, Volume 27, Issue 6, pp 565–583 | Cite as

Emerging Targets and Novel Approaches to Ebola Virus Prophylaxis and Treatment

  • Jin Huk Choi
  • Maria A. CroyleEmail author
Review Article


Ebola is a highly virulent pathogen causing severe hemorrhagic fever with a high case fatality rate in humans and non-human primates (NHPs). Although safe and effective vaccines or other medicinal agents to block Ebola infection are currently unavailable, a significant effort has been put forth to identify several promising candidates for the treatment and prevention of Ebola hemorrhagic fever. Among these, recombinant adenovirus–based vectors have been identified as potent vaccine candidates, with some affording both pre- and post-exposure protection from the virus. Recently, Investigational New Drug (IND) applications have been approved by the US Food and Drug Administration (FDA) and phase I clinical trials have been initiated for two small-molecule therapeutics: anti-sense phosphorodiamidate morpholino oligomers (PMOs: AVI-6002, AVI-6003) and lipid nanoparticle/small interfering RNA (LNP/siRNA: TKM-Ebola). These potential alternatives to vector-based vaccines require multiple doses to achieve therapeutic efficacy, which is not ideal with regard to patient compliance and outbreak scenarios. These concerns have fueled a quest for even better vaccination and treatment strategies. Here, we summarize recent advances in vaccines or post-exposure therapeutics for prevention of Ebola hemorrhagic fever. The utility of novel pharmaceutical approaches to refine and overcome barriers associated with the most promising therapeutic platforms are also discussed.


Hemorrhagic Fever Rift Valley Fever Rift Valley Fever Virus Lethal Challenge Vaccine Platform 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was funded by National Institutes of Health NIAID [National Institute of Allergy and Infectious Diseases] grant number U01AI078045 (Maria A. Croyle). The content and the views expressed in this article do not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases. The authors would like to thank Mr. Stephen C. Schafer for his excellent technical assistance in designing the figures presented in this article. The authors do not have any conflicts nor financial interests to declare that are directly relevant to the content of this article.


  1. 1.
    Bray M, Murphy FA. Filovirus research: knowledge expands to meet a growing threat. J Infect Dis. 2007;196(Suppl 2):S438–43.PubMedGoogle Scholar
  2. 2.
    Huang Y, Xu L, Sun Y, Nabel GJ. The assembly of Ebola virus nucleocapsid requires virion-associated proteins 35 and 24 and posttranslational modification of nucleoprotein. Mol Cell. 2002;10(2):307–16.PubMedGoogle Scholar
  3. 3.
    Muhlberger E, Weik M, Volchkov VE, Klenk HD, Becker S. Comparison of the transcription and replication strategies of Marburg virus and Ebola virus by using artificial replication systems. J Virol. 1999;73(3):2333–42.PubMedGoogle Scholar
  4. 4.
    Volchkov VE, Volchkova VA, Muhlberger E, Kolesnikova LV, Weik M, Dolnik O, Klenk HD. Recovery of infectious Ebola virus from complementary DNA: RNA editing of the GP gene and viral cytotoxicity. Science. 2001;291(5510):1965–9.PubMedGoogle Scholar
  5. 5.
    Bamberg S, Kolesnikova L, Moller P, Klenk HD, Becker S. VP24 of Marburg virus influences formation of infectious particles. J Virol. 2005;79(21):13421–33.PubMedGoogle Scholar
  6. 6.
    Han Z, Boshra H, Sunyer JO, Zwiers SH, Paragas J, Harty RN. Biochemical and functional characterization of the Ebola virus VP24 protein: implications for a role in virus assembly and budding. J Virol. 2003;77(3):1793–800.PubMedGoogle Scholar
  7. 7.
    Noda T, Halfmann P, Sagara H, Kawaoka Y. Regions in Ebola virus VP24 that are important for nucleocapsid formation. J Infect Dis. 2007;196(Suppl 2):S247–50.PubMedGoogle Scholar
  8. 8.
    Noda T, Watanabe S, Sagara H, Kawaoka Y. Mapping of the VP40-binding regions of the nucleoprotein of Ebola virus. J Virol. 2007;81(7):3554–62.PubMedGoogle Scholar
  9. 9.
    Noda T, Sagara H, Suzuki E, Takada A, Kida H, Kawaoka Y. Ebola virus VP40 drives the formation of virus-like filamentous particles along with GP. J Virol. 2002;76(10):4855–65.PubMedGoogle Scholar
  10. 10.
    Watanabe S, Watanabe T, Noda T, Takada A, Feldmann H, Jasenosky LD, Kawaoka Y. Production of novel Ebola virus-like particles from cDNAs: an alternative to Ebola virus generation by reverse genetics. J Virol. 2004;78(2):999–1005.PubMedGoogle Scholar
  11. 11.
    Sanchez A, Trappier SG, Mahy BW, Peters CJ, Nichol ST. The virion glycoproteins of Ebola viruses are encoded in two reading frames and are expressed through transcriptional editing. Proc Natl Acad Sci USA. 1996;93(8):3602–7.PubMedGoogle Scholar
  12. 12.
    Volchkov VE, Feldmann H, Volchkova VA, Klenk HD. Processing of the Ebola virus glycoprotein by the proprotein convertase furin. Proc Natl Acad Sci USA. 1998;95(10):5762–7.PubMedGoogle Scholar
  13. 13.
    Volchkov VE, Volchkova VA, Muhlberger E, Kolesnikova LV, Weik M, Dolnik O, Klenk HD. Recovery of infectious Ebola virus from complementary DNA: RNA editing of the GP gene and viral cytotoxicity. Science. 2001;291(5510):1965–9.PubMedGoogle Scholar
  14. 14.
    Volchkov VE, Volchkova VA, Slenczka W, Klenk HD, Feldmann H. Release of viral glycoproteins during Ebola virus infection. Virology. 1998;245(1):110–9.PubMedGoogle Scholar
  15. 15.
    Chan SY, Empig CJ, Welte FJ, Speck RF, Schmaljohn A, Kreisberg JF, Goldsmith MA. Folate receptor-alpha is a cofactor for cellular entry by Marburg and Ebola viruses. Cell. 2001;106(1):117–26.PubMedGoogle Scholar
  16. 16.
    Chan SY, Speck RF, Ma MC, Goldsmith MA. Distinct mechanisms of entry by envelope glycoproteins of Marburg and Ebola (Zaire) viruses. J Virol. 2000;74(10):4933–7.PubMedGoogle Scholar
  17. 17.
    Chepurnov AA, Tuzova MN, Ternovoy VA, Chernukhin IV. Suppressive effect of Ebola virus on T cell proliferation in vitro is provided by a 125-kDa GP viral protein. Immunol Lett. 1999;68(2–3):257–61.PubMedGoogle Scholar
  18. 18.
    Volchkov VE, Blinov VM, Netesov SV. The envelope glycoprotein of Ebola virus contains an immunosuppressive-like domain similar to oncogenic retroviruses. FEBS Lett. 1992;305(3):181–4.PubMedGoogle Scholar
  19. 19.
    Wool-Lewis RJ, Bates P. Characterization of Ebola virus entry by using pseudotyped viruses: identification of receptor-deficient cell lines. J Virol. 1998;72(4):3155–60.PubMedGoogle Scholar
  20. 20.
    Yang Z, Delgado R, Xu L, Todd RF, Nabel EG, Sanchez A, Nabel GJ. Distinct cellular interactions of secreted and transmembrane Ebola virus glycoproteins. Science. 1998;279(5353):1034–7.PubMedGoogle Scholar
  21. 21.
    Yang ZY, Duckers HJ, Sullivan NJ, Sanchez A, Nabel EG, Nabel GJ. Identification of the Ebola virus glycoprotein as the main viral determinant of vascular cell cytotoxicity and injury. Nat Med. 2000;6(8):886–9.PubMedGoogle Scholar
  22. 22.
