Review of Current Non-Vaccine Based Approaches for the Prevention and Treatment of Flaviviral Diseases

Main Article Content

Monika Simmons Joseph Robert Putnak

Abstract

Although there are nearly 70 medically important Flaviviruses including Dengue and Zika, which cause over 100 million new infections each year with significant morbidity and mortality, vaccines are available for only a few of these viruses.  Furthermore, some of these vaccines require lengthy immunization courses or multiple boosters subjecting recipients to potential gaps in protection.  Therefore, non-vaccine based prophylactics and therapeutics could play a significant role in filling these gaps.  Unfortunately, despite over a decade of research only a few antiviral drug candidates have been advanced to clinical trials and for most of these the results have been disappointing.  Also, funding for antiviral research has been relatively scant in recent years.  Nevertheless, there are reasons for optimism.  There has been significant progress made in our understanding of Flaviviral infections, in the identification of promising drug targets and transmission abatement strategies, and in the establishment of protocols for drug discovery and for conducting human clinical safety and efficacy trials.  Multipronged efforts are currently ongoing to evaluate highly diverse approaches including (i) small molecule antivirals, (ii) virus-neutralizing and infection-blocking antibodies, (iii) viral receptor antagonists, (iv) infection-blocking oligonucleotides, and (v) strategies targeting the arthropod vectors.  A few areas of research that deserve special mention are phosphorodiamidate morpholino oligomers and peptide-linked phosphorodiamidate morpholino oligomers (PMOs/PPMOs), a class of infection-inhibiting, antisense oligonucleotides, which already have shown promising clinical safety and efficacy data, and the novel strategies being developed aimed at reducing viral transmission in endemic areas by targeting the arthropod vector-hosts, which have also shown promise.  The hope is that renewed commitment by government, academic, and private institutions will lead to licensed antiviral therapeutics, prophylactics, and other strategies aimed at preventing Flaviviral diseases in the not too distant future. 

Article Details

How to Cite
SIMMONS, Monika; PUTNAK, Joseph Robert. Review of Current Non-Vaccine Based Approaches for the Prevention and Treatment of Flaviviral Diseases. Medical Research Archives, [S.l.], v. 5, n. 10, oct. 2017. ISSN 2375-1924. Available at: <http://journals.ke-i.org/index.php/mra/article/view/1524>. Date accessed: 15 dec. 2017.
Keywords
Flaviviruses, Dengue, Zika, Diseases, Prevention, Treatment, Non-Vaccine
Section
Review Articles

