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`Transcutaneous immunization and immunostimulant strategies
`
`Table 1. Percent subject responders within experimental groups.
`Group
`Pretreatment
`LT (µg)
`IgG (%)
`Day 42
`88
`
`1
`
`Hydration
`
`50
`
`Day 21
`63
`
`Day 180
`100
`
`Day 21
`0
`
`IgA (%)
`Day 42
`50
`
`Day 180
`25
`
`2
`
`3
`
`4
`
`5
`
`Tape stripping
`
`Pumice pad
`
`Emery paper
`
`Hydration
`
`50
`
`50
`
`50
`
`400
`
`100
`
`25
`
`75
`
`63
`
`100
`
`86
`
`100
`
`88
`
`100
`
`100
`
`100
`
`100
`
`38
`
`13
`
`50
`
`25
`
`50
`
`0
`
`57
`
`38
`
`50
`
`0
`
`71
`
`38
`
`Ig: Immunoglobulin; LT: Heat-labile toxin of Escherichia coli.
`
`2
`
`3
`
`References
`Papers of special note have been highlighted as:
`(cid:127) of interest
`(cid:127)(cid:127) of considerable interest
`1 Glenn GM, Kenney RT. Transcutaneous
`immunization. In: New Generation
`(cid:127)
`Vaccines. Levine MM, Kaper JB,
`Rappuoli R, Liu M, Good M (Eds.).
`Marcel Dekker, Inc., NY, USA (In Press).
`Jakob T, Udey MC. Epidermal
`Langerhans cells: from neurons to
`nature’s adjuvants. Adv. Dermatol. 14,
`209–258 (1999).
`Yu RC, Abrams DC, Alaibac M, Chu AC.
`Morphological and quantitative analyses
`of normal epidermal Langerhans cells
`using confocal scanning laser microscopy.
`Br. J. Dermatol. 131(6), 843–848 (1994).
`4 Udey MC. Cadherins and Langerhans
`cell immunobiology. Clin. Exp. Immunol.
`107(Suppl. 1), 6–8 (1997).
`5 Guereña-Burgueño F, Hall ER, Taylor
`(cid:127)(cid:127) DN et al. Safety and immunogenicity of a
`prototype enterotoxigenic Escherichia coli
`vaccine administered transcutaneously.
`Infect. Immun. 70(4), 1874–1880 (2002).
`Roberts MS, Walker M. Water, the most
`natural penetration enhancer. Marcel
`Dekker, NY, USA, 1–30 (1993).
`7 Mikszta JA, Alarcon JB, Brittingham JM,
`Sutter DE, Pettis RJ, Harvey NG.
`Improved genetic immunization via
`micromechanical disruption of skin-
`barrier function and targeted epidermal
`delivery. Nat. Med. 8(4), 415–419
`(2002).
`8 Chen D, Erickson CA, Endres RL et al.
`Adjuvantation of epidermal powder
`immunization. Vaccine 19(20–22),
`2908–2917 (2001).
`Baca-Estrada ME, Foldvari M, Ewen C,
`Badea I, Babiuk LA. Effects of IL-12 on
`immune responses induced by
`
`6
`
`9
`
`www.future-drugs.com
`
`transcutaneous immunization with
`antigens formulated in a novel lipid-
`based biphasic delivery system. Vaccine
`18(17), 1847–1854 (2000).
`10 Glenn GM, Rao M, Matyas GR, Alving
`CR. Skin immunization made possible by
`cholera toxin. Nature 391(6670), 851
`(1998).
`Scharton-Kersten T, Yu J, Vassell R,
`11
`(cid:127) O’Hagan D, Alving CR, Glenn GM.
`Transcutaneous immunization with
`bacterial ADP-ribosylating exotoxins,
`subunits and unrelated adjuvants. Infect.
`Immun. 68(9), 5306–5313 (2000).
`12 O’Hagan DT (Ed.). Methods in Molecular
`Medicine. Humana Press, Inc., NJ, USA
`(2000).
`13 Dickinson BL, Clements JD.
`Dissociation of Escherichia coli heat-labile
`enterotoxin adjuvanticity from ADP-
`ribosyltransferase activity. Infect. Immun.
`63(5), 1617–1623 (1995).
`14 Freytag LC, Clements JD. Bacterial
`toxins as mucosal adjuvants. Curr. Top.
`Microbiol. Immunol. 236, 215–236
`(1999).
`15 Gluck R, Mischler R, Durrer P et al.
`Safety and immunogenicity of
`intranasally administered inactivated
`trivalent virosome-formulated influenza
`vaccine containing Escherichia coli heat-
`labile toxin as a mucosal adjuvant. J.