    Yaddanapudi K, Palacios G, Towner JS, Chen I, Sariol CA, Nichol ST, Lipkin WI. Implication of a retrovirus-like glycoprotein peptide in the immunopathogenesis of Ebola and Marburg viruses. FASEB J. 2006;20(14):2519–30.PubMedGoogle Scholar
  23. 23.
    Sanchez A, Yang ZY, Xu L, Nabel GJ, Crews T, Peters CJ. Biochemical analysis of the secreted and virion glycoproteins of Ebola virus. J Virol. 1998;72(8):6442–7.PubMedGoogle Scholar
  24. 24.
    Volchkova VA, Feldmann H, Klenk HD, Volchkov VE. The nonstructural small glycoprotein sGP of Ebola virus is secreted as an antiparallel-orientated homodimer. Virology. 1998;250(2):408–14.PubMedGoogle Scholar
  25. 25.
    Ito H, Watanabe S, Takada A, Kawaoka Y. Ebola virus glycoprotein: proteolytic processing, acylation, cell tropism, and detection of neutralizing antibodies. J Virol. 2001;75(3):1576–80.PubMedGoogle Scholar
  26. 26.
    Radoshitzky SR, Warfield KL, Chi X, Dong L, Kota K, Bradfute SB, Gearhart JD, Retterer C, Kranzusch PJ, Misasi JN, Hogenbirk MA, Wahl-Jensen V, Volchkov VE, Cunningham JM, Jahrling PB, Aman MJ, Bavari S, Farzan M, Kuhn JH. Ebola virus delta-peptide immunoadhesins inhibit Marburg virus and Ebola virus cell entry. J Virol. 2011;85(17):8502–13.PubMedGoogle Scholar
  27. 27.
    Mehedi M, Falzarano D, Seebach J, Hu X, Carpenter MS, Schnittler HJ, Feldmann H. A new Ebola virus nonstructural glycoprotein expressed through RNA editing. J Virol. 2011;85(11):5406–14.PubMedGoogle Scholar
  28. 28.
    Zaki SR, Goldsmith CS. Pathologic features of filovirus infections in humans. Curr Top Microbiol Immunol. 1999;235:97–116.PubMedGoogle Scholar
  29. 29.
    Bosio CM, Aman MJ, Grogan C, Hogan R, Ruthel G, Negley D, Mohamadzadeh M, Bavari S, Schmaljohn A. Ebola and Marburg viruses replicate in monocyte-derived dendritic cells without inducing the production of cytokines and full maturation. J Infect Dis. 2003;188(11):1630–8.PubMedGoogle Scholar
  30. 30.
    Mahanty S, Hutchinson K, Agarwal S, Mcrae M, Rollin PE, Pulendran B. Cutting edge: impairment of dendritic cells and adaptive immunity by Ebola and Lassa viruses. J Immunol. 2003;170(6):2797–27801.PubMedGoogle Scholar
  31. 31.
    Basler CF, Mikulasova A, Martinez-Sobrido L, Paragas J, Muhlberger E, Bray M, Klenk HD, Palese P, Garcia-Sastre A. The Ebola virus VP35 protein inhibits activation of interferon regulatory factor 3. J Virol. 2003;77(14):7945–56.PubMedGoogle Scholar
  32. 32.
    Reid SP, Leung LW, Hartman AL, Martinez O, Shaw ML, Carbonnelle C, Volchkov VE, Nichol ST, Basler CF. Ebola virus VP24 binds karyopherin alpha1 and blocks STAT1 nuclear accumulation. J Virol. 2006;80(11):5156–67.PubMedGoogle Scholar
  33. 33.
    Feng Z, Cerveny M, Yan Z, He B. The VP35 protein of Ebola virus inhibits the antiviral effect mediated by double-stranded RNA-dependent protein kinase PKR. J Virol. 2007;81(1):182–92.PubMedGoogle Scholar
  34. 34.
    Halfmann P, Neumann G, Kawaoka Y. The Ebola virus VP24 protein blocks phosphorylation of P38 mitogen-activated protein kinase. J Infect Dis. 2011;204(Suppl 3):S953–6.PubMedGoogle Scholar
  35. 35.
    Schumann M, Gantke T, Muhlberger E. Ebola virus VP35 antagonizes Pkr activity through its C-terminal interferon inhibitory domain. J Virol. 2009;83(17):8993–7.PubMedGoogle Scholar
  36. 36.
    Martinez O, Leung LW, Basler CF. The role of antigen-presenting cells in filoviral hemorrhagic fever: gaps in current knowledge. Antivir Res. 2012;93(3):416–28.PubMedGoogle Scholar
  37. 37.
    Baize S, Leroy EM, Georges AJ, Georges-Courbot MC, Capron M, Bedjabaga I, Lansoud-Soukate J, Mavoungou E. Inflammatory responses in Ebola virus-infected patients. Clin Exp Immunol. 2002;128(1):163–8.PubMedGoogle Scholar
  38. 38.
    Baize S, Leroy EM, Georges-Courbot MC, Capron M, Lansoud-Soukate J, Debre P, Fisher-Hoch SP, Mccormick JB, Georges AJ. Defective humoral responses and extensive intravascular apoptosis are associated with fatal outcome in Ebola virus-infected patients. Nat Med. 1999;5(4):423–6.PubMedGoogle Scholar
  39. 39.
    Villinger F, Rollin PE, Brar SS, Chikkala NF, Winter J, Sundstrom JB, Zaki SR, Swanepoel R, Ansari AA, Peters CJ. Markedly elevated levels of interferon (IFN)-gamma, IFN-alpha, interleukin (IL)-2, IL-10, and tumor necrosis factor-alpha associated with fatal Ebola virus infection. J Infect Dis. 1999;179(Suppl 1):S188–91.PubMedGoogle Scholar
  40. 40.
    Connolly BM, Steele KE, Davis KJ, Geisbert TW, Kell WM, Jaax NK, Jahrling PB. Pathogenesis of experimental Ebola virus infection in guinea pigs. J Infect Dis. 1999;179(Suppl 1):S203–17.PubMedGoogle Scholar
  41. 41.
    Geisbert TW, Hensley LE, Larsen T, Young HA, Reed DS, Geisbert JB, Scott DP, Kagan E, Jahrling PB, Davis KJ. Pathogenesis of Ebola hemorrhagic fever in cynomolgus macaques: evidence that dendritic cells are early and sustained targets of infection. Am J Pathol. 2003;163(6):2347–70.PubMedGoogle Scholar
  42. 42.
    Hensley LE, Young HA, Jahrling PB, Geisbert TW. Proinflammatory response during Ebola virus infection of primate models: possible involvement of the tumor necrosis factor receptor superfamily. Immunol Lett. 2002;80(3):169–79.PubMedGoogle Scholar
  43. 43.
    Zampieri CA, Sullivan NJ, Nabel GJ. Immunopathology of highly virulent pathogens: insights from Ebola virus. Nat Immunol. 2007;8(11):1159–64.PubMedGoogle Scholar
  44. 44.
    Leroy EM, Gonzalez JP, Baize S. Ebola and Marburg haemorrhagic fever viruses: major scientific advances, but a relatively minor public health threat for Africa. Clin Microbiol Infect. 2011;17(7):964–76.PubMedGoogle Scholar
  45. 45.
    Kuhn JH, Bao Y, Bavari S, Becker S, Bradfute S, Brister JR, Bukreyev AA, Caì Y, Chandran K, Davey RA, Dolnik O, Dye JM, Enterlein S, Gonzalez JP, et al. Virus nomenclature below the species level: a standardized nomenclature for laboratory animal-adapted strains and variants of viruses assigned to the family Filoviridae. Arch Virol. 2013;158(1):301–11.PubMedGoogle Scholar
  46. 46.
