The mucosal immune system is the target of diseases like cholera, whooping cough and HIV among others and mucosal vaccines induce immune responses at the site. Despite this knowledge there are very few effective mucosal vaccines on the market. This review gives an introduction to the underlying immunological events that lead to tolerance in the gut, the events behind an antigen breach, the challenges facing new vaccine design and how those hurdles may be overcome in the years to come. Although not exhaustive the review covers adjuvants, delivery systems and touches upon the recent advances in the field of mucosal vaccine design.
Vaccines have come a long way in terms of design; scope, implementation and can protect us from many diseases. The pinnacle of vaccination success is undoubtedly the eradication of smallpox in 1979. Yet there are many more deadly diseases like HIV which still remain unchallenged. These diseases exploit the mucosal surfaces in the human body which include the gut, respiratory and urogenital tracts. So as logic goes, it would be prudent to introduce mucosal immunity at the site of infection and as a consequence confer systemic immunity to the host. The dearth of effective mucosal vaccines is a cause of concern and needs addressing. Simply put, the vaccine should induce an immune response at the mucosal site after penetrating the epithelium, by activating T and B cell responses. However antigen uptake is poor, a well established immune response doesn't occur and mucosal tolerance to the vaccine is possible (Borges et al. 2009). To circumvent these issues, researchers have devised bacterial and synthetic adjuvants, tried different delivery vehicles and routes to elicit a lasting immune response (Ryan et al. 2001; Neutra and Kozlowski 2006). There are safety concerns involved about delivery, dosage, efficacy and quantification of immune response (Eriksson and Holmgren 2002), but the number of advantages and the diseases that could be vaccinated against encourage further research into this field (Borges et al. 2009).
The mucosal immune system
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The mucosal immune system comprising the gastrointestinal tract, lower and upper respiratory tracts and the urogenital tract, plays a vital role in preventing the advent of disease in these organs. Characteristic features that distinguishes it from the systemic immune system include organized compartments of lymphoid tissue like Peyer's patches (PP) with specialized microfold (M) cells that take up antigen, constant presence of memory and non-specific activated T-cells even in homeostatic conditions, production of secretory IgA (SIgA) (Brandtzaeg 2009) and the ability to control dendritic cell (DC) maturation that leads to mucosal tolerance.
Antigens are internalized by M cells (Fig 1) by ways of endocytosis and phagocytosis and sampled by DCs which in turn activate naïve T-cells brought into the PP via high endothelial venules. These mature T-cells lose their CCR7 and L-selectin receptors and drain out to the thoracic duct by the mesenteric lymph nodes (MLN) and recirculate back to the gut, whereupon these T-cells bearing CCR9 and α4:β7 integrin interact with the mucosal vascular addressin (MAdCAM-1) and CCL25 and gain access to the lamina propia of the gut. As MAdCAM-1 is expressed in other mucosal systems, priming the gut can produce effector T-cells that target the respiratory and urogenital tracts (Neutra and Kozlowski 2006; Murphy 2007; Borges et al. 2009; Chadwick et al. 2009).
Fig 1 : Events of antigen uptake and processing by gut associated lymphoid tissue(GALT). a| Entry of DCs via the high epithelial venule (HEV). b| Migration of T and B cells to M cells. c| A few DCs migrate to the follicle-associated epithelium. d| DCs capture antigens that arrive via M cells. e| movement of the antigen into the B-cell zone and drainage to MLN. f| The presentation of antigen to naïve T-cells by the DCs. Figure from (Neutra and Kozlowski 2006).
The plasma cells of the gut produce secretory IgA (dimeric IgA with a J chain) by the class switching of naïve B cells, mediated by the presence of transforming factor β (TGF-β). SIgA migrates across the epithelium by transcytosis (carrying out with it any antigen) and protects the cell from antigen contact with the epithelium and by antigen neutralization (Holmgren and Czerkinsky 2005; Neutra and Kozlowski 2006; Murphy 2007; Borges et al. 2009; Chadwick et al. 2009).
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Understanding mucosal tolerance
Figure 2 : Mucosal tolerance and the role of DCs . a| Commensal bacteria do not invade the mucosa and hence does not mount an immune response. The DCs that sample commensals give weak co-stimulatory signals to the naïve CD4 T-cells, which then differentiate into Treg cells. Once activated they produce transcription factor Foxp3 and secrete IL-10 that functions as an immunosuppressant which dampens the cell mediated activities of Th1 and antibody producing activities of Th2. b| When the antigen invades the mucosa, the DCs are activated and express IL-12 and presentation to T-cells in the MLN results in differentiation into Th1 and Th2 cells. Figure from (Coombes and Powrie 2008).
The gut is constantly bombarded by innocuous food particles, microflora and occasionally foreign microbial antigens. Therefore the mucosal system has to discern which antigens to tolerate and which to induce a response to (Fig 2) (Murphy 2007; Coombes and Powrie 2008). A concern is that the vaccine might elicit a weak immune response and therefore induce tolerance instead of a T-cell response. A better understanding of tolerance and targeting of the cellular elements (example: TLR7 and TLR9) responsible will yield efficacious vaccines (Borges et al. 2009).