`Infect. Dis. 181(3), 1129–1132 (2000).
`16 Michetti P, Kreiss C, Kotloff KL et al.
`Oral immunization with urease and
`Escherichia coli heat-labile enterotoxin is
`safe and immunogenic in Helicobacter
`pylori-infected adults. Gastroenterology
`116(4), 804–812 (1999).
`Snider DP. The mucosal adjuvant
`activities of ADP-ribosylating bacterial
`enterotoxins. Crit. Rev. Immunol.
`15(3–4), 317–348 (1995).
`
`17
`
`18 Weltzin R, Guy B, Thomas WD Jr,
`Giannasca PJ, Monath TP. Parenteral
`adjuvant activities of Escherichia coli heat-
`labile toxin and its B subunit for
`immunization of mice against gastric
`Helicobacter pylori infection. Infect.
`Immun. 68(5), 2775–2782 (2000).
`19 Hammond SA, Walwender D, Alving
`CR, Glenn GM. Transcutaneous
`immunization: T-cell responses and
`boosting of existing immunity. Vaccine
`19, 2701–2707 (2001).
`20 Porgador A, Staats HF, Faiola B, Gilboa
`E, Palker TJ. Intranasal immunization
`with CTL epitope peptides from HIV-1
`or ovalbumin and the mucosal adjuvant
`cholera toxin induces peptide- specific
`CTLs and protection against tumor
`development in vivo. J. Immunol. 158(2),
`834–841 (1997).
`21 Neidleman JA, Ott G, O’Hagan D.
`Mutant heat-labile enterotoxins as
`adjuvants for CTL induction. In: Vaccine
`Adjuvants: Preparation Methods and
`Research Protocols. O’Hagan D (Ed.).
`Humana Press, NJ, USA, 327–336
`(2000).
`Seo N, Tokura Y, Nishijima T,
`Hashizume H, Furukawa F, Takigawa M.
`Percutaneous peptide immunization via
`corneum barrier-disrupted murine skin
`for experimental tumor
`immunoprophylaxis. Proc. Natl Acad. Sci.
`USA 97(1), 371–376 (2000).
`23 Levine MM, Kaper JB, Black RE, Clements
`ML. New knowledge on pathogenesis of
`bacterial enteric infections as applied to
`vaccine development. Microbiol. Rev. 47(4),
`510–550 (1983).
`24 Murphy GF, Messadi D, Fonferko E,
`Hancock WW. Phenotypic
`transformation of macrophages to
`Langerhans cells in the skin. Am. J.
`Pathol. 123(3), 401–406 (1986).
`
`22
`
`265
`
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`Glenn, Kenney, Ellingsworth, Frech, Hammond & Zoeteweij
`
`28
`
`25 Glenn GM, Taylor DN, Li X, Frankel S,
`(cid:127)(cid:127) Montemarano A, Alving CR.
`Transcutaneous immunization: a human
`vaccine delivery strategy using a patch.
`Nat. Med. 6(12), 1403–1406 (2000).
`26 El-Ghorr AA, Williams RM, Heap C,
`Norval M. Transcutaneous immunisation
`with herpes simplex virus stimulates
`immunity in mice. FEMS Immunol. Med.
`Microbiol. 29(4), 255–261 (2000).
`27 Gockel CM, Bao S, Beagley KW.
`Transcutaneous immunization induces
`mucosal and systemic immunity: a potent
`method for targeting immunity to the
`female reproductive tract. Mol. Immunol.
`37(9), 537–544 (2000).
`Jakob T, Walker PS, Krieg AM, von
`Stebut E, Udey MC, Vogel JC. Bacterial
`DNA and CpG-containing
`oligodeoxynucleotides activate cutaneous
`dendritic cells and induce IL-12
`production: implications for the
`augmentation of Th1 responses. Int.
`Arch. Allergy Immunol. 118(2–4),
`457–461 (1999).
`29 Kremer IB, Stevens SR, Gould JW,
`DiCarlo J, Quinby GE, Cooper KD.
`Intradermal granulocyte–macrophage
`colony-stimulating factor alters
`cutaneous antigen-presenting cells and
`differentially affects local versus distant
`immunization in humans. Clin. Immunol.
`96(1), 29–37 (2000).
`30 Aiba S, Katz SI. Phenotypic and
`functional characteristics of in vivo-
`activated Langerhans cells. J. Immunol.
`145(9), 2791–2796 (1990).
`31 Hernando RA, Ruby JC, Halliday GM.
`Changes in epidermal Langerhans cells,
`γδ T-cells and CD4 T-cells after
`intradermal infection with recombinant
`vaccinia virus expressing cytokine genes.