    Hayes CG, Burans JP, Ksiazek TG, Del Rosario RA, Miranda ME, Manaloto CR, Barrientos AB, Robles CG, Dayrit MM, Peters CJ. Outbreak of fatal illness among captive macaques in the Philippines caused by an Ebola-related filovirus. Am J Trop Med Hyg. 1992;46(6):664–71.PubMedGoogle Scholar
  47. 47.
    Jahrling PB, Geisbert TW, Dalgard DW, Johnson ED, Ksiazek TG, Hall WC, Peters CJ. Preliminary report: isolation of Ebola virus from monkeys imported to USA. Lancet. 1990;335(8688):502–5.PubMedGoogle Scholar
  48. 48.
    Rollin PE, Williams RJ, Bressler DS, Pearson S, Cottingham M, Pucak G, Sanchez A, Trappier SG, Peters RL, Greer PW, Zaki S, Demarcus T, et al. Ebola (subtype Reston) virus among quarantined nonhuman primates recently imported from the Philippines to the United States. J Infect Dis. 1999;179(Suppl 1):S108–14.PubMedGoogle Scholar
  49. 49.
    Weingartl HM, Embury-Hyatt C, Nfon C, Leung A, Smith G, Kobinger G. Transmission of Ebola virus from pigs to non-human primates. Sci Rep. 2012;2:811.PubMedGoogle Scholar
  50. 50.
    Reed DS, Lackemeyer MG, Garza NL, Sullivan LJ, Nichols DK. Aerosol exposure to Zaire ebolavirus in three nonhuman primate species: differences in disease course and clinical pathology. Microbes Infect. 2011;13(11):930–6.PubMedGoogle Scholar
  51. 51.
    Feldmann H, Geisbert TW. Ebola haemorrhagic fever. Lancet. 2011;377(9768):849–62.PubMedGoogle Scholar
  52. 52.
    Kuhn JH, Dodd LE, Wahl-Jensen V, Radoshitzky SR, Bavari S, Jahrling PB. Evaluation of perceived threat differences posed by filovirus variants. Biosecur Bioterror. 2011;9(4):361–71.PubMedGoogle Scholar
  53. 53.
    Kortepeter MG, Bausch DG, Bray M. Basic clinical and laboratory features of filoviral hemorrhagic fever. J Infect Dis. 2011;204(Suppl 3):S810–6.PubMedGoogle Scholar
  54. 54.
    Paessler S, Walker DH. Pathogenesis of the viral hemorrhagic fevers. Annu Rev Pathol Mech Dis. 2013;8:411–40.Google Scholar
  55. 55.
    Lupton HW, Lambert RD, Bumgardner DL, Moe JB, Eddy GA. Inactivated vaccine for Ebola virus efficacious in guineapig model. Lancet. 1980;2(8207):1294–5.PubMedGoogle Scholar
  56. 56.
    Chupurnov AA, Chernukhin IV, Ternovoi VA, Kudoiarova NM, Makhova NM, Azaev MS, Smolina MP. Attempts to develop a vaccine against Ebola fever. Vopr Virusol. 1995;40(6):257–60.PubMedGoogle Scholar
  57. 57.
    Sullivan NJ, Sanchez A, Rollin PE, Yang ZY, Nabel GJ. Development of a preventive vaccine for Ebola virus infection in primates. Nature. 2000;408(6812):605–9.PubMedGoogle Scholar
  58. 58.
    Sullivan NJ, Geisbert TW, Geisbert JB, Xu L, Yang ZY, Roederer M, Koup RA, Jahrling PB, Nabel GJ. Accelerated vaccination for Ebola virus haemorrhagic fever in non-human primates. Nature. 2003;424(6949):681–4.PubMedGoogle Scholar
  59. 59.
    Richardson JS, Yao MK, Tran KN, Croyle MA, Strong JE, Feldmann H, Kobinger GP. Enhanced protection against Ebola virus mediated by an improved adenovirus-based vaccine. PloS One. 2009;4(4):e5308.PubMedGoogle Scholar
  60. 60.
    Choi JH, Schafer SC, Zhang L, Kobinger GP, Juelich T, Freiberg AN, Croyle MA. A single sublingual dose of an adenovirus-based vaccine protects against lethal Ebola challenge in mice and guinea pigs. Mol Pharm. 2012;9(1):156–67.PubMedGoogle Scholar
  61. 61.
    Croyle MA, Patel A, Tran KN, Gray M, Zhang Y, Strong JE, Feldmann H, Kobinger GP. Nasal delivery of an adenovirus-based vaccine bypasses pre-existing immunity to the vaccine carrier and improves the immune response in mice. PLoS One. 2008;3(10):e3548.PubMedGoogle Scholar
  62. 62.
    Mast TC, Kierstead L, Gupta SB, Nikas AA, Kallas EG, Novitsky V, Mbewe B, Pitisuttithum P, Schechter M, Vardas E, Wolfe ND, Aste-Amezaga M, et al. International epidemiology of human pre-existing adenovirus (Ad) type-5, type-6, type-26 and type-36 neutralizing antibodies: correlates of high Ad5 titers and implications for potential HIV vaccine trials. Vaccine. 2010;28(4):950–7.PubMedGoogle Scholar
  63. 63.
    Pilankatta R, Chawla T, Khanna N, Swaminathan S. The prevalence of antibodies to adenovirus serotype 5 in an adult Indian population and implications for adenovirus vector vaccines. J Med Virol. 2010;82(3):407–14.PubMedGoogle Scholar
  64. 64.
    Nwanegbo E, Vardas E, Gao W, Whittle H, Sun H, Rowe D, Robbins PD, Gambotto A. Prevalence of neutralizing antibodies to adenoviral serotypes 5 and 35 in the adult populations of the Gambia, South Africa, and the United States. Clin Diagn Lab Immunol. 2004;11(2):351–7.PubMedGoogle Scholar
  65. 65.
    Aldhamen YA, Seregin SS, Amalfitano A. Immune recognition of gene transfer vectors: focus on adenovirus as a paradigm. Front Immunol. 2011;2:40. doi: 10.3389/fimmu.2011.00040.PubMedGoogle Scholar
  66. 66.
    Geisbert TW, Bailey M, Hensley L, Asiedu C, Geisbert J, Stanley D, Honko A, Johnson J, Mulangu S, Pau MG, Custers J, Vellinga J, Hendriks J, Jahrling P, et al. Recombinant adenovirus serotype 26 (Ad26) and Ad35 vaccine vectors bypass immunity to Ad5 and protect nonhuman primates against Ebola virus challenge. J Virol. 2011;85(9):4222–33.PubMedGoogle Scholar
  67. 67.
    Patel A, Tikoo S, Kobinger G. A porcine adenovirus with low human seroprevalence is a promising alternative vaccine vector to human adenovirus 5 in an H5N1 virus disease model. PLoS One 2010. 5(12). doi: 10.1371/journal.pone.0015301.
  68. 68.
    Singh N, Pandey A, Jayashankar L, Mittal SK. Bovine adenoviral vector-based H5N1 influenza vaccine overcomes exceptionally high levels of pre-existing immunity against human adenovirus. Mol Ther. 2008;16(5):965–71.PubMedGoogle Scholar
  69. 69.
    Kobinger GP, Feldmann H, Zhi Y, Schumer G, Gao G, Feldmann F, Jones S, Wilson JM. Chimpanzee adenovirus vaccine protects against Zaire Ebola virus. Virology. 2006;346(2):394–401.PubMedGoogle Scholar
  70. 70.
