.; Dietzschold, B.; Mattis, J.; Rupprecht, C.E. Oral immunization of raccoons and skunks with a canine adenovirus recombinant rabies vaccine. Vaccine 2009, 27, 7194–7197, doi:10.1016/j.vaccine.2009.09.030.
  56. Xiang, Z.Q.; Greenberg, L.; Ertl, H.C.; Rupprecht, C.E. Protection of non-human primates against rabies with an adenovirus recombinant vaccine. Virology 2014, 450-451, 243-249, doi:10.1016/j.virol.2013.12.029.
  57. Serradell, M.C.; Rupil, L.L.; Martino, R.A.; Prucca, C.G.; Carranza, P.G.; Saura, A.; Fernandez, E.A.; Gargantini, P.R.; Tenaglia, A.H.; Petiti, J.P.; et al. Efficient oral vaccination by bioengineering virus-like particles with protozoan surface proteins. Nat. Commun. 2019, 10, 361, doi:10.1038/s41467-018-08265-9.
  58. Marasini, N.; Skwarczynski, M.; Toth, I. Oral delivery of nanoparticle-based vaccines. Expert Rev. Vaccines 2014, 13, 1361–1376, doi:10.1586/14760584.2014.936852.
  59. Kour, P.; Rath, G.; Sharma, G.; Goyal, A.K. Recent advancement in nanocarriers for oral vaccination. Artif. Cells Nanomed. Biotechnol. 2018, 46, S1102–S1114, doi:10.1080/21691401.2018.1533842.
  60. Baert, K.; de Geest, B.G.; de Rycke, R.; da Fonseca Antunes, A.B.; de Greve, H.; Cox, E.; Devriendt, B. beta-glucan microparticles targeted to epithelial APN as oral antigen delivery system. J. Control. Release Off. J. Control. Release Soc. 2015, 220, 149–159, doi:10.1016/j.jconrel.2015.10.025.
  61. Liu, J.; Wu, J.; Wang, B.; Zeng, S.; Qi, F.; Lu, C.; Kimura, Y.; Liu, B. Oral vaccination with a liposome-encapsulated influenza DNA vaccine protects mice against respiratory challenge infection. J. Med Virol. 2014, 86, 886–894, doi:10.1002/jmv.23768.
  62. Wang, D.; Xu, J.; Feng, Y.; Liu, Y.; McHenga, S.S.; Shan, F.; Sasaki, J.; Lu, C. Liposomal oral DNA vaccine (mycobacterium DNA) elicits immune response. Vaccine 2010, 28, 3134–3142, doi:10.1016/j.vaccine.2010.02.058.
  63. Pang, Y.; Zhang, Y.; Wang, H.; Jin, J.; Piao, J.; Piao, J.; Liu, Q.; Li, W. Reduction of Salmonella enteritidis number after infections by immunization of liposome-associated recombinant SefA. Avian Dis. 2013, 57, 627–633, doi:10.1637/10427-101812-Reg.1.
  64. Marasini, N.; Giddam, A.K.; Ghaffar, K.A.; Batzloff, M.R.; Good, M.F.; Skwarczynski, M.; Toth, I. Multilayer engineered nanoliposomes as a novel tool for oral delivery of lipopeptide-based vaccines against group A Streptococcus. Nanomedicine 2016, 11, 1223–1236, doi:10.2217/nnm.16.36.
  65. Shukla, A.; Katare, O.P.; Singh, B.; Vyas, S.P. M-cell targeted delivery of recombinant hepatitis B surface antigen using cholera toxin B subunit conjugated bilosomes. Int. J. Pharm. 2010, 385, 47–52, doi:10.1016/j.ijpharm.2009.10.027.
  66. Singh, P.; Prabakaran, D.; Jain, S.; Mishra, V.; Jaganathan, K.S.; Vyas, S.P. Cholera toxin B subunit conjugated bile salt stabilized vesicles (bilosomes) for oral immunization. Int. J. Pharm. 2004, 278, 379–390, doi:10.1016/j.ijpharm.2004.03.014.