References

References
1. Fendrick AM. Viral respiratory infections due to rhinoviruses: current knowledge, new developments. Am J Ther. 2003;10(3):193-202.
2. U.S. Food and Drug Administration Website. Vaccines licensed for use in the U.S. https://www.fda.gov/biologicsbloodvaccines/vaccines/approvedproducts/ucm093833.htm.
3. Lang P-O, Mendes A, Socquet J, Assir N, Govind S, Aspinall R. Effectiveness of influenza vaccine in aging and older adults: comprehensive analysis of the evidence. Clin Interv Aging. 2012;7:55.
4. Norrby E. Yellow fever and Max Theiler: the only Nobel Prize for a virus vaccine. J Exp Med. 2007;204(12):2779-2784.
5. Erra EO, Kantele A. The Vero cell-derived, inactivated, SA14-14-2 strain-based vaccine (Ixiaro) for prevention of Japanese encephalitis. Expert Rev Vaccines. 2015;14(9):1167-1179.
6. Amicizia D, Domnich A, Panatto D, et al. Epidemiology of tick-borne encephalitis (TBE) in Europe and its prevention by available vaccines. Hum Vaccin Immunother. 2013;9(5):1163-1171.
7. Torresi J, Ebert G, Pellegrini M. Vaccines licensed and in clinical trials for the prevention of dengue. Hum Vaccin Immunother. 2017;13(5):1059-1072.
8. Yauch LE, Shresta S. Dengue virus vaccine development. Adv Virus Res. 2014;88:315-372.
9. Aguiar M, Stollenwerk N, Halstead SB. The Impact of the Newly Licensed Dengue Vaccine in Endemic Countries. PLoS Negl Trop Dis. 2016;10(12):e0005179.
10. McCloskey B, Endericks T. The rise of Zika infection and microcephaly: what can we learn from a public health emergency? Public Health. 2017;150:87-92.
11. US FDA website: https://www.fda.gov/forpatients/illness/hivaids/treatment/ucm118915.htm
12. US FDA website: https://www.fda.gov/drugs/drugsafety/informationbydrugclass/ucm100228.htm#AntiviralMedications.
13. Jefferson T, Jones M, Doshi P, Spencer EA, Onakpoya I, Heneghan CJ. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ. 2014;348:g2545.
14. Lyons AG. The human dengue challenge experience at the Walter Reed Army Institute of Research. The Journal of infectious diseases. 2014;209(suppl_2):S49-S55.
15. Hart J, Tillman G, Kraut MA, et al. West Nile virus neuroinvasive disease: neurological manifestations and prospective longitudinal outcomes. BMC Infect Dis. 2014;14(1):248.
16. Parra B, Lizarazo J, Jiménez-Arango JA, et al. Guillain–Barré syndrome associated with Zika virus infection in Colombia. N Engl J Med. 2016;375(16):1513-1523.
17. Vaughn DW, Green S, Kalayanarooj S, et al. Dengue viremia titer, antibody response pattern, and virus serotype correlate with disease severity. The Journal of infectious diseases. 2000;181(1):2-9.
18. Simmonds P BP, Bukh J, Gould EA, Meyers G, MonathT, Muerhoff S, Pletnev A, Rico-Hesse R, Smith DB, Stapleton JT. ICTV Virus Taxonomy Profile: Flaviviridae. J Gen Virol. 2017;Jan;98(1):2-3.
19. Liu P, Ridilla M, Patel P, et al. Beyond attachment: Roles of DC‐SIGN in dengue virus infection. Traffic. 2017;18(4):218-231.
20. Artpradit C, Robinson LN, Gavrilov BK, Rurak TT, Ruchirawat M, Sasisekharan R. Recognition of heparan sulfate by clinical strains of dengue virus serotype 1 using recombinant subviral particles. Virus Res. 2013;176(1):69-77.
21. Ong EZ, Zhang SL, Tan HC, Gan ES, Chan KR, Ooi EE. Dengue virus compartmentalization during antibody-enhanced infection. Sci Rep. 2017;7.
22. Wang TT, Sewatanon J, Memoli MJ, et al. IgG antibodies to dengue enhanced for FcγRIIIA binding determine disease severity. Science. 2017;355(6323):395-398.
23. Kouretova J, Hammamy MZ, Epp A, et al. Effects of NS2B-NS3 protease and furin inhibition on West Nile and Dengue virus replication. J Enzyme Inhib Med Chem. 2017;32(1):712-721.
24. Oliphant T, Nybakken GE, Engle M, et al. Antibody recognition and neutralization determinants on domains I and II of West Nile Virus envelope protein. J Virol. 2006;80(24):12149-12159.
25. Gromowski GD, Barrett AD. Characterization of an antigenic site that contains a dominant, type-specific neutralization determinant on the envelope protein domain III (ED3) of dengue 2 virus. Virology. 2007;366(2):349-360.
26. Selisko B, Wang C, Harris E, Canard B. Regulation of Flavivirus RNA synthesis and replication. Curr Opin Virol. 2014;9:74-83.
27. Apte-Sengupta S, Sirohi D, Kuhn RJ. Coupling of replication and assembly in flaviviruses. Curr Opin Virol. 2014;9:134-142.
28. Scaturro P, Cortese M, Chatel-Chaix L, Fischl W, Bartenschlager R. Dengue Virus Non-structural Protein 1 Modulates Infectious Particle Production via Interaction with the Structural Proteins. PLoS Pathog. 2015;11(11):e1005277.
29. Green AM, Beatty PR, Hadjilaou A, Harris E. Innate immunity to dengue virus infection and subversion of antiviral responses. J Mol Biol. 2014;426(6):1148-1160.
