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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

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          Abstract

          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 The individual component(s) responsible for paralysis were not identified, and the vaccine was withdrawn.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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          Most cited references 19

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          Cholera toxin structure, gene regulation and pathophysiological and immunological aspects.

          Many notions regarding the function, structure and regulation of cholera toxin expression have remained essentially unaltered in the last 15 years. At the same time, recent findings have generated additional perspectives. For example, the cholera toxin genes are now known to be carried by a non-lytic bacteriophage, a previously unsuspected condition. Understanding of how the expression of cholera toxin genes is controlled by the bacterium at the molecular level has advanced significantly and relationships with cell-density-associated (quorum-sensing) responses have recently been discovered. Regarding the cell intoxication process, the mode of entry and intracellular transport of cholera toxin are becoming clearer. In the immunological field, the strong oral immunogenicity of the non-toxic B subunit of cholera toxin (CTB) has been exploited in the development of a now widely licensed oral cholera vaccine. Additionally, CTB has been shown to induce tolerance against co-administered (linked) foreign antigens in some autoimmune and allergic diseases.
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            Safety of MF59 adjuvant.

            The need to enhance the immunogenicity of purified subunit antigens has prompted the development of new adjuvants. The adjuvant emulsion MF59 has been tested in animals in combination with different antigens and finally evaluated in humans. It was licensed after the successful outcome of preclinical and clinical testing. This paper summarizes the main characteristics of the MF59 adjuvant, including animal testing, clinical experience with various vaccines, and information from current postmarketing surveillance data. This review supports the hypothesis that MF59 is a safe adjuvant for human use.
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              Cutting edge: the mucosal adjuvant cholera toxin redirects vaccine proteins into olfactory tissues.

              We tested the notion that the mucosal adjuvant cholera toxin (CT) could target, in addition to nasal-associated lymphoreticular tissues, the olfactory nerves/epithelium (ON/E) and olfactory bulbs (OBs) when given intranasally. Radiolabeled CT ((125)I-CT) or CT-B subunit ((125)I-CT-B), when given intranasally to mice, entered the ON/E and OB and persisted for 6 days; however, neither molecule was present in nasal-associated lymphoreticular tissues beyond 24 h. This uptake into olfactory regions was monosialoganglioside (GM1) dependent. Intranasal vaccination with (125)I-tetanus toxoid together with unlabeled CT as adjuvant resulted in uptake into the ON/E but not the OB, whereas (125)I-tetanus toxoid alone did not penetrate into the CNS. We conclude that GM1-binding molecules like CT target the ON/E and are retrograde transported to the OB and may promote uptake of vaccine proteins into olfactory neurons. This raises concerns about the role of GM1-binding molecules that target neuronal tissues in mucosal immunity.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2009
                16 September 2009
                : 4
                : 9
                Affiliations
                [1 ]St George's Vaccine Institute, St George's University of London, London, United Kingdom
                [2 ]Novartis Vaccines, Siena, Italy
                [3 ]Staten Serum Institute, Copenhagen, Denmark
                Charité-Universitätsmedizin Berlin, Germany
                Author notes

                Conceived and designed the experiments: DJML SB IK BTC PA DN GDG RR. Performed the experiments: DJML ZH RG EG MW. Analyzed the data: DJML. Contributed reagents/materials/analysis tools: RR. Wrote the paper: DJML ZH SB IK RG EG MW BTC PA DN GDG RR.

                Article
                09-PONE-RA-11063
                10.1371/journal.pone.0006999
                2737308
                19756141
                0a87df15-f8f9-47e1-842e-a0954d6b36ec
                Lewis et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 5
                Categories
                Research Article
                Virology/Vaccines
                Infectious Diseases/HIV Infection and AIDS
                Infectious Diseases/Respiratory Infections

                Uncategorized

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