  67. Jain, S.; Harde, H.; Indulkar, A.; Agrawal, A.K. Improved stability and immunological potential of tetanus toxoid containing surface engineered bilosomes following oral administration. Nanomed. Nanotechnol. Biol. Med. 2014, 10, 431–440, doi:10.1016/j.nano.2013.08.012.
  68. Mann, J.F.; Ferro, V.A.; Mullen, A.B.; Tetley, L.; Mullen, M.; Carter, K.C.; Alexander, J.; Stimson, W.H. Optimisation of a lipid based oral delivery system containing A/Panama influenza haemagglutinin. Vaccine 2004, 22, 2425–2429, doi:10.1016/j.vaccine.2003.11.067.
  69. Mann, J.F.; Shakir, E.; Carter, K.C.; Mullen, A.B.; Alexander, J.; Ferro, V.A. Lipid vesicle size of an oral influenza vaccine delivery vehicle influences the Th1/Th2 bias in the immune response and protection against infection. Vaccine 2009, 27, 3643–3649, doi:10.1016/j.vaccine.2009.03.040.
  70. Hernandez-Adame, L.; Angulo, C.; Garcia-Silva, I.; Palestino, G.; Rosales-Mendoza, S. An overview of nanogel-based vaccines. Expert Rev. Vaccines 2019, 18, 951–968, doi:10.1080/14760584.2019.1647783.
  71. Rochereau, N.; Drocourt, D.; Perouzel, E.; Pavot, V.; Redelinghuys, P.; Brown, G.D.; Tiraby, G.; Roblin, X.; Verrier, B.; Genin, C.; et al. Dectin-1 is essential for reverse transcytosis of glycosylated SIgA-antigen complexes by intestinal M cells. PLoS Biol. 2013, 11, e1001658, doi:10.1371/journal.pbio.1001658.
  72. Langermann, S.; Mollby, R.; Burlein, J.E.; Palaszynski, S.R.; Auguste, C.G.; DeFusco, A.; Strouse, R.; Schenerman, M.A.; Hultgren, S.J.; Pinkner, J.S.; et al. Vaccination with FimH adhesin protects cynomolgus monkeys from colonization and infection by uropathogenic Escherichia coli. J. Infect. Dis. 2000, 181, 774–778, doi:10.1086/315258.
  73. Kim, S.H.; Yang, I.Y.; Jang, S.H.; Kim, J.; Truong, T.T.; Van Pham, T.; Truong, N.U.; Lee, K.Y.; Jang, Y.S. C5a receptor-targeting ligand-mediated delivery of dengue virus antigen to M cells evokes antigen-specific systemic and mucosal immune responses in oral immunization. Microbes Infect. 2013, 15, 895–902, doi:10.1016/j.micinf.2013.07.006.
  74. Pridgen, E.M.; Alexis, F.; Kuo, T.T.; Levy-Nissenbaum, E.; Karnik, R.; Blumberg, R.S.; Langer, R.; Farokhzad, O.C. Transepithelial transport of Fc-targeted nanoparticles by the neonatal fc receptor for oral delivery. Sci. Transl. Med. 2013, 5, 213ra167, doi:10.1126/scitranslmed.3007049.
  75. Snoeck, V.; Van den Broeck, W.; De Colvenaer, V.; Verdonck, F.; Goddeeris, B.; Cox, E. Transcytosis of F4 fimbriae by villous and dome epithelia in F4-receptor positive pigs supports importance of receptor-dependent endocytosis in oral immunization strategies. Vet. Immunol. Immunopathol. 2008, 124, 29–40, doi:10.1016/j.vetimm.2006.10.014.
  76. Melkebeek, V.; Rasschaert, K.; Bellot, P.; Tilleman, K.; Favoreel, H.; Deforce, D.; De Geest, B.G.; Goddeeris, B.M.; Cox, E. Targeting aminopeptidase N, a newly identified receptor for F4ac fimbriae, enhances the intestinal mucosal immune response. Mucosal Immunol. 2012, 5, 635–645, doi:10.1038/mi.2012.37.