30. Boldescu V, Behnam MAM, Vasilakis N, Klein CD. Broad-spectrum agents for flaviviral infections: dengue, Zika and beyond. Nat Rev Drug Discov. 2017.
31. Garcia LL, Padilla L, Castano JC. Inhibitors compounds of the flavivirus replication process. Virol J. 2017;14(1):95.
32. Garcia-Blanco MA, Vasudevan SG, Bradrick SS, Nicchitta C. Flavivirus RNA transactions from viral entry to genome replication. Antiviral Res. 2016;134:244-249.
33. Lim SP, Shi P-Y. West Nile virus drug discovery. Viruses. 2013;5(12):2977-3006.
34. Sarathy VV, Milligan GN, Bourne N, Barrett AD. Mouse models of dengue virus infection for vaccine testing. Vaccine. 2015;33(50):7051-7060.
35. Tan GK, Ng JK, Lim AH, Yeo KP, Angeli V, Alonso S. Subcutaneous Infection with Non-mouse Adapted Dengue Virus D2Y98P Strain Induces Systemic Vascular Leakage in AG129 Mice. Ann Acad Med Singapore. 2011;40(12):523-510.
36. Whitehorn J, Van VC, Simmons CP. Dengue human infection models supporting drug development. J Infect Dis. 2014;209 Suppl 2:S66-70.
37. Whitehorn J, Yacoub S, Anders KL, et al. Dengue therapeutics, chemoprophylaxis, and allied tools: state of the art and future directions. PLoS Negl Trop Dis. 2014;8(8):e3025.
38. Lim SP, Wang Q-Y, Noble CG, et al. Ten years of dengue drug discovery: progress and prospects. Antiviral Res. 2013;100(2):500-519.
39. Low JG, Sung C, Wijaya L, et al. Efficacy and safety of celgosivir in patients with dengue fever (CELADEN): a phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial. Lancet Infect Dis. 2014;14(8):706-715.
40. Chang J, Schul W, Butters TD, et al. Combination of alpha-glucosidase inhibitor and ribavirin for the treatment of dengue virus infection in vitro and in vivo. Antiviral Res. 2011;89(1):26-34.
41. Nguyen NM, Tran CNB, Phung LK, et al. A randomized, double-blind placebo controlled trial of balapiravir, a polymerase inhibitor, in adult dengue patients. The Journal of infectious diseases. 2012;207(9):1442-1450.
42. Chen Y-L, Ghafar NA, Karuna R, et al. Activation of peripheral blood mononuclear cells by dengue virus infection depotentiates balapiravir. J Virol. 2014;88(3):1740-1747.
43. Tabata T, Petitt M, Puerta-Guardo H, et al. Zika virus targets different primary human placental cells, suggesting two routes for vertical transmission. Cell host & microbe. 2016;20(2):155-166.
44. Retallack H, Di Lullo E, Arias C, et al. Zika virus cell tropism in the developing human brain and inhibition by azithromycin. Proceedings of the National Academy of Sciences. 2016;113(50):14408-14413.
45. Teixeira RR, Pereira WL, Oliveira AFCdS, et al. Natural products as source of potential dengue antivirals. Molecules. 2014;19(6):8151-8176.
46. Pu J, He L, Xie H, et al. Antiviral activity of Carbenoxolone disodium against dengue virus infection. J Med Virol. 2017;89(4):571-581.
47. VanBlargan LA, Goo L, Pierson TC. Deconstructing the Antiviral Neutralizing-Antibody Response: Implications for Vaccine Development and Immunity. Microbiol Mol Biol Rev. 2016;80(4):989-1010.
48. Van Gessel Y, Klade CS, Putnak R, et al. Correlation of protection against Japanese encephalitis virus and JE vaccine (IXIARO((R))) induced neutralizing antibody titers. Vaccine. 2011;29(35):5925-5931.
49. Fujiyama S SY. Immune serum Globulin (ISG) and its usefulness for prevention of hepatitis A. Nihon Rinsho. 2004;Aug;62(Suppl 8:):496-498.
50. Engle MJ, Diamond MS. Antibody prophylaxis and therapy against West Nile virus infection in wild-type and immunodeficient mice. J Virol. 2003;77(24):12941-12949.
51. Haley M, Retter AS, Fowler D, Gea-Banacloche J, O'grady NP. The role for intravenous immunoglobulin in the treatment of West Nile virus encephalitis. Clin Infect Dis. 2003;37(6):e88-e90.
52. Moudgil A, Shidban H, Nast CC, et al. PARVOVIRUS B19 INFECTION-RELATED COMPLICATIONS IN RENAL TRANSPLANT RECIPIENTS: Treatment with Intravenous Immunoglobulin1. Transplantation. 1997;64(12):1847-1850.
53. Goldstein G, Rutenberg TF, Mendelovich SL, et al. The role of immunoglobulin prophylaxis for prevention of cytomegalovirus infection in pediatric hematopoietic stem cell transplantation recipients. Pediatr Blood Cancer. 2017;64(7).
54. Kaufman B, Summers P, Dubois D, Eckels K. Monoclonal antibodies against dengue 2 virus E-glycoprotein protect mice against lethal dengue infection. The American journal of tropical medicine and hygiene. 1987;36(2):427-434.
55. Kaufman B, Summers P, Dubois D, Cohen WH, Gentry M. Monoclonal antibodies for dengue virus prM glycoprotein protect mice against lethal dengue infection. DTIC Document;1989.
56. Schlesinger JJ, Brandriss MW, Cropp CB, Monath TP. Protection against yellow fever in monkeys by immunization with yellow fever virus nonstructural protein NS1. J Virol. 1986;60(3):1153-1155.
