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      Buccal and sublingual vaccine delivery.

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          Abstract

          Because of their large surface area and immunological competence, mucosal tissues are attractive administration and target sites for vaccination. An important characteristic of mucosal vaccination is its ability to elicit local immune responses, which act against infection at the site of pathogen entry. However, mucosal surfaces are endowed with potent and sophisticated tolerance mechanisms to prevent the immune system from overreacting to the many environmental antigens. Hence, mucosal vaccination may suppress the immune system instead of induce a protective immune response. Therefore, mucosal adjuvants and/or special antigen delivery systems as well as appropriate dosage forms are required in order to develop potent mucosal vaccines. Whereas oral, nasal and pulmonary vaccine delivery strategies have been described extensively, the sublingual and buccal routes have received considerably less attention. In this review, the characteristics of and approaches for sublingual and buccal vaccine delivery are described and compared with other mucosal vaccine delivery sites. We discuss recent progress and highlight promising developments in the search for vaccine formulations, including adjuvants and suitable dosage forms, which are likely critical for designing a successful sublingual or buccal vaccine. Finally, we outline the challenges, hurdles to overcome and formulation issues relevant for sublingual or buccal vaccine delivery.

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          Most cited references74

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          Transient Facial Nerve Paralysis (Bell's Palsy) following Intranasal Delivery of a Genetically Detoxified Mutant of Escherichia coli Heat Labile Toxin

          Background An association was previously established between facial nerve paralysis (Bell's palsy) and intranasal administration of an inactivated influenza virosome vaccine containing an enzymatically active Escherichia coli Heat Labile Toxin (LT) adjuvant. The individual component(s) responsible for paralysis were not identified, and the vaccine was withdrawn. Methodology/Principal Findings Subjects participating in two contemporaneous non-randomized Phase 1 clinical trials of nasal subunit vaccines against Human Immunodeficiency Virus and tuberculosis, both of which employed an enzymatically inactive non-toxic mutant LT adjuvant (LTK63), underwent active follow-up for adverse events using diary-cards and clinical examination. Two healthy subjects experienced transient peripheral facial nerve palsies 44 and 60 days after passive nasal instillation of LTK63, possibly a result of retrograde axonal transport after neuronal ganglioside binding or an inflammatory immune response, but without exaggerated immune responses to LTK63. Conclusions/Significance While the unique anatomical predisposition of the facial nerve to compression suggests nasal delivery of neuronal-binding LT–derived adjuvants is inadvisable, their continued investigation as topical or mucosal adjuvants and antigens appears warranted on the basis of longstanding safety via oral, percutaneous, and other mucosal routes.
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            Characterization of a mutant Escherichia coli heat-labile toxin, LT(R192G/L211A), as a safe and effective oral adjuvant.

            Despite the fact that the adjuvant properties of the heat-labile enterotoxins of Escherichia coli (LT) and Vibrio cholerae (CT) have been known for more than 20 years, there are no available oral vaccines containing these molecules as adjuvants, primarily because they are both very potent enterotoxins. A number of attempts with various degrees of success have been made to reduce or eliminate the enterotoxicity of LT and CT so they can safely be used as oral adjuvants or immunogens. In this report we characterize the structural, enzymatic, enterotoxic, and adjuvant properties of a novel mutant of LT, designated LT(R192G/L211A), or dmLT. dmLT was not sensitive to trypsin activation, had reduced enzymatic activity for induction of cyclic AMP in Caco-2 cells, and exhibited no enterotoxicity in the patent mouse assay. Importantly, dmLT retained the ability to function as an oral adjuvant for a coadministered antigen (tetanus toxoid) and to elicit anti-LT antibodies. In vitro and in vivo data suggest that the reduced enterotoxicity of this molecule compared to native LT or the single mutant, LT(R192G), is a consequence of increased sensitivity to proteolysis and rapid intracellular degradation in mammalian cells. In conclusion, dmLT is a safe and powerful detoxified enterotoxin with the potential to function as a mucosal adjuvant for coadministered antigens and to elicit anti-LT antibodies without undesirable side effects.
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              Function of mucosa-associated lymphoid tissue in antibody formation.

              Abundant evidence supports the notion that human intestinal plasma cells are largely derived from B cells initially activated in gut-associated lymphoid tissue (GALT). Nevertheless, insufficient knowledge exists about the uptake, processing, and presentation of luminal antigens occurring in GALT to accomplish priming and sustained expansion of mucosal B cells. Also, it is unclear how the germinal center reaction so strikingly promotes class switch to IgA and expression of J chain, although the commensal microbiota appears to contribute to both diversification and memory. B-cell migration from GALT to the intestinal lamina propria is guided by rather well-defined adhesion molecules and chemokines/chemokine receptors, but the cues directing homing to secretory effector sites beyond the gut require better definition. In this respect, the role of human Waldeyer's ring (including adenoids and the palatine tonsils) as a regional mucosa-associated lymphoid tissue must be better defined, although the balance of evidence suggests that it functions as nasopharynx-associated lymphoid tissue (NALT) like the characteristic NALT structures in rodents. Altogether, data suggest a remarkable compartmentalization of the mucosal immune system that must be taken into account in the development of effective local vaccines to protect specifically the airways, small and large intestines, and the female genital tract.
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                Author and article information

                Journal
                J Control Release
                Journal of controlled release : official journal of the Controlled Release Society
                Elsevier BV
                1873-4995
                0168-3659
                Sep 28 2014
                : 190
                Affiliations
                [1 ] Intravacc (Institute for Translational Vaccinology), Bilthoven, The Netherlands. Electronic address: heleen.kraan@intravacc.nl.
                [2 ] Division of Drug Delivery Technology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands.
                [3 ] Institut de Pharmacologie Moleculaire et Cellulaire, UMR 7275 CNRS-INSERM-UNSA, Valbonne, France.
                [4 ] Intravacc (Institute for Translational Vaccinology), Bilthoven, The Netherlands; Division of Drug Delivery Technology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands.
                [5 ] Intravacc (Institute for Translational Vaccinology), Bilthoven, The Netherlands. Electronic address: Jean-pierre.amorij@intravacc.nl.
                Article
                S0168-3659(14)00386-1
                10.1016/j.jconrel.2014.05.060
                24911355
                ab0cb1c1-426a-4dfa-ac0c-e037dfcc9e04
                History

                Adjuvant,Administration route,Buccal,Dosage form,Sublingual,Vaccine delivery

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