    Ledgerwood JE, Costner P, Desai N, Holman L, Enama ME, Yamshchikov G, Mulangu S, Hu Z, Andrews CA, Sheets RA, Koup RA, Roederer M, Bailer R, et al, and the VRC 205 Study Team. A replication defective recombinant Ad5 vaccine expressing Ebola virus GP is safe and immunogenic in healthy adults. Vaccine. 2010;29(2):304–13.Google Scholar
  71. 71.
    Garbutt M, Liebscher R, Wahl-Jensen V, Jones S, Moller P, Wagner R, Volchkov V, Klenk HD, Feldmann H, Stroher U. Properties of replication-competent vesicular stomatitis virus vectors expressing glycoproteins of filoviruses and arenaviruses. J Virol. 2004;78(10):5458–65.PubMedGoogle Scholar
  72. 72.
    Tsuda Y, Safronetz D, Brown K, Lacasse R, Marzi A, Ebihara H, Feldmann H. Protective efficacy of a bivalent recombinant vesicular stomatitis virus vaccine in the Syrian hamster model of lethal Ebola virus infection. J Infect Dis. 2011;204(Suppl 3):S1090–7.PubMedGoogle Scholar
  73. 73.
    Geisbert TW, Feldmann H. Recombinant vesicular stomatitis virus-based vaccines against Ebola and Marburg virus infections. J Infect Dis. 2011;204(Suppl 3):S1075–81.PubMedGoogle Scholar
  74. 74.
    Qiu X, Fernando L, Alimonti JB, Melito PL, Feldmann F, Dick D, Stroher U, Feldmann H, Jones SM. Mucosal immunization of cynomolgus macaques with the VSVdeltaG/ZEBOVGP vaccine stimulates strong Ebola GP-specific immune responses. PLoS One. 2009;4(5):e5547.PubMedGoogle Scholar
  75. 75.
    Geisbert TW, Daddario-Dicaprio KM, Geisbert JB, Reed DS, Feldmann F, Grolla A, Stroher U, Fritz EA, Hensley LE, Jones SM, Feldmann H. Vesicular stomatitis virus-based vaccines protect nonhuman primates against aerosol challenge with Ebola and Marburg viruses. Vaccine. 2008;26(52):6894–900.PubMedGoogle Scholar
  76. 76.
    Geisbert TW, Daddario-Dicaprio KM, Williams KJ, Geisbert JB, Leung A, Feldmann F, Hensley LE, Feldmann H, Jones SM. Recombinant vesicular stomatitis virus vector mediates postexposure protection against Sudan Ebola hemorrhagic fever in nonhuman primates. J Virol. 2008;82(11):5664–8.PubMedGoogle Scholar
  77. 77.
    Jones SM, Stroher U, Fernando L, Qiu X, Alimonti J, Melito P, Bray M, Klenk HD, Feldmann H. Assessment of a vesicular stomatitis virus-based vaccine by use of the mouse model of Ebola virus hemorrhagic fever. J Infect Dis. 2007;196(Suppl 2):S404–12.PubMedGoogle Scholar
  78. 78.
    Jones SM, Feldmann H, Stroher U, Geisbert JB, Fernando L, Grolla A, Klenk HD, Sullivan NJ, Volchkov VE, Fritz EA, Daddario KM, Hensley LE, Jahrling PB, Geisbert TW. Live attenuated recombinant vaccine protects nonhuman primates against Ebola and Marburg viruses. Nat Med. 2005;11(7):786–90.PubMedGoogle Scholar
  79. 79.
    Jones SM, Feldmann H, Stroher U, Geisbert JB, Fernando L, Grolla A, Klenk HD, Sullivan NJ, Volchkov VE, Fritz EA, Daddario KM, Hensley LE, Jahrling PB, Geisbert TW. Live attenuated recombinant vaccine protects nonhuman primates against Ebola and Marburg viruses. Nat Med. 2005;11(7):786–90.PubMedGoogle Scholar
  80. 80.
    Feldmann H, Jones SM, Daddario-Dicaprio KM, Geisbert JB, Ströher U, Grolla A, Bray M, Fritz EA, Fernando L, Feldmann F, Hensley LE, Geisbert TW. Effective post-exposure treatment of Ebola infection. PLoS Pathog. 2007;3(1):e2.PubMedGoogle Scholar
  81. 81.
    Geisbert TW, Daddario-Dicaprio KM, Lewis MG, Geisbert JB, Grolla A, Leung A, Paragas J, Matthias L, Smith MA, Jones SM, Hensley LE, Feldmann H, Jahrling PB. Vesicular stomatitis virus-based Ebola vaccine is well-tolerated and protects immunocompromised nonhuman primates. PLoS Pathog. 2008;4(11):e1000225.PubMedGoogle Scholar
  82. 82.
    Mire CE, Miller AD, Carville A, Westmoreland SV, Geisbert JB, Mansfield KG, Feldmann H, Hensley LE, Geisbert TW. Recombinant vesicular stomatitis virus vaccine vectors expressing filovirus glycoproteins lack neurovirulence in nonhuman primates. PLoS Negl Trop Dis. 2012;6(3):e1567. doi: 10.1371/journal.pntd.0001567.PubMedGoogle Scholar
  83. 83.
    Gunther S, Feldmann H, Geisbert TW, Hensley LE, Rollin PE, Nichol ST, Stroher U, Artsob H, Peters CJ, Ksiazek TG, Becker S, Ter Meulen J, Olschlager S, Schmidt-Chanasit J, Sudeck H, Burchard GD, Schmiedel S. Management of accidental exposure to Ebola virus in the biosafety level 4 laboratory, Hamburg, Germany. J Infect Dis. 2011;204(Suppl 3):S785–90.PubMedGoogle Scholar
  84. 84.
    Bukreyev A, Skiadopoulos MH, Murphy BR, Collins PL. Nonsegmented negative-strand viruses as vaccine vectors. J Virol. 2006;80(21):10293–306.PubMedGoogle Scholar
  85. 85.
    Bukreyev A, Yang L, Zaki SR, Shieh WJ, Rollin PE, Murphy BR, Collins PL, Sanchez A. A single intranasal inoculation with a paramyxovirus-vectored vaccine protects guinea pigs against a lethal-dose Ebola virus challenge. J Virol. 2006;80(5):2267–79.PubMedGoogle Scholar
  86. 86.
    Bukreyev AA, Dinapoli JM, Yang L, Murphy BR, Collins PL. Mucosal parainfluenza virus-vectored vaccine against Ebola virus replicates in the respiratory tract of vector-immune monkeys and is immunogenic. Virology. 2010;399(2):290–8.PubMedGoogle Scholar
  87. 87.
    Bukreyev A, Marzi A, Feldmann F, Zhang L, Yang L, Ward JM, Dorward DW, Pickles RJ, Murphy BR, Feldmann H, Collins PL. Chimeric human parainfluenza virus bearing the Ebola virus glycoprotein as the sole surface protein is immunogenic and highly protective against Ebola virus challenge. Virology. 2009;383(2):348–61.PubMedGoogle Scholar
  88. 88.
    Carroll SA, Towner JS, Sealy TK, Mcmullan LK, Khristova ML, Burt FJ, Swanepoel R, Rollin PE, Nichol ST. Molecular evolution of viruses of the family filoviridae based on 97 whole-genome sequences. J Virol. 2013;5(5):2608–16.Google Scholar
  89. 89.
    Hensley L, Mulangu S, Asiedu C, Johnson J, Honko AN, Stanley D, Fabozzi G, Nichol ST, Ksiazek TG, Rollin PE, Wahl-Jensen V, Bailey M, Jahrling PB, Roederer M, Koup RA, Sullivan NJ. Demonstration of cross-protective vaccine immunity against an emerging pathogenic Ebola virus species. PLoS Pathog. 2010;6(5):e1000904.PubMedGoogle Scholar
  90. 90.