57. Henchal E, Henchal L, Schlesinger J. Synergistic interactions of anti-NS1 monoclonal antibodies protect passively immunized mice from lethal challenge with dengue 2 virus. The Journal of general virology. 1988;69:2101-2107.
58. Sukupolvi-Petty S, Austin SK, Engle M, et al. Structure and function analysis of therapeutic monoclonal antibodies against dengue virus type 2. J Virol. 2010;84(18):9227-9239.
59. Dowd KA, Mukherjee S, Kuhn RJ, Pierson TC. Combined effects of the structural heterogeneity and dynamics of flaviviruses on antibody recognition. J Virol. 2014;88(20):11726-11737.
60. Austin SK, Dowd KA, Shrestha B, et al. Structural basis of differential neutralization of DENV-1 genotypes by an antibody that recognizes a cryptic epitope. PLoS Pathog. 2012;8(10):e1002930.
61. Rodrigo WW, Block OK, Lane C, et al. Dengue virus neutralization is modulated by IgG antibody subclass and Fcgamma receptor subtype. Virology. 2009;394(2):175-182.
62. Pierson TC, Diamond MS. Molecular mechanisms of antibody-mediated neutralisation of flavivirus infection. Expert Rev Mol Med. 2008;10.
63. Dowd KA, Pierson TC. Antibody-mediated neutralization of flaviviruses: a reductionist view. Virology. 2011;411(2):306-315.
64. Pierson TC. Modeling antibody-enhanced dengue virus infection and disease in mice: protection or pathogenesis? Cell Host Microbe. 2010;7(2):85-86.
65. Schlesinger JJ, Foltzer M, Chapman S. The Fc portion of antibody to yellow fever virus NS1 is a determinant of protection against YF encephalitis in mice. Virology. 1993;192(1):132-141.
66. Lai CJ, Goncalvez AP, Men R, et al. Epitope determinants of a chimpanzee dengue virus type 4 (DENV-4)-neutralizing antibody and protection against DENV-4 challenge in mice and rhesus monkeys by passively transferred humanized antibody. J Virol. 2007;81(23):12766-12774.
67. Reyes-del Valle J, Salas-Benito J, Soto-Acosta R, del Angel RM. Dengue virus cellular receptors and tropism. Current Tropical Medicine Reports. 2014;1(1):36-43.
68. Arbuthnot P. MicroRNA-like antivirals. Biochimica et Biophysica Acta (BBA)-Gene Regulatory Mechanisms. 2011;1809(11):746-755.
69. Liu YP, Berkhout B. miRNA cassettes in viral vectors: problems and solutions. Biochimica et Biophysica Acta (BBA)-Gene Regulatory Mechanisms. 2011;1809(11):732-745.
70. Kakumani PK, Ponia SS, Sood V, et al. Role of RNA interference (RNAi) in dengue virus replication and identification of NS4B as an RNAi suppressor. J Virol. 2013;87(16):8870-8883.
71. Wu X, Hong H, Yue J, et al. Inhibitory effect of small interfering RNA on dengue virus replication in mosquito cells. Virol J. 2010;7:270.
72. Raviprakash K, Liu K, Matteucci M, Wagner R, Riffenburgh R, Carl M. Inhibition of dengue virus by novel, modified antisense oligonucleotides. J Virol. 1995;69(1):69-74.
73. Warren TK, Shurtleff AC, Bavari S. Advanced morpholino oligomers: a novel approach to antiviral therapy. Antiviral Res. 2012;94(1):80-88.
74. Kinali M, Arechavala-Gomeza V, Feng L, et al. Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-escalation, proof-of-concept study. The Lancet Neurology. 2009;8(10):918-928.
75. Iversen PL, Warren TK, Wells JB, et al. Discovery and early development of AVI-7537 and AVI-7288 for the treatment of Ebola virus and Marburg virus infections. Viruses. 2012;4(11):2806-2830.
76. Stein DA, Huang CY-H, Silengo S, et al. Treatment of AG129 mice with antisense morpholino oligomers increases survival time following challenge with dengue 2 virus. J Antimicrob Chemother. 2008;62(3):555-565.
77. Heald AE, Charleston JS, Iversen PL, et al. AVI-7288 for Marburg virus in nonhuman primates and humans. N Engl J Med. 2015;373(4):339-348.
78. Falzarano MS, Passarelli C, Ferlini A. Nanoparticle delivery of antisense oligonucleotides and their application in the exon skipping strategy for Duchenne muscular dystrophy. Nucleic Acid Ther. 2014;24(1):87-100.
79. Carrington LB, Simmons CP. Human to mosquito transmission of dengue viruses. Front Immunol. 2014;5.
80. Alphey L, McKemey A, Nimmo D, et al. Genetic control of Aedes mosquitoes. Pathogens and global health. 2013;107(4):170-179.
81. Bull JJ, Turelli M. Wolbachia versus dengue: evolutionary forecasts. Evolution, medicine, and public health. 2013;2013(1):197-207.
82. Liu Y, Zhang F, Liu J, et al. Transmission-blocking antibodies against mosquito C-type lectins for dengue prevention. PLoS Pathog. 2014;10(2):e1003931.

Most read articles by the same author(s)

Obs.: This plugin requires at least one statistics/report plugin to be enabled. If your statistics plugins provide more than one metric then please also select a main metric on the admin's site settings page and/or on the journal manager's settings pages.