  77. Van den Broeck, W.; Cox, E.; Goddeeris, B.M. Induction of immune responses in pigs following oral administration of purified F4 fimbriae. Vaccine 1999, 17, 2020–2029, doi:10.1016/s0264-410x(98)00406-x.
  78. Verdonck, F.; De Hauwere, V.; Bouckaert, J.; Goddeeris, B.M.; Cox, E. Fimbriae of enterotoxigenic Escherichia coli function as a mucosal carrier for a coupled heterologous antigen. J. Control. Release Off. J. Control. Release Soc. 2005, 104, 243–258, doi:10.1016/j.jconrel.2005.02.007.
  79. Bakshi, S.; Sanz Garcia, R.; Van der Weken, H.; Tharad, A.; Pandey, S.; Juarez, P.; Virdi, V.; Devriendt, B.; Cox, E.; Depicker, A. Evaluating single-domain antibodies as carriers for targeted vaccine delivery to the small intestinal epithelium. J. Control. Release Off. J. Control. Release Soc. 2020, 321, 416–429, doi:10.1016/j.jconrel.2020.01.033.
  80. da Silva, A.J.; Zangirolami, T.C.; Novo-Mansur, M.T.; Giordano Rde, C.; Martins, E.A. Live bacterial vaccine vectors: An overview. Braz. J. Microbiol. 2014, 45, 1117–1129, doi:10.1590/s1517-83822014000400001.
  81. Perrie, Y.; Mohammed, A.R.; Kirby, D.J.; McNeil, S.E.; Bramwell, V.W. Vaccine adjuvant systems: Enhancing the efficacy of sub-unit protein antigens. Int. J. Pharm. 2008, 364, 272–280, doi:10.1016/j.ijpharm.2008.04.036.
  82. Shah, R. Vaccine uptake in under 19s: NICE Quality Standard (QS 145) 2017. Arch. Dis. Child. Educ. Pract. Ed. 2018, 103, 109, doi:10.1136/archdischild-2017-313391.
  83. Lavelle, E.C.; O’Hagan, D.T. Delivery systems and adjuvants for oral vaccines. Expert Opin. Drug Deliv. 2006, 3, 747–762, doi:10.1517/17425247.3.6.747.
  84. Naili, I.; Vinot, J.; Baudner, B.C.; Bernalier-Donadille, A.; Pizza, M.; Desvaux, M.; Jubelin, G.; D’Oro, U.; Buonsanti, C. Mixed mucosal-parenteral immunizations with the broadly conserved pathogenic Escherichia coli antigen SslE induce a robust mucosal and systemic immunity without affecting the murine intestinal microbiota. Vaccine 2019, 37, 314–324, doi:10.1016/j.vaccine.2018.10.008.
  85. Davitt, C.J.; Lavelle, E.C. Delivery strategies to enhance oral vaccination against enteric infections. Adv. Drug Deliv. Rev. 2015, 91, 52–69, doi:10.1016/j.addr.2015.03.007.
  86. Vajdy, M.; Lycke, N.Y. Cholera toxin adjuvant promotes long-term immunological memory in the gut mucosa to unrelated immunogens after oral immunization. Immunology 1992, 75, 488–492.
  87. Clements, J.D.; Hartzog, N.M.; Lyon, F.L. Adjuvant activity of Escherichia coli heat-labile enterotoxin and effect on the induction of oral tolerance in mice to unrelated protein antigens. Vaccine 1988, 6, 269–277, doi:10.1016/0264-410x(88)90223-x.
  88. Snider, D.P. The Mucosal Adjuvant Activities of ADP-Ribosylating Bacterial Enterotoxins. Crit. Rev. Immunol. 2017, 37, 499–530, doi:10.1615/CritRevImmunol.v37.i2-6.150.
