Macpherson, K. McCoy, F. Johansen, and P. Macpherson, B. Yilmaz, J. Limenitakis, and S. Macpherson and N. Pabst, V. Cerovic, and M. S8—S15, Tarelli, A. Smith, B. Hendry, S. Challacombe, and S. Castro and M. Kaetzel, J. Mestecky, and F. Johansen and C. Ahluwalia, M. Magnusson, and L. Brandtzaeg, I. Farstad, F. Johansen et al. Craig and J. Brandtzaeg, H.
Kiyono, R. Pabst, and M. Farache, I. Koren, I. Milo et al. Mabbott, D. Donaldson, H. Ohno, I. Williams, and A. Kujala, C. Raymond, M. Romeijn et al. McDole, L. Wheeler, K. McDonald et al. Reboldi, T. Arnon, L. Rodda, A. Atakilit, D. Sheppard, and J. Stavnezer and C. Stavnezer and J. Cao, S. Yao, B. Gong, R. Nurieva, C. Elson, and Y.
Bergqvist, E. Stensson, M. Bemark, and N. Ferrari, S. Giliani, A. Insalaco et al. Kubinak, C. Petersen, W. Stephens et al. Lycke, L. Specific inactivation of these allergen-specific T H 2 cells through clonal anergy, induction of T H 1-like cells, which are known to antagonize T H 2 cells immune deviation , or induction of regulatory cells, are considered to be promising approaches for intervention in type I allergic diseases. Systemic allergen-specific immunotherapy by the injection of multiple 20 doses or more small but increasing amounts of allergen can change a pre-existing allergic T H 2 immune response to a nonallergic T H 1 response.
It is expensive and complicated, and also carries the risk of allergic and sometimes even life-threatening anaphylactic reactions. The ability of secretory antibodies to interfere with the entry of allergens through the airway and the gut epithelium has been underestimated, despite the fact that SIgA is known to be noninflammatory and its daily output in external secretions exceeds that of IgG and by far that of IgE antibodies, which it could outcompete for binding to the target allergen.
Furthermore, and at variance with systemic immunization, mucosal administration of antigens can induce SIgA antibody responses and, concomitantly, local and peripheral suppression of inflammatory responses.
Because mucosal, especially oral or sublingual, vaccines are easier to deliver and safer than injectable vaccines, the concept of 'mucosal desensitization' has become increasingly attractive as an alternative to subcutaneous immunotherapy against type I allergies.
To date, more than 20 double-blind, placebo-controlled clinical trials of mucosal desensitization have been performed in individuals with allergic rhinitis and in individuals with bronchial asthma 83 Table 2. Beneficial effects have been reported in the majority of these studies. In long-term studies of individuals with allergic asthma to house dust mites, oral-sublingual immunotherapy with allergen extract was efficient in reducing the frequency of asthmatic attacks and the use of antiasthmatic drugs Promising results have also been reported in individuals with atopic dermatitis Overall, the doses of allergen used in these trials and the frequency of allergen administrations have been rather high and, in the majority of trials, natural, and thus inherently heterogeneous, allergen extracts have been used.
New techniques including allergen modification, allergen gene vaccination or peptide analogs in combination with selected adjuvants should further increase the safety and efficacy of mucosal immunotherapy in allergies and asthma The development of mucosal vaccines, whether for prevention of infectious diseases or for oral-tolerance immunotherapy, requires efficient antigen delivery and adjuvant systems.
Ideally, such systems should i protect the vaccine from physical elimination and enzymatic digestion, ii target mucosal inductive sites including membrane, or M, cells, and iii at least for vaccines against infections, appropriately stimulate the innate immune system to generate effective adaptive immunity.
Mucosal delivery systems. A multitude of such vehicles have been developed, including various inert systems as well as live attenuated bacterial or viral vector systems 87 , 88 , Best known among the inert systems are various lipid-based structures with entrapped antigens, such as liposomes, immunostimulating complexes ISCOMs and so-called cochleates; different types of biodegradable particles based on starch or copolymers of lactic and glycolic acid; and different mucosa-binding proteins, including both classical plant lectins and bacterial proteins such as the binding subunit portions of cholera toxin or E.
Among the many live bacterial vectors developed, two main categories can be distinguished: those based on attenuated pathogens such as Salmonella typhi or S. The initial use of vaccinia as the primary virus vector candidate has progressively been replaced by other poxviruses, such as canary poxvirus, and by adenoviruses. Several of the live vectors of both bacterial and viral origin have also been engineered to provide various cytokines to further stimulate or modulate the immune responses induced.
But although many of these systems have shown promise in animal studies, there is still neither an inert nor a live vector approved for human use. Promising results have recently been reported from the use of so-called pseudoviruses, or virus-like particles VLPs. These are self-assembling, nonreplicating viral core structures, often from nonenveloped viruses, that are produced recombinantly in vitro. VLPs are cheap and easy to make, as well as highly immunogenic, and are therefore of commercial interest as viral vaccines in their own right.