    Marzi A, Ebihara H, Callison J, Groseth A, Williams KJ, Geisbert TW, Feldmann H. Vesicular stomatitis virus-based Ebola vaccines with improved cross-protective efficacy. J Infect Dis. 2011;204(Suppl 3):1066–74.Google Scholar
  91. 91.
    Pratt WD, Wang D, Nichols DK, Luo M, Woraratanadharm J, Dye JM, Holman DH, Dong JY. Protection of nonhuman primates against two species of Ebola virus infection with a single complex adenovirus vector. Clin Vaccine Immunol. 2010;17(4):572–81.PubMedGoogle Scholar
  92. 92.
    Geisbert TW, Geisbert JB, Leung A, Daddario-Dicaprio KM, Hensley LE, Grolla A, Feldmann H. Single-injection vaccine protects nonhuman primates against infection with Marburg virus and three species of Ebola virus. J Virol. 2009;83(14):7296–304.PubMedGoogle Scholar
  93. 93.
    Ndhlovu ZM, Piechocka-Trocha A, Vine S, Mcmullen A, Koofhethile KC, Goulder PJ, Ndung’u T, Barouch DH, Walker BD. Mosaic HIV-1 Gag antigens can be processed and presented to human HIV-specific CD8+ T cells. J Immunol. 2011;186(12):6914–24.PubMedGoogle Scholar
  94. 94.
    Santra S, Liao HX, Zhang R, Muldoon M, Watson S, Fischer W, Theiler J, Szinger J, Balachandran H, Buzby A, Quinn D, Parks RJ, Tsao CY, Carville, et al. Mosaic vaccines elicit CD8+ T lymphocyte responses that confer enhanced immune coverage of diverse HIV strains in monkeys. Nat Med. 2010;16(3):324–8.PubMedGoogle Scholar
  95. 95.
    Barouch DH, O’brien KL, Simmons NL, King SL, Abbink P, Maxfield LF, Sun YH, La Porte A, Riggs AM, Lynch DM, Clark SL, Backus K, et al. Mosaic HIV-1 vaccines expand the breadth and depth of cellular immune responses in rhesus monkeys. Nat Med. 2010;16(3):319–23.PubMedGoogle Scholar
  96. 96.
    Zahn R, Gillisen G, Roos A, Koning M, Van Der Helm E, Spek D, Weijtens M, Grazia Pau M, Radošević K, Weverling GJ, Custers J, Vellinga J, et al. Ad35 and Ad26 vaccine vectors induce potent and cross-reactive antibody and T-cell responses to multiple filovirus species. PLoS One. 2012;7(12):e44115.PubMedGoogle Scholar
  97. 97.
    Fenimore PW, Muhammad MA, Fischer WM, Foley BT, Bakken RR, Thurmond JR, Yusim K, Yoon H, Parker M, Hart MK, Dye JM, Korber B, Kuiken C. Designing and testing broadly-protective filoviral vaccines optimized for cytotoxic T-lymphocyte epitope coverage. PLoS One. 2012;7(10):e4469.Google Scholar
  98. 98.
    Phoolcharoen W, Dye JM, Kilbourne J, Piensook K, Pratt WD, Arntzen CJ, Chen Q, Mason HS, Herbst-Kralovetz MM. A nonreplicating subunit vaccine protects mice against lethal Ebola virus challenge. Proc Natl Acad Sci USA. 2011;108(51):20695–700.PubMedGoogle Scholar
  99. 99.
    Emond RT, Evans B, Bowen ET, Lloyd G. A case of Ebola virus infection. BMJ. 1977;2(6086):541–4.PubMedGoogle Scholar
  100. 100.
    Kudoyarova-Zubavichene NM, Sergeyev NN, Chepurnov AA, Netesov SV. Preparation and use of hyperimmune serum for prophylaxis and therapy of Ebola virus infections. J Infect Dis. 1999;179(Suppl 1):S218–23.PubMedGoogle Scholar
  101. 101.
    Mupapa K, Massamba M, Kibadi K, Kuvula K, Bwaka A, Kipasa M, Colebunders R, Muyembe-Tamfum JJ. Treatment of Ebola hemorrhagic fever with blood transfusions from convalescent patients. International Scientific and Technical Committee. J Infect Dis. 1999;179(Suppl 1):S18–23.PubMedGoogle Scholar
  102. 102.
    Jahrling PB, Geisbert JB, Swearengen JR, Larsen T, Geisbert TW. Ebola hemorrhagic fever: evaluation of passive immunotherapy in nonhuman primates. J Infect Dis. 2007;196(Suppl 2):S400–3.PubMedGoogle Scholar
  103. 103.
    Oswald WB, Geisbert TW, Davis KJ, Geisbert JB, Sullivan NJ, Jahrling PB, Parren PW, Burton DR. Neutralizing antibody fails to impact the course of Ebola virus infection in monkeys. PLoS Pathog. 2007;3(1):e9.PubMedGoogle Scholar
  104. 104.
    Shedlock DJ, Bailey MA, Popernack PM, Cunningham JM, Burton DR, Sullivan NJ. Antibody-mediated neutralization of Ebola virus can occur by two distinct mechanisms. Virology. 2010;401(2):228–35.PubMedGoogle Scholar
  105. 105.
    Qiu X, Alimonti JB, Melito PL, Fernando L, Stroher U, Jones SM. Characterization of Zaire Ebola virus glycoprotein-specific monoclonal antibodies. Clin Immunol. 2011;141(2):218–27.PubMedGoogle Scholar
  106. 106.
    Qiu X, Audet J, Wong G, Pillet S, Bello A, Cabral T, Strong JE, Plummer F, Corbett CR, Alimonti JB, Kobinger GP. Successful treatment of Ebola virus-infected cynomolgus macaques with monoclonal antibodies. Sci Transl Med. 2012;4(138):138ra81.PubMedGoogle Scholar
  107. 107.
    Qiu X, Fernando L, Melito PL, Audet J, Feldmann H, Kobinger G, Alimonti JB, Jones SM. Ebola Gp-specific monoclonal antibodies protect mice and guinea pigs from lethal Ebola virus infection. PLoS Negl Trop Dis. 2012;6(3):e1575.PubMedGoogle Scholar
  108. 108.
    Kondratowicz AS, Lennemann NJ, Sinn PL, Davey RA, Hunt CL, Moller-Tank S, Meyerholz DK, Rennert P, Mullins RF, Brindley M, Sandersfeld LM, Quinn K, Weller M, Mccray PB, Chiorini J, Maury W. T-cell immunoglobulin and mucin domain 1 (TIM-1) is a receptor for Zaire Ebolavirus and Lake Victoria Marburgvirus. Proc Natl Acad Sci USA. 2011;108(20):8426–31.PubMedGoogle Scholar
  109. 109.
    Basu A, Li B, Mills DM, Panchal RG, Cardinale SC, Butler MM, Peet NP, Majgier-Baranowska H, Williams JD, Patel I, Moir DT, Bavari S, Ray R, Farzan MR, Rong L, Bowlin TL. Identification of a small-molecule entry inhibitor for filoviruses. J Virol. 2011;85(7):3106–19.PubMedGoogle Scholar
  110. 110.
    Côté M, Misasi J, Ren T, Bruchez A, Lee K, Filone CM, Hensley L, Li Q, Ory D, Chandran K, Cunningham J. Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection. Nature. 2011;477(7364):344–8.PubMedGoogle Scholar
  111. 111.
    King G, Sharom FJ. Proteins that bind and move lipids: MsbA and NPC1. Crit Rev Biochem Mol Biol. 2012;47(1):75–95.PubMedGoogle Scholar
  112. 112.