  89. Lycke, N.; Lebrero-Fernandez, C. ADP-ribosylating enterotoxins as vaccine adjuvants. Curr. Opin. Pharmacol. 2018, 41, 42–51, doi:10.1016/j.coph.2018.03.015.
  90. Kim, K.J.; Kim, H.A.; Seo, K.H.; Lee, H.K.; Kang, B.Y.; Im, S.Y. Cholera toxin breakdowns oral tolerance via activation of canonical NF-kappaB. Cell. Immunol. 2013, 285, 92–99, doi:10.1016/j.cellimm.2013.09.006.
  91. Sanchez, J.; Holmgren, J. Virulence factors, pathogenesis and vaccine protection in cholera and ETEC diarrhea. Curr. Opin. Immunol. 2005, 17, 388–398, doi:10.1016/j.coi.2005.06.007.
  92. Holmgren, J.; Czerkinsky, C. Mucosal immunity and vaccines. Nat. Med. 2005, 11, S45-53, doi:10.1038/nm1213.
  93. Wang, J.; Gusti, V.; Saraswati, A.; Lo, D.D. Convergent and divergent development among M cell lineages in mouse mucosal epithelium. J. Immunol. 2011, 187, 5277–5285, doi:10.4049/jimmunol.1102077.
  94. Lu, T.; Moxley, R.A.; Zhang, W. Application of a novel epitope and structure vaccinology-assisted fimbria-toxin multiepitope fusion antigen of enterotoxigenic Escherichia coli for multivalent vaccine development against porcine post-weaning diarrhea. Appl. Environ. Microbiol. 2020, doi:10.1128/AEM.00274-20.
  95. Duan, Q.; Pang, S.; Wu, W.; Jiang, B.; Zhang, W.; Liu, S.; Wang, X.; Pan, Z.; Zhu, G. A multivalent vaccine candidate targeting enterotoxigenic Escherichia coli fimbriae for broadly protecting against porcine post-weaning diarrhea. Vet. Res. 2020, 51, 93, doi:10.1186/s13567-020-00818-5.
  96. Nandre, R.; Ruan, X.; Lu, T.; Duan, Q.; Sack, D.; Zhang, W. Enterotoxigenic Escherichia coli Adhesin-Toxoid Multiepitope Fusion Antigen CFA/I/II/IV-3xSTaN12S-mnLTG192G/L211A-Derived Antibodies Inhibit Adherence of Seven Adhesins, Neutralize Enterotoxicity of LT and STa Toxins, and Protect Piglets against Diarrhea. Infect. Immun. 2018, 86, doi:10.1128/IAI.00550-17.
  97. Ruan, X.; Sack, D.A.; Zhang, W. Genetic fusions of a CFA/I/II/IV MEFA (multiepitope fusion antigen) and a toxoid fusion of heat-stable toxin (STa) and heat-labile toxin (LT) of enterotoxigenic Escherichia coli (ETEC) retain broad anti-CFA and antitoxin antigenicity. PLoS ONE 2015, 10, e0121623, doi:10.1371/journal.pone.0121623.
  98. Seo, H.; Lu, T.; Mani, S.; Bourgeois, A.L.; Walker, R.; Sack, D.A.; Zhang, W. Adjuvant effect of enterotoxigenic Escherichia coli (ETEC) double-mutant heat-labile toxin (dmLT) on systemic immunogenicity induced by the CFA/I/II/IV MEFA ETEC vaccine: Dose-related enhancement of antibody responses to seven ETEC adhesins (CFA/I, CS1-CS6). Hum. Vaccines Immunother. 2020, 16, 419–425, doi:10.1080/21645515.2019.1649555.
  99. Duan, Q.; Lee, K.H.; Nandre, R.M.; Garcia, C.; Chen, J.; Zhang, W. MEFA (multiepitope fusion antigen)-Novel Technology for Structural Vaccinology, Proof from Computational and Empirical Immunogenicity Characterization of an Enterotoxigenic Escherichia coli (ETEC) Adhesin MEFA. J. Vaccines Vaccin. 2017, 8, doi:10.4172/2157-7560.1000367.