Mucosal Vaccines: Advantages and Pitfalls
The need for mucosal vaccines is justified as they are easy to administer, painless, easy to store and could potentially treat a variety of diseases like Human Immunodeficiency Virus (HIV), Tuberculosis, Hepatitis B, whooping cough that infect the body through the mucosal route.
However as of 2009 there are only six licensed mucosal vaccines that treat polio, cholera, typhoid, rotavirus and influenza (Holmgren and Czerkinsky 2005). Mucosal vaccine design has taken a hit because of several factors: dilution upon epithelial deposition, trapping by mucus, greater required dosages due to low uptake of antigen, stability issues due to protease attack and inability to accurately quantify mucosal immune response (Neutra and Kozlowski 2006; Borges et al. 2009) . A great concern is that the vaccine might cause tolerance and hence not mount an immune response (Mayer and Shao 2004).
Countering the Pitfalls
Optimizing the delivery routes, designing appropriate adjuvants and design of micro particles that specifically bind to the M cells are certain ways that future vaccines could see success.
Re-engineered cholera toxin (CT) and E.coli heat labile enterotoxin (LT) can be used to elicit SIgA response to pathogens, although there is a reduced adjuvanicity due to the removal of the A1 subunit that causes toxicity (Chadwick et al. 2009; Negri et al. 2009). However these compounds could make their way to the brain via the olfactory nerve and has caused concern in their use (Fujihashi et al. 2002). DNA ( bacterial or synthetic) that contain unmethylated CpG motifs acts as an adjuvant by stimulating Toll-like receptor 9 (TLR) cells (Ryan et al. 2001; Eriksson and Holmgren 2002; Borges et al. 2009; Pun et al. 2009). Another adjuvant available is CTA1-DD (Lycke 2005); a molecule that is made from the cholera A1 toxin subunit linked to a Staph.aureus protein A. Monophosphoryl lipid A from Salmonella minnesota induces macrophage mediated Interferon γ and Interleukin 12 release by the NFκB pathway (Ryan et al. 2001) .
Different delivery systems exist that can introduce the vaccine to the mucosal delivery site and ensure its safety against degradation (Table 1). Several factors like surface charge, hydrophobicity and particle size affects the antigen integrity and success of uptake by mucosal epithelia's M cells. Poly (lactide-co-glycolide) or PLG is a biodegradable polymer that has shown to mediate M cell targeting by conjugating an antigen that targets claudin 4 (Rajapaksa et al. 2009).
Liposomes have been shown to be stable under varying pH conditions and work best when conjugated to the immunomodulator. Mutated Streptococcus mutans delivered with liposomes nasally drove the increased production of SIgA (Childers et al. 1999).
Chitosan (glucosamine and N-acetylglucosamine),derived from chitin (Ryan et al. 2001), helps in the opening of tight junctions at the mucosal surface and has been shown to induce T-helper cells (Th2) in mice when conjugated with a mutant diphtheria toxin and introduced nasally (van der Lubben et al. 2003; Kang et al. 2009).
Plant based vaccines have been used to evoke an immune response in mice recently (Takahashi et al. 2009).
Table 1: A list of carriers, antigens and mucosal routes. These are adopted in vaccine design in an effort to overcome poor antigen uptake by the epithelium (Shahiwala et al. 2007).
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A mucosal vaccine for AIDS is in the works which employs a modified Tian Tan vaccinia carrying a spike glycoprotein from SARS (Chen 2009). Another promising effort shows lowered SIV load in the gut of macaques after a cutaneous delivery of several genes conjugated to LT .An efficacious murine model sublingual vaccine for influenza with a modified LT adjuvant showed no collection in the olfactory bulb. And lectin mimetics has driven elevated levels of INF-γ and IL-17 (Cranage and Manoussaka 2009).
Although the majority of micro-organisms invade the human body via mucosal epithelia, there are still far too few effective vaccinations on the market. This is attributed to low antigen uptake by the epithelium, lack of memory cell formation, antigen degradation by harsh environments, possible tolerance to vaccine and safety concerns. Also the results obtained in animal models cannot be directly related to human cases which further compounds data interpretation. To bypass some of the issues, antigens are conjugated to adjuvants to elicit a better, lasting immune response. There are also better delivery systems ranging from liposomes to chitosan nanoparticles that effectively deliver the antigen load to the microfold cell. But safety concerns regarding adjuvants coupled with the decision of delivery route and technical issues relating to immune response post vaccination are some hurdles that face mucosal vaccine design despite the increase in knowledge base in this area. Despite the setbacks, there are promising strides in design of oral and nasal vaccines for a number of diseases including HIV that are in its initial stages, but as always, rigorous testing ,efficacy and safety in animal models must be confirmed before clinical trials on humans can commence.