    Lee K, Ren T, Côté M, Gholamreza B, Misasi J, Bruchez A, Cunningham J. Inhibition of Ebola virus infection: identification of Niemann-Pick C1 as the target by optimization of a chemical probe. ACS Med Chem Lett. 2013;4(2):239–43.PubMedGoogle Scholar
  113. 113.
    Shoemaker CJ, Schornberg KL, Delos SE, Scully C, Pajouhesh H, Olinger GG, Johansen LM, White JM. Multiple cationic amphiphiles induce a Niemann-Pick C phenotype and inhibit Ebola virus entry and infection. PLoS One. 2013;8(2):e56265. doi: 10.1371/journal.pone.0056265.PubMedGoogle Scholar
  114. 114.
    Miller EH, Harrison JS, Radoshitzky SR, Higgins CD, Chi X, Dong L, Kuhn JH, Bavari S, Lai JR, Chandran K. Inhibition of Ebola virus entry by a C-peptide targeted to endosomes. J Biol Chem. 2011;286(18):15854–61.PubMedGoogle Scholar
  115. 115.
    Spurgers KB, Alefantis T, Peyser BD, Ruthel GT, Bergeron AA, Costantino JA, Enterlein S, Kota KP, Boltz RC, Aman MJ, Delvecchio VG, Bavari S. Identification of essential filovirion-associated host factors by serial proteomic analysis and RNAi screen. Mol Cell Proteomics. 2010;9(12):2690–703.PubMedGoogle Scholar
  116. 116.
    Barrientos LG, Rollin PE. Release of cellular proteases into the acidic extracellular milieu exacerbates Ebola virus-induced cell damage. Virology. 2007;358(1):1–9.PubMedGoogle Scholar
  117. 117.
    Chandran K, Sullivan NJ, Felbor U, Whelan SP, Cunningham JM. Endosomal proteolysis of the Ebola virus glycoprotein is necessary for infection. Science. 2005;308(5728):1643–5.PubMedGoogle Scholar
  118. 118.
    Schornberg K, Matsuyama S, Kabsch K, Delos S, Bouton A, White J. Role of endosomal cathepsins in entry mediated by the Ebola virus glycoprotein. J Virol. 2006;80(8):4174–8.PubMedGoogle Scholar
  119. 119.
    Crotty S, Cameron CE, Andino R. RNA virus error catastrophe: direct molecular test by using ribavirin. Proc Natl Acad Sci USA. 2001;98(12):6895–900.PubMedGoogle Scholar
  120. 120.
    Huggins JW. Prospects for treatment of viral hemorrhagic fevers with ribavirin, a broad-spectrum antiviral drug. Rev Infect Dis. 1989;11(Suppl 4):S750–61.PubMedGoogle Scholar
  121. 121.
    Ignat’ev GM, Strel’tsova MA, Agafonov AP, Kashentseva EA, Prozorovskii NS. Experimental study of possible treatment of Marburg hemorrhagic fever with desferal, ribavirin, and homologous interferon. Vopr Virusol. 1996;41(5):206–9.PubMedGoogle Scholar
  122. 122.
    Geisbert TW, Hensley LE, Kagan E, Yu EZ, Geisbert JB, Daddario-Dicaprio K, Fritz EA, Jahrling PB, Mcclintock K, Phelps JR, Lee AC, Judge A, Jeffs LB, Maclachlan I. Postexposure protection of guinea pigs against a lethal Ebola virus challenge is conferred by RNA interference. J Infect Dis. 2006;193(12):1650–7.PubMedGoogle Scholar
  123. 123.
    Geisbert TW, Lee AC, Robbins M, Geisbert JB, Honko AN, Sood V, Johnson JC, De Jong S, Tavakoli I, Judge A, Hensley LE, Maclachlan I. Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study. Lancet. 2010;375(9729):1896–905.PubMedGoogle Scholar
  124. 124.
    Garcia M, Cooper A, Shi W, Bornmann W, Carrion R, Kalman D, Nabel GJ. Productive replication of Ebola virus is regulated by the C-Abl1 tyrosine kinase. Sci Transl Med. 2012;4(123):123ra24. doi: 10.1126/scitranslmed.3003500.PubMedGoogle Scholar
  125. 125.
    Warren TK, Shurtleff AC, Bavari S. Advanced morpholino oligomers: a novel approach to antiviral therapy. Antiviral Res. 2012;94(1):80–8.PubMedGoogle Scholar
  126. 126.
    Dirin M, Winkler J. Influence of diverse chemical modifications on the ADME characteristics and toxicology of antisense oligonucleotides. Expert Opin Biol Ther. 2013. Epub ahead of print.Google Scholar
  127. 127.
    Swenson DL, Warfield KL, Warren TK, Lovejoy C, Hassinger JN, Ruthel G, Blouch RE, Moulton HM, Weller DD, Iversen PL, Bavari S. Chemical modifications of antisense morpholino oligomers enhance their efficacy against Ebola virus infection. Antimicrob Agents Chemother. 2009;53(5):2089–99.PubMedGoogle Scholar
  128. 128.
    Warfield KL, Swenson DL, Olinger GG, Nichols DK, Pratt WD, Blouch R, Stein DA, Aman MJ, Iversen PL, Bavari S. Gene-specific countermeasures against Ebola virus based on antisense phosphorodiamidate morpholino oligomers. PLoS Pathog. 2006;2(1):e1.PubMedGoogle Scholar
  129. 129.
    Iversen PL, Warren TK, Wells JB, Garza NL, Mourich DV, Welch LS, Panchal RG, Bavari S. Discovery and early development of AVI-7537 and AVI-7288 for the treatment of Ebola virus and Marburg virus infections. Viruses. 2012;4(11):2806–30.PubMedGoogle Scholar
  130. 130.
    Warren TK, Warfield KL, Wells J, Swenson DL, Donner KS, Van Tongeren SA, Garza NL, Dong L, Mourich DV, Crumley S, Nichols DK, Iversen PL, Bavari S. Advanced antisense therapies for postexposure protection against lethal filovirus infections. Nat Med. 2010;16(9):991–4.PubMedGoogle Scholar
  131. 131.
    Warren TK, Warfield KL, Wells J, Enterlein S, Smith M, Ruthel G, Yunus AS, Kinch MS, Goldblatt M, Aman MJ, Bavari S. Antiviral activity of a small-molecule inhibitor of filovirus infection. Antimicrob Agents Chemother. 2010;54(5):2152–9.PubMedGoogle Scholar
  132. 132.
    Kinch MS, Yunus AS, Lear C, Mao H, Chen H, Fesseha Z, Luo G, Nelson EA, Li L, Huang Z, Murray M, Ellis WY, Hensley L, Christopher-Hennings J, Olinger GG, Goldblatt M. FGI-104: a broad-spectrum small molecule inhibitor of viral infection. Am J Transl Res. 2009;1(1):87–98.PubMedGoogle Scholar
  133. 133.
    Aman MJ, Kinch MS, Warfield K, Warren T, Yunus A, Enterlein S, Stavale E, Wang P, Chang S, Tang Q, Porter K, Goldblatt M, Bavari S. Development of a broad-spectrum antiviral with activity against Ebola virus. Antiviral Res. 2009;83(3):245–51.PubMedGoogle Scholar
  134. 134.
    Bradfute SB, Warfield KL, Bray M. Mouse models for filovirus infections. Viruses. 2012;4(9):1477–508.PubMedGoogle Scholar
  135. 135.
    Subbotina E, Dadaeva A, Kachko A, Chepurnov A. Genetic factors of Ebola virus virulence in guinea pigs. Virus Res. 2010;153(1):121–33.PubMedGoogle Scholar
  136. 136.