  100. Duverger, A.; Jackson, R.J.; van Ginkel, F.W.; Fischer, R.; Tafaro, A.; Leppla, S.H.; Fujihashi, K.; Kiyono, H.; McGhee, J.R.; Boyaka, P.N. Bacillus anthracis edema toxin acts as an adjuvant for mucosal immune responses to nasally administered vaccine antigens. J. Immunol. 2006, 176, 1776–1783, doi:10.4049/jimmunol.176.3.1776.
  101. Price, A.E.; Shamardani, K.; Lugo, K.A.; Deguine, J.; Roberts, A.W.; Lee, B.L.; Barton, G.M. A Map of Toll-like Receptor Expression in the Intestinal Epithelium Reveals Distinct Spatial, Cell Type-Specific, and Temporal Patterns. Immunity 2018, 49, 560–575 e566, doi:10.1016/j.immuni.2018.07.016.
  102. O’Neill, L.A. DNA makes RNA makes innate immunity. Cell 2009, 138, 428–430, doi:10.1016/j.cell.2009.07.021.
  103. Takeda, K.; Akira, S. Toll-like receptors. Curr. Protoc. Immunol. 2015, 109, 14 12 11-14 12 10, doi:10.1002/0471142735.im1412s109.
  104. Kawasaki, T.; Kawai, T. Toll-like receptor signaling pathways. Front. Immunol. 2014, 5, 461, doi:10.3389/fimmu.2014.00461.
  105. Shao, L.; Fischer, D.D.; Kandasamy, S.; Saif, L.J.; Vlasova, A.N. Tissue-specific mRNA expression profiles of porcine Toll-like receptors at different ages in germ-free and conventional pigs. Vet. Immunol. Immunopathol. 2016, 171, 7–16, doi:10.1016/j.vetimm.2016.01.008.
  106. Henrick, B.M.; Yao, X.D.; Zahoor, M.A.; Abimiku, A.; Osawe, S.; Rosenthal, K.L. TLR10 Senses HIV-1 Proteins and Significantly Enhances HIV-1 Infection. Front. Immunol. 2019, 10, 482, doi:10.3389/fimmu.2019.00482.
  107. Williams, A.; Flavell, R.A.; Eisenbarth, S.C. The role of NOD-like Receptors in shaping adaptive immunity. Curr. Opin. Immunol. 2010, 22, 34–40, doi:10.1016/j.coi.2010.01.004.
  108. Sahoo, M.; Ceballos-Olvera, I.; del Barrio, L.; Re, F. Role of the inflammasome, IL-1beta, and IL-18 in bacterial infections. Sci. World J. 2011, 11, 2037–2050, doi:10.1100/2011/212680.
  109. Hardison, S.E.; Brown, G.D. C-type lectin receptors orchestrate antifungal immunity. Nat. Immunol. 2012, 13, 817–822, doi:10.1038/ni.2369.
  110. Rehwinkel, J.; Reis e Sousa, C. RIGorous detection: Exposing virus through RNA sensing. Science 2010, 327, 284–286, doi:10.1126/science.1185068.
  111. Saxena, M.; Yeretssian, G. NOD-Like Receptors: Master Regulators of Inflammation and Cancer. Front. Immunol. 2014, 5, 327, doi:10.3389/fimmu.2014.00327.
  112. Kelley, N.; Jeltema, D.; Duan, Y.; He, Y. The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation. Int. J. Mol. Sci. 2019, 20, 3328, doi:10.3390/ijms20133328.
  113. Hjelm, B.E.; Kilbourne, J.; Herbst-Kralovetz, M.M. TLR7 and 9 agonists are highly effective mucosal adjuvants for norovirus virus-like particle vaccines. Hum. Vaccines Immunother. 2014, 10, 410–416, doi:10.4161/hv.27147.