VLPs can, however, also be used as combined carriers and adjuvants both for foreign antigens expressed recombinantly on their surface, and for DNA vaccines carried within VLPs. VLPs are especially interesting from a mucosal vaccine point of view, as they offer the opportunity to use the natural route of transmission of the parent virus for vaccine delivery.
Promising use of this principle, resulting in both SIgA and CTL mucosal immune responses and protection against mucosal pathogen challenge, has been reported from studies both in animals and in humans with VLPs from several mucosal viral pathogens including papillomavirus 90 , calicivirus 91 and hepatitis E virus Mucosal adjuvants. When it comes to specific adjuvants, the best-studied and most potent mucosal adjuvants in experimental systems are cholera toxin and E. One such product is the completely nontoxic recombinantly produced CTB, which, depending upon the nature of the coadministered antigen, can be used to promote either mucosal immunity mainly SIgA to pathogens or peripheral anti-inflammatory tolerance to self-antigens or allergens 93 ; the latter approach has recently also been tested clinically with promising results in individuals with Behcet disease Mutant heat-labile enterotoxin or cholera toxin proteins have also been made in which the toxic-active A A1 subunit has been modified in various ways to remove the 'toxic' ADP-ribosylating activity, which leads to toxicity.
In general, a loss of toxicity has been matched with a corresponding loss of adjuvanticity, but a few proteins are available with significant adjuvanticity in the absence of detectable toxicity when given intranasally 95 , 96 , Yet another approach has been to prepare hybrid molecules in which the fully active cholera toxin A1 subunit has been linked to an engineered specific APC-binding protein derived from Staphylococcus aureus protein A CTA1-DD This specifically targets the molecule to B cells and has, in experimental systems, proven to be a very efficient and safe adjuvant for coadministered antigens when given intranasally.
CpG ODN stimulate cells that express Toll-like receptor 9, thereby initiating an immunomodulating cascade. Although as yet mainly considered for systemic use, CpG ODN has been found after nasal, oral or vaginal administration to markedly enhance both innate and adaptive mucosal immunity in animal models 99 , , effects which were especially pronounced when CpG ODN was linked to the B subunit protein of cholera toxin For many years, mucosal immunity and mucosal vaccines have attracted less than their due share of research and development, considering that most infections and environmental allergies have a mucosal portal of entry.
But in recent years, methodological advances allowing more intense study of mucosal immune responses have led to growing interest in both trying to better understand the specific features of mucosal as compared with systemic immunity, and to develop mucosal vaccines for preventing mucosal infections and for treating allergic or autoimmune diseases.
Methods that facilitate the monitoring of mucosal immune responses in humans including infants and young children—the major target groups for vaccination against infectious diseases—have been developed, primarily for measuring secretory antibody responses.
But practical assays for assessing mucosal T cell reactivity in clinical and in field settings are still scarce and methods for predicting efficacy of candidate mucosal immunotherapeutics in humans are lacking. Mucosal immune responses in the humoral-secretory arm of the immune system develop earlier than systemic immune responsiveness, conferring a logistical advantage for mucosal vaccination in infants.
On the other hand, it seems that mucosal tolerance develops much later, explaining, in part, the frequency and often transient nature of food allergies in young children. There is yet no precise knowledge regarding the ontogeny of the different mucosal regulatory cells for which selective targeting and activation by appropriate delivery systems and immunomodulating agents could be advantageous for preventing allergies and tissue-damaging inflammatory reactions.
Although effective oral-mucosal vaccines for human use are available, it is increasingly appreciated that the development of a broader range of mucosal vaccines, whether for prevention of infectious diseases or for immunotherapy of autoimmune, allergic or infectious inflammatory disorders, will require access to antigen delivery systems that can help present the relevant 'protective antigens' efficiently to the mucosal immune system as well as effective adjuvants to promote and direct the mucosal immune response toward the desired effect.
Significant advances have recently been made in the development of improved mucosal vaccine delivery systems. Novel mucosal adjuvants with prospects for human use have also been designed. Although these developments may promising useful mucosal vaccines, their usefulness in humans has yet to be established. It remains to be seen to what extent the safety and efficacy profiles established in animal models hold true in genetically diverse human subjects who also may differ significantly in their intestinal flora, nutritional status and previous immunological experience, all of which are factors that have been found to affect mucosal vaccine efficacy.
Indeed, several mucosal vaccines, including oral live cholera vaccine and rotavirus vaccine candidates as well as OPV, have been found to work less well in developing country settings than in industrialized countries. The pandemic HIV infection problem presents additional challenges with regard to both vaccine safety and efficacy, especially for live attenuated vaccines.
Although the main problems to date have dealt with lesser than expected efficacy of mucosal vaccines when tested in specific populations and settings, usually those prevailing in developing countries, it is also notable that two recently developed mucosal vaccines for human use—a live attenuated oral rotavirus vaccine and a nasal influenza subunit vaccine given together with unmodified E.
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