    Geisbert TW, Young HA, Jahrling PB, Davis KJ, Larsen T, Kagan E, Hensley LE. Pathogenesis of Ebola hemorrhagic fever in primate models: evidence that hemorrhage is not a direct effect of virus-induced cytolysis of endothelial cells. Am J Pathol. 2003;163(6):2371–82.PubMedGoogle Scholar
  137. 137.
    Bray M, Davis K, Geisbert T, Schmaljohn C, Huggins J. A mouse model for evaluation of prophylaxis and therapy of Ebola hemorrhagic fever. J Infect Dis. 1998;178(3):651–61.PubMedGoogle Scholar
  138. 138.
    Bray M. The role of the type I interferon response in the resistance of mice to filovirus infection. J Gen Virol. 2001;82(Pt 6):1365–73.PubMedGoogle Scholar
  139. 139.
    Bray M, Raymond JL, Geisbert T, Baker RO. 3-Deazaneplanocin a induces massively increased interferon-alpha production in Ebola virus-infected mice. Antiviral Res. 2002;55(1):151–9.PubMedGoogle Scholar
  140. 140.
    Bray M, Driscoll J, Huggins JW. Treatment of lethal Ebola virus infection in mice with a single dose of an S-adenosyl-l-homocysteine hydrolase inhibitor. Antiviral Res. 2000;45(2):135–47.PubMedGoogle Scholar
  141. 141.
    Jahrling PB, Geisbert TW, Geisbert JB, Swearengen JR, Bray M, Jaax NK, Huggins JW, Leduc JW, Peters CJ. Evaluation of immune globulin and recombinant interferon-Alpha2b for treatment of experimental Ebola virus infections. J Infect Dis. 1999;179(Suppl 1):S224–34.PubMedGoogle Scholar
  142. 142.
    Markin VA, Mikhailov VV, Krasnianskii VP, Borisevich IV, Firsova IV. Developing principles for emergency prevention and treatment of Ebola fever. Vopr Virusol. 1997;42(1):31–4.PubMedGoogle Scholar
  143. 143.
    Kolokoltsov AA, Davidovich IA, Streltsova MA, Nesterov AE, Agafonova OA, Agafonov AP. The use of interferon for emergency prophylaxis of Marburg hemorrhagic fever in monkeys. Bull Exp Biol Med. 2001;132(1):686–8.Google Scholar
  144. 144.
    Panchal RG, Reid SP, Tran JP, Bergeron AA, Wells J, Kota KP, Aman J, Bavari S. Identification of an antioxidant small-molecule with broad-spectrum antiviral activity. Antiviral Res. 2012;93(1):23–9.PubMedGoogle Scholar
  145. 145.
    Geisbert TW, Young HA, Jahrling PB, Davis KJ, Kagan E, Hensley LE. Mechanisms underlying coagulation abnormalities in Ebola hemorrhagic fever: overexpression of tissue factor in primate monocytes/macrophages is a key event. J Infect Dis. 2003;188(11):1618–29.PubMedGoogle Scholar
  146. 146.
    Geisbert TW, Hensley LE, Jahrling PB, Larsen T, Geisbert JB, Paragas J, Young HA, Fredeking TM, Rote WE, Vlasuk GP. Treatment of Ebola virus infection with a recombinant inhibitor of factor VIIa/tissue factor: a study in rhesus monkeys. Lancet. 2003;362(9400):1953–8.PubMedGoogle Scholar
  147. 147.
    Hensley LE, Stevens EL, Yan SB, Geisbert JB, Macias WL, Larsen T, Daddario-Dicaprio KM, Cassell GH, Jahrling PB, Geisbert TW. Recombinant human activated protein C for the postexposure treatment of Ebola hemorrhagic fever. J Infect Dis. 2007;196(Suppl 2):S390–9.PubMedGoogle Scholar
  148. 148.
    Mungall D. rNAPc2. Nuvelo. Curr Opin Investig Drugs. 2004;5(3):327–33.PubMedGoogle Scholar
  149. 149.
    Ranieri V, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Finfer S, Gårdlund B, Marshall JC, Rhodes A, Artigas A, et al. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med. 2012;366(22):2055–64.PubMedGoogle Scholar
  150. 150.
    Food and Drug Administration. Voluntary withdrawal of Xigris (drotrecogin alfa (activated)) due to failure to show a survival benefit. 2011 [cited 2013 May 1].
  151. 151.
    Foged C. siRNA delivery with lipid-based systems: promises and pitfalls. Curr Top Med Chem. 2012;12(2):97–107.PubMedGoogle Scholar
  152. 152.
    Jiskoot W, Randolph TW, Volkin DB, Middaugh CR, Schoneich C, Winter G, Friess W, Crommelin DJ, Carpenter JF. Protein instability and immunogenicity: roadblocks to clinical application of injectable protein delivery systems for sustained release. J Pharm Sci. 2012;101(3):946–54.PubMedGoogle Scholar
  153. 153.
    Shaikh R, Raj Singh TR, Garland MJ, Woolfson AD, Donnelly RF. Mucoadhesive drug delivery systems. J Pharm Bioallied Sci. 2011;3(1):89–100.PubMedGoogle Scholar
  154. 154.
    Leucuta SE. Systemic and biophase bioavailability and pharmacokinetics of nanoparticulate drug delivery systems. Curr Drug Deliv. 2013;10(2):208–40.PubMedGoogle Scholar
  155. 155.
    Khutoryanskiy VV. Advances in mucoadhesion and mucoadhesive polymers. Macromol Biosci. 2011;11(6):748–64.PubMedGoogle Scholar
  156. 156.
    Das Neves J, Bahia MF, Amiji MM, Sarmento B. Mucoadhesive nanomedicines: characterization and modulation of mucoadhesion at the nanoscale. Expert Opin Drug Deliv. 2011;8(8):1085–104.PubMedGoogle Scholar
  157. 157.
    Laffleur F, Bernkop-Schnürch A. Thiomers: promising platform for macromolecular drug delivery. Future Med Chem. 2013;5(5):511–22.PubMedGoogle Scholar
  158. 158.
    Hauptstein S, Bernkop-Schnürch A. Thiomers and thiomer-based nanoparticles in protein and DNA drug delivery. Expert Opin Drug Deliv. 2012;9(9):1069–81.PubMedGoogle Scholar
  159. 159.
    Aungst BJ. Absorption enhancers: applications and advances. AAPS J. 2012;14(1):10–8.PubMedGoogle Scholar
  160. 160.
    Hamman J, Steenekamp J. Excipients with specialized functions for effective drug delivery. Expert Opin Drug Deliv. 2012;9(2):219–30.PubMedGoogle Scholar
  161. 161.
    Frankel AD, Pabo CO. Cellular uptake of the tat protein from human immunodeficiency virus. Cell. 1988;55(6):1189–93.PubMedGoogle Scholar
  162. 162.
    Derossi D, Joliot AH, Chassaing G, Prochiantz A. The third helix of the Antennapedia homeodomain translocates through biological membranes. J Biol Chem. 1994;269(14):10444–50.PubMedGoogle Scholar
  163. 163.
    Gooding M, Browne LP, Quinteiro FM, Selwood DL. siRNA delivery: from lipids to cell-penetrating peptides and their mimics. Chem Biol Drug Des. 2012;80(6):787–809.PubMedGoogle Scholar
  164. 164.
    Sen K, Mandal M. Second generation liposomal cancer therapeutics: transition from laboratory to clinic. Int J Pharm. 2013;448(1):28–43.PubMedGoogle Scholar
  165. 165.
    Musacchio T, Torchilin VP. Recent developments in lipid-based pharmaceutical nanocarriers. Front Biosci. 2011;16:1388–412.Google Scholar
  166. 166.
    Pardeshi C, Rajput P, Belgamwar V, Tekade A, Patil G, Chaudhary K, Sonje A. Solid lipid based nanocarriers: an overview. Acta Pharm. 2012;62(4):433–72.PubMedGoogle Scholar
  167. 167.