  114. Baldrick, P.; Richardson, D.; Elliott, G.; Wheeler, A.W. Safety evaluation of monophosphoryl lipid A (MPL): An immunostimulatory adjuvant. Regul. Toxicol. Pharmacol. 2002, 35, 398–413, doi:10.1006/rtph.2002.1541.
  115. Mizel, S.B.; Bates, J.T. Flagellin as an adjuvant: Cellular mechanisms and potential. J. Immunol. 2010, 185, 5677–5682, doi:10.4049/jimmunol.1002156.
  116. Cui, B.; Liu, X.; Fang, Y.; Zhou, P.; Zhang, Y.; Wang, Y. Flagellin as a vaccine adjuvant. Expert Rev. Vaccines 2018, 17, 335–349, doi:10.1080/14760584.2018.1457443.
  117. Treanor, J.J.; Taylor, D.N.; Tussey, L.; Hay, C.; Nolan, C.; Fitzgerald, T.; Liu, G.; Kavita, U.; Song, L.; Dark, I.; et al. Safety and immunogenicity of a recombinant hemagglutinin influenza-flagellin fusion vaccine (VAX125) in healthy young adults. Vaccine 2010, 28, 8268–8274, doi:10.1016/j.vaccine.2010.10.009.
  118. Taylor, D.N.; Treanor, J.J.; Strout, C.; Johnson, C.; Fitzgerald, T.; Kavita, U.; Ozer, K.; Tussey, L.; Shaw, A. Induction of a potent immune response in the elderly using the TLR-5 agonist, flagellin, with a recombinant hemagglutinin influenza-flagellin fusion vaccine (VAX125, STF2.HA1 SI). Vaccine 2011, 29, 4897–4902, doi:10.1016/j.vaccine.2011.05.001.
  119. Bode, C.; Yang, X.P.; Kiu, H.; Klinman, D.M. Suppressive oligodeoxynucleotides promote the development of Th17 cells. PLoS ONE 2013, 8, e67991, doi:10.1371/journal.pone.0067991.
  120. Pirahmadi, S.; Zakeri, S.; Mehrizi, A.A.; Djadid, N.D.; Raz, A.A.; Sani, J.J. Combining Monophosphoryl Lipid A (MPL), CpG Oligodeoxynucleotide (ODN), and QS-21 Adjuvants Induces Strong and Persistent Functional Antibodies and T Cell Responses against Cell-Traversal Protein for Ookinetes and Sporozoites (CelTOS) of Plasmodium falciparum in BALB/c Mice. Infect. Immun. 2019, 87, doi:10.1128/IAI.00911-18.
  121. Ugolini, M.; Gerhard, J.; Burkert, S.; Jensen, K.J.; Georg, P.; Ebner, F.; Volkers, S.M.; Thada, S.; Dietert, K.; Bauer, L.; et al. Recognition of microbial viability via TLR8 drives TFH cell differentiation and vaccine responses. Nat. Immunol. 2018, 19, 386–396, doi:10.1038/s41590-018-0068-4.
  122. Carreno, L.J.; Kharkwal, S.S.; Porcelli, S.A. Optimizing NKT cell ligands as vaccine adjuvants. Immunotherapy 2014, 6, 309–320, doi:10.2217/imt.13.175.
  123. Gutjahr, A.; Papagno, L.; Nicoli, F.; Kanuma, T.; Kuse, N.; Cabral-Piccin, M.P.; Rochereau, N.; Gostick, E.; Lioux, T.; Perouzel, E.; et al. The STING ligand cGAMP potentiates the efficacy of vaccine-induced CD8+ T cells. JCI Insight 2019, 4, doi:10.1172/jci.insight.125107.
  124. Kawane, K.; Motani, K.; Nagata, S. DNA degradation and its defects. Cold Spring Harb. Perspect. Biol. 2014, 6, doi:10.1101/cshperspect.a016394.
  125. Picker, L.J.; Butcher, E.C. Physiological and molecular mechanisms of lymphocyte homing. Annu. Rev. Immunol. 1992, 10, 561–591, doi:10.1146/annurev.iy.10.040192.003021.