`Immunol. Cell Biol. 72(5), 383–389
`(1994).
`32 Nagao S, Inaba S, Iijima S. Langerhans
`cells at the sites of vaccinia virus
`inoculation. Arch. Dermatol. Res. 256(1),
`23–31 (1976).
`33 Vassell R, Glenn GM, Udey MC,
`Scharton-Kersten T, Alving CR, Jakob T.
`In: 5th National Symposium, Basic Aspects
`of Vaccines. MD, USA (1999).
`34 Guebre-Xabier M, Hammond SA,
`(cid:127)(cid:127) Epperson DE, Yu J, Ellingsworth L,
`Glenn GM. Immunostimulant patch
`containing heat labile enterotoxin from
`E. coli enhances immune responses to
`injected influenza vaccine through
`activation of skin dendritic cells.
`J. Virol. (In Press).
`
`266
`
`35 Hammond SA, Guebre-Xabier M, Yu J,
`Glenn GM. Transcutaneous
`immunization: an emerging route of
`immunization and potent
`immunostimulation strategy. Crit. Rev.
`Ther. Drug Carrier Sys. 18(5), 503–526
`(2001).
`36 Arrington J, Braun RP, Dong L et al.
`Plasmid vectors encoding cholera toxin or
`the heat-labile enterotoxin from
`Escherichia coli are strong adjuvants for
`DNA vaccines. J. Virol. 76(9),
`4536–4546 (2002).
`37 Kripke ML, Munn CG, Jeevan A, Tang
`(cid:127)
`JM, Bucana C. Evidence that cutaneous
`antigen-presenting cells migrate to
`regional lymph nodes during contact
`sensitization. J. Immunol. 145(9),
`2833–2838 (1990).
`38 Enioutina EY, Visic D, Daynes RA. The
`induction of systemic and mucosal
`immune responses to antigen–adjuvant
`compositions administered into the skin:
`alterations in the migratory properties of
`dendritic cells appears to be important
`for stimulating mucosal immunity.
`Vaccine 18(24), 2753–2767 (2000).
`39 Gasparini R, Pozzi T, Montomoli E et al.
`Increased immunogenicity of the MF59-
`adjuvanted influenza vaccine compared
`to a conventional subunit vaccine in
`elderly subjects. Eur. J. Epidemiol. 17(2),
`135–140 (2001).
`Singh M, O’Hagan D. Advances in
`vaccine adjuvants. Nat. Biotechnol.
`17(11), 1075–1081 (1999).
`41 Banchereau J, Briere F, Caux C et al.
`Immunobiology of dendritic cells. Ann.
`Rev. Immunol. 18, 767–811 (2000).
`42 Morein B, Lovgren-Bengtsson K, Cox J.
`Modern adjuvants, functional aspects. In:
`Concepts in Vaccine Development.
`Kaufmann SHE (Ed.) Walter de Gruyter,
`Berlin, Germany, 243–263 (1996).
`43 Cella M, Engering A, Pinet V, Pieters J,
`Lanzavecchia A. Inflammatory stimuli
`induce accumulation of MHC class II
`complexes on dendritic cells. Nature
`388(6644), 782–787 (1997).
`44 Rescigno M, Citterio S, Thery C et al.
`Bacteria-induced neo-biosynthesis,
`stabilization and surface expression of
`functional class I molecules in mouse
`dendritic cells. Proc. Natl Acad. Sci. USA
`95(9), 5229–5234 (1998).
`45 de Bruijn IA, Remarque EJ, Jol-van der
`Zijde CM, van Tol MJ, Westendorp RG,
`Knook DL. Quality and quantity of the
`humoral immune response in healthy
`elderly and young subjects after annually
`
`40
`
`repeated influenza vaccination. J. Infect.
`Dis. 179(1), 31–36 (1999).
`46 Hammond SA, Tsonis C, Sellins K et al.
`Transcutaneous immunization of
`domestic animals: opportunities and
`challenges. Adv. Drug Delivery Rev. 43,
`45–55 (2000).
`47 Glenn GM, Scharton-Kersten T, Vassell
`(cid:127)
`R, Matyas GR, Alving CR.
`Transcutaneous immunization with
`bacterial ADP-ribosylating exotoxins as
`antigens and adjuvants. Infect. Immun.
`67(3), 1100–1106 (1999).
`48 Kotloff KL, Sztein MB, Wasserman SS,
`Losonsky GA, DiLorenzo SC, Walker RI.
`Safety and immunogenicity of oral
`inactivated whole-cell Helicobacter pylori
`vaccine with adjuvant among volunteers
`with or without subclinical infection.
`Infect. Immun. 69(6), 3581–3590 (2001).