    Lim SB, Banerjee A, Önyüksel H. Improvement of drug safety by the use of lipid-based nanocarriers. J Control Release. 2012;163(1):34–45.PubMedGoogle Scholar
  168. 168.
    Van Rooijen N, Van Nieuwmegen R. Liposomes in immunology: the immune response against antigen-containing liposomes. Immunol Commun. 1977;6(5):489–98.PubMedGoogle Scholar
  169. 169.
    Hsu MJ, Juliano RL. Interactions of liposomes with the reticuloendothelial system. II: Nonspecific and receptor-mediated uptake of liposomes by mouse peritoneal macrophages. Biochim Biophys Acta. 1982;720(4):411–9.PubMedGoogle Scholar
  170. 170.
    Shahum E, Thérien HM. Liposomal adjuvanticity: effect of encapsulation and surface-linkage on antibody production and proliferative response. Int J Immunopharmacol. 1995;17(1):9–20.PubMedGoogle Scholar
  171. 171.
    Agrewala JN, Owais M, Gupta CM, Mishra GC. Antigen incorporation into liposomes results in the enhancement of Il-4 and IgG1 secretion: evidence for preferential expansion of Th-2 cells. Cytokines Mol Ther. 1996;2(1):59–65.PubMedGoogle Scholar
  172. 172.
    Watson DS, Endsley AN, Huang L. Design considerations for liposomal vaccines: influence of formulation parameters on antibody and cell-mediated immune responses to liposome associated antigens. Vaccine. 2012;30(13):2256–72.PubMedGoogle Scholar
  173. 173.
    Christensen D, Korsholm KS, Andersen P, Agger EM. Cationic liposomes as vaccine adjuvants. Expert Rev Vaccines. 2011;10(4):513–21.PubMedGoogle Scholar
  174. 174.
    Chang HI, Yeh MK. Clinical development of liposome-based drugs: formulation, characterization, and therapeutic efficacy. Int J Nanomed. 2012;7:49–60.Google Scholar
  175. 175.
    Yoo JW, Irvine DJ, Discher DE, Mitragotri S. Bio-inspired, bio-engineered and biomimetic drug delivery carriers. Nat Rev Drug Discov. 2011;10(7):521–35.PubMedGoogle Scholar
  176. 176.
    Salmaso S, Caliceti P, Stealth properties to improve therapeutic efficacy of drug nanocarriers. J Drug Deliv. 2013. Epub ahead of print.Google Scholar
  177. 177.
    Webster DM, Sundaram P, Byrne ME. Injectable nanomaterials for drug delivery: carriers, targeting moieties, and therapeutics. Eur J Pharm Biopharm. 2013;84(1):1–20.PubMedGoogle Scholar
  178. 178.
    Mandal B, Bhattacharjee H, Mittal N, Sah H, Balabathula P, Thoma LA, Wood GC. Core-shell-type lipid-polymer hybrid nanoparticles as a drug delivery platform. Nanomedicine. 2013;9(4):474–91.PubMedGoogle Scholar
  179. 179.
    Hudson D, Margaritis A., Biopolymer nanoparticle production for controlled release of biopharmaceuticals. Crit Rev Biotechnol. 2013. Epub ahead of print.Google Scholar
  180. 180.
    Balmayor ER, Azevedo HS, Reis RL. Controlled delivery systems: from pharmaceuticals to cells and genes. Pharm Res. 2011;28(6):1241–58.PubMedGoogle Scholar
  181. 181.
    Fredenberg S, Wahlgren M, Reslow M, Axelsson A. The mechanisms of drug release in poly(lactic-co-glycolic acid)-based drug delivery systems—a review. Int J Pharm. 2011;415(1–2):34–52.PubMedGoogle Scholar
  182. 182.
    Naeye B, Raemdonck K, Remaut K, Demeester J, De Smedt SC. Matrix systems for siRNA delivery. Curr Top Med Chem. 2012;12(2):89–96.PubMedGoogle Scholar
  183. 183.
    Danhier F, Ansorena E, Silva JM, Coco R, Le Breton A, Préat V. PLGA-based nanoparticles: an overview of biomedical applications. J Control Release. 2012;161(2):505–22.PubMedGoogle Scholar
  184. 184.
    Lv Y, Tan T, Svec F, Molecular imprinting of proteins in polymers attached to the surface of nanomaterials for selective recognition of biomacromolecules. Biotechnol Adv. 2013. Epub ahead of print.Google Scholar
  185. 185.
    Cheong WJ, Yang SH, Ali F. Molecular imprinted polymers for separation science: a review of reviews. J Sep Sci. 2013;36(3):609–28.PubMedGoogle Scholar
  186. 186.
    Wrenn SP, Dicker SM, Small EF, Dan NR, Mleczko M, Schmitz G, Lewin PA. Bursting bubbles and bilayers. Theranostics. 2012;2(12):1140–59.PubMedGoogle Scholar
  187. 187.
    Cheng R, Meng F, Deng C, Klok HA, Zhong Z. Dual and multi-stimuli responsive polymeric nanoparticles for programmed site-specific drug delivery. Biomaterials. 2013;34(14):3647–57.PubMedGoogle Scholar
  188. 188.
    Gibson MI, O’reilly RK, To aggregate, or not to aggregate? Considerations in the design and application of polymeric thermally-responsive nanoparticles. Chem Soc Rev. 2013. Epub ahead of print.Google Scholar
  189. 189.
    Sullivan NJ, Hensley L, Asiedu C, Geisbert TW, Stanley D, Johnson J, Honko A, Olinger G, Bailey M, Geisbert JB, Reimann KA, Bao S, Rao S, Roederer M, Jahrling PB, Koup RA, Nabel GJ. CD8+ cellular immunity mediates rAd5 vaccine protection against Ebola virus infection of nonhuman primates. Nat Med. 2011;17(9):1128–31.PubMedGoogle Scholar
  190. 190.
    Geisbert TW, Bailey M, Geisbert JB, Asiedu C, Roederer M, Grazia-Pau M, Custers J, Jahrling P, Goudsmit J, Koup R, Sullivan NJ. Vector choice determines immunogenicity and potency of genetic vaccines against Angola Marburg virus in nonhuman primates. J Virol. 2010;84(19):10386–94.PubMedGoogle Scholar
  191. 191.
    Bukreyev A, Rollin PE, Tate MK, Yang L, Zaki SR, Shieh WJ, Murphy BR, Collins PL, Sanchez A. Successful topical respiratory tract immunization of primates against Ebola virus. J Virol. 2007;81(12):6379–88.PubMedGoogle Scholar
  192. 192.
    Hevey M, Negley D, Pushko P, Smith J, Schmaljohn A. Marburg virus vaccines based upon alphavirus replicons protect guinea pigs and nonhuman primates. Virology. 1998;251(1):28–37.PubMedGoogle Scholar
  193. 193.
    Warfield KL, Swenson DL, Olinger GG, Kalina WV, Aman MJ, Bavari S. Ebola virus-like particle-based vaccine protects nonhuman primates against lethal Ebola virus challenge. J Infect Dis. 2007;196(Suppl 2):S430–7.PubMedGoogle Scholar
  194. 194.
    Parren PW, Geisbert TW, Maruyama T, Jahrling PB, Burton DR. Pre- and postexposure prophylaxis of Ebola virus infection in an animal model by passive transfer of a neutralizing human antibody. J Virol. 2002;76(12):6408–12.PubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  1. 1.Division of PharmaceuticsThe University of Texas at Austin, College of Pharmacy, PHR 4.214DAustinUSA
  2. 2.Institute of Cellular and Molecular BiologyThe University of Texas at AustinAustinUSA

Personalised recommendations