  126. Gregor, C.E.; Foeng, J.; Comerford, I.; McColl, S.R. Chemokine-Driven CD4(+) T Cell Homing: New Concepts and Recent Advances. Adv. Immunol. 2017, 135, 119–181, doi:10.1016/
  127. Mwanza-Lisulo, M.; Kelly, P. Potential for use of retinoic acid as an oral vaccine adjuvant. Philos. Trans. R. Soc. Lond. Ser. B Biol. Sci. 2015, 370, doi:10.1098/rstb.2014.0145.
  128. Sirisinha, S. The pleiotropic role of vitamin A in regulating mucosal immunity. Asian Pac. J. Allergy Immunol. 2015, 33, 71–89.
  129. Wang, S.; Wu, C.; Zhang, Y.; Zhong, Q.; Sun, H.; Cao, W.; Ge, G.; Li, G.; Zhang, X.F.; Chen, J. Integrin alpha4beta7 switches its ligand specificity via distinct conformer-specific activation. J. Cell Biol. 2018, 217, 2799–2812, doi:10.1083/jcb.201710022.
  130. Kunkel, E.J.; Campbell, J.J.; Haraldsen, G.; Pan, J.; Boisvert, J.; Roberts, A.I.; Ebert, E.C.; Vierra, M.A.; Goodman, S.B.; Genovese, M.C.; et al. Lymphocyte CC chemokine receptor 9 and epithelial thymus-expressed chemokine (TECK) expression distinguish the small intestinal immune compartment: Epithelial expression of tissue-specific chemokines as an organizing principle in regional immunity. J. Exp. Med. 2000, 192, 761–768, doi:10.1084/jem.192.5.761.
  131. Papadakis, K.A.; Prehn, J.; Nelson, V.; Cheng, L.; Binder, S.W.; Ponath, P.D.; Andrew, D.P.; Targan, S.R. The role of thymus-expressed chemokine and its receptor CCR9 on lymphocytes in the regional specialization of the mucosal immune system. J. Immunol. 2000, 165, 5069–5076, doi:10.4049/jimmunol.165.9.5069.
  132. Parmo-Cabanas, M.; Garcia-Bernal, D.; Garcia-Verdugo, R.; Kremer, L.; Marquez, G.; Teixido, J. Intracellular signaling required for CCL25-stimulated T cell adhesion mediated by the integrin alpha4beta1. J. Leukoc. Biol. 2007, 82, 380–391, doi:10.1189/jlb.1206726.
  133. Gehad, A.; Al-Banna, N.A.; Vaci, M.; Issekutz, A.C.; Mohan, K.; Latta, M.; Issekutz, T.B. Differing requirements for CCR4, E-selectin, and alpha4beta1 for the migration of memory CD4 and activated T cells to dermal inflammation. J. Immunol. 2012, 189, 337–346, doi:10.4049/jimmunol.1102315.
  134. Habtezion, A.; Nguyen, L.P.; Hadeiba, H.; Butcher, E.C. Leukocyte Trafficking to the Small Intestine and Colon. Gastroenterology 2016, 150, 340–354, doi:10.1053/j.gastro.2015.10.046.
  135. Cerutti, A. The regulation of IgA class switching. Nat. Rev. Immunol. 2008, 8, 421–434, doi:10.1038/nri2322.
  136. Chorny, A.; Puga, I.; Cerutti, A. Innate signaling networks in mucosal IgA class switching. Adv. Immunol. 2010, 107, 31–69, doi:10.1016/B978-0-12-381300-8.00002-2.
  137. Marks, E.; Ortiz, C.; Pantazi, E.; Bailey, C.S.; Lord, G.M.; Waldschmidt, T.J.; Noelle, R.J.; Elgueta, R. Retinoic Acid Signaling in B Cells Is Required for the Generation of an Effective T-Independent Immune Response. Front. Immunol. 2016, 7, 643, doi:10.3389/fimmu.2016.00643.