`49 Watabe S, Xin K, Ihata A et al. Protection
`against influenza virus challenge by
`topical application of influenza DNA
`vaccine. Vaccine 19(31), 4434–4444
`(2001).
`50 Glenn GM, Scharton-Kersten T, Vassell
`R, Mallett CP, Hale TL, Alving CR.
`Transcutaneous immunization with
`cholera toxin protects mice against lethal
`mucosal toxin challenge. J. Immunol.
`161(7), 3211–3214 (1998).
`51 Gebhart W, Metze D, Jurecka W. IgA in
`human skin appendages. In:
`Immunodermatology. Caputo R (Ed.).
`CIC Edizioni Internazionali, Rome, Italy,
`185 (1987).
`52 Okada T, Konishi H, Ito M, Nagura H,
`Asai J. Identification of secretory
`immunoglobulin A in human sweat and
`sweat glands. J. Invest. Dermatol. 90(5),
`648–651 (1988).
`53 Hard GC. Electron microscopic
`examination of Corynebacterium ovis. J.
`Bacteriol. 97(3), 1480–1485 (1969).
`54 Metze D, Kersten A, Jurecka W, Gebhart
`W. Immunoglobulins coat
`microorganisms of skin surface: a
`comparative immunohistochemical and
`ultrastructural study of cutaneous and
`oral microbial symbionts. J. Invest.
`Dermatol. 96(4), 439–445 (1991).
`55 Yu J, Cassels F, Scharton-Kersten T et al.
`(cid:127)
`Transcutaneous immunization using
`colonization factor and heat labile
`enterotoxin induces correlates of
`protective immunity for enterotoxigenic
`Escherichia coli. Infect. Immun. 70(3),
`1056–1068 (2002).
`56 Wolf MK, de Haan LA, Cassels FJ et al.
`The CS6 colonization factor of human
`
`Expert Rev. Vaccines 2(2), (2003)
`
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`enterotoxigenic Escherichia coli contains
`two heterologous major subunits. FEMS
`Microbiol. Lett. 148(1), 35–42 (1997).
`57 Levine MM, Ristaino P, Sack RB, Kaper
`JB, Orskov F, Orskov I. Colonization
`factor antigens I and II and Type 1
`somatic pili in enterotoxigenic Escherichia
`coli: relation to enterotoxin type. Infect.
`Immun. 39(2), 889–897 (1983).
`58 Wolf M, Hall E, Taylor D et al. In: The
`35th Joint Conference of the US–Japan
`Co-operative Medical Science Program.
`Baltimore, MD, USA (1999).
`59 Trach DD, Clemens JD, Ke NT et al.
`Field trial of a locally produced, killed,
`oral cholera vaccine in Vietnam. Lancet
`349(9047), 231–235 (1997).
`
`Patents
`101 Glenn GM, Alving CR. WO9943350
`(1999).
`102 Glenn GM, Alving CR. US5980898
`(1999).
`
`Affiliations
`(cid:127)
`Gregory M Glenn, MD, IOMAI Corporation, 20
`Firstfield Road, Suite 250, Gaithersburg, MD
`20878, USA, Tel.: +1 301 556 4500
`Fax: +1 301 556 4501, gglenn@iomai.com
`Richard T Kenney, MD, FACS, IOMAI
`Corporation, 20 Firstfield Road, Suite 250,
`Gaithersburg, MD 20878, USA
`Tel.: +1 301 556 4500
` Fax: +1 301 556 4501, rkenney@iomai.com
`
`(cid:127)
`
`(cid:127)
`
`(cid:127)
`
`(cid:127)
`
`(cid:127)
`
`Larry R Ellingsworth, PhD, IOMAI Corporation
`20 Firstfield Road, Suite 250, Gaithersburg,
`MD 20878, USA
`Tel.: +1 301 556 4500
` Fax: +1 301 556 4501
`lellingsworth@iomai.com
`Sarah A Frech, DVM, MPH, IOMAI
`Corporation, 20 Firstfield Road, Suite 250,
`Gaithersburg, MD 20878, USA
`Tel.: +1 301 556 4500
` Fax: +1 301 556 4501, sfrech@iomai.com
`Scott A Hammond, PhD, IOMAI Corporation,
`20 Firstfield Road, Suite 250, Gaithersburg,
`MD 20878, USA, Tel.: +1 301 556 4500
`Fax: +1 301 556 4501, shammond@iomai.com
`J Paul Zoeteweij, PhD, IOMAI Corporation, 20
`Firstfield Road, Suite 250, Gaithersburg, MD
`20878, USA, Tel.: +1 301 556 4500
`Fax +1 301 556 4501, pzoet@iomai.com
`
`www.future-drugs.com
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