  138. Upham, J.W.; Sehmi, R.; Hayes, L.M.; Howie, K.; Lundahl, J.; Denburg, J.A. Retinoic acid modulates IL-5 receptor expression and selectively inhibits eosinophil-basophil differentiation of hemopoietic progenitor cells. J. Allergy Clin. Immunol. 2002, 109, 307–313, doi:10.1067/mai.2002.121527.
  139. Diehl, S.A.; Schmidlin, H.; Nagasawa, M.; Blom, B.; Spits, H. IL-6 triggers IL-21 production by human CD4+ T cells to drive STAT3-dependent plasma cell differentiation in B cells. Immunol. Cell Biol. 2012, 90, 802–811, doi:10.1038/icb.2012.17.
  140. Kumar, A.; Saba, J.D. Regulation of Immune Cell Migration by Sphingosine-1-Phosphate. Cell. Mol. Biol. (OMICS) 2015, 61, 121.
  141. Mora, J.R.; Iwata, M.; Eksteen, B.; Song, S.Y.; Junt, T.; Senman, B.; Otipoby, K.L.; Yokota, A.; Takeuchi, H.; Ricciardi-Castagnoli, P.; et al. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 2006, 314, 1157–1160, doi:10.1126/science.1132742.
  142. Cao, A.T.; Yao, S.; Gong, B.; Nurieva, R.I.; Elson, C.O.; Cong, Y. Interleukin (IL)-21 promotes intestinal IgA response to microbiota. Mucosal Immunol. 2015, 8, 1072–1082, doi:10.1038/mi.2014.134.
  143. Tezuka, H.; Ohteki, T. Regulation of IgA Production by Intestinal Dendritic Cells and Related Cells. Front. Immunol. 2019, 10, 1891, doi:10.3389/fimmu.2019.01891.
  144. Hatayama, T.; Segawa, R.; Mizuno, N.; Eguchi, S.; Akamatsu, H.; Fukuda, M.; Nakata, F.; Leonard, W.J.; Hiratsuka, M.; Hirasawa, N. All-Trans Retinoic Acid Enhances Antibody Production by Inducing the Expression of Thymic Stromal Lymphopoietin Protein. J. Immunol. 2018, 200, 2670–2676, doi:10.4049/jimmunol.1701276.
  145. Xiao, S.; Jin, H.; Korn, T.; Liu, S.M.; Oukka, M.; Lim, B.; Kuchroo, V.K. Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-beta-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression. J. Immunol. 2008, 181, 2277–2284, doi:10.4049/jimmunol.181.4.2277.
  146. Hammerschmidt, S.I.; Friedrichsen, M.; Boelter, J.; Lyszkiewicz, M.; Kremmer, E.; Pabst, O.; Forster, R. Retinoic acid induces homing of protective T and B cells to the gut after subcutaneous immunization in mice. J. Clin. Investig. 2011, 121, 3051–3061, doi:10.1172/JCI44262.
  147. Tan, X.; Sande, J.L.; Pufnock, J.S.; Blattman, J.N.; Greenberg, P.D. Retinoic acid as a vaccine adjuvant enhances CD8+ T cell response and mucosal protection from viral challenge. J. Virol. 2011, 85, 8316–8327, doi:10.1128/JVI.00781-11.
  148. Chen, X.; Tu, C.; Qin, T.; Zhu, L.; Yin, Y.; Yang, Q. Retinoic acid facilitates inactivated transmissible gastroenteritis virus induction of CD8(+) T-cell migration to the porcine gut. Sci. Rep. 2016, 6, 24152, doi:10.1038/srep24152.
  149. Christensen, D.; Bollehuus Hansen, L.; Leboux, R.; Jiskoot, W.; Christensen, J.P.; Andersen, P.; Dietrich, J. A Liposome-Based Adjuvant Containing Two Delivery Systems with the Ability to Induce Mucosal Immunoglobulin A Following a Parenteral Immunization. ACS Nano 2019, 13, 1116–1126, doi:10.1021/acsnano.8b05209.
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