Clinical trials of therapeutics for the prevention of congenital zika virus disease: Challenges and potential solutions

Annals of Internal Medicine

Volumn 166, Issue 10, 2017, Pages 725-732

  Salam, Alex P ^a   Rojek, Amanda ^a   Dunning, Jake ^a   Horby, Peter W ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIVIRUS AGENT; VIRUS ANTIBODY; ANTIBODY; AXL RECEPTOR TYROSINE KINASE; ONCOPROTEIN; PROTEIN TYROSINE KINASE; TERATOGENIC AGENT;

ANTIVIRAL THERAPY; ARTICLE; CENTRAL NERVOUS SYSTEM MALFORMATION; CONGENITAL INFECTION; DRUG TARGETING; HUMAN; INFECTION PREVENTION; NONHUMAN; PHASE 3 CLINICAL TRIAL (TOPIC); PLACENTA DISORDER; PREGNANCY; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); TERATOGENICITY; VIRUS IMMUNITY; VIRUS REPLICATION; ZIKA FEVER; CELLULAR IMMUNITY; CLINICAL TRIAL (TOPIC); COMPLICATION; DRUG EFFECTS; FEMALE; METABOLISM; MICROCEPHALY; PLACENTA; PREGNANCY COMPLICATIONS, INFECTIOUS; VIROLOGY; ZIKA VIRUS INFECTION;

ANTIBODIES; ANTIVIRAL AGENTS; CLINICAL TRIALS AS TOPIC; FEMALE; HUMANS; IMMUNITY, CELLULAR; MICROCEPHALY; PLACENTA; PREGNANCY; PREGNANCY COMPLICATIONS, INFECTIOUS; PROTO-ONCOGENE PROTEINS; RECEPTOR PROTEIN-TYROSINE KINASES; TERATOGENS; VIRUS REPLICATION; ZIKA VIRUS INFECTION;

EID: 85020895781     PISSN: 00034819     EISSN: 15393704     Source Type: Journal    
DOI: 10.7326/M16-2530     Document Type: Article

References (70)

1. Petersen LR, Jamieson DJ, Powers AM, Honein MA. Zika virus. N Engl J Med. 2016;374:1552-63. [PMID: 27028561] doi:10.1056/NEJMra1602113
2. World Health Organization. Situation report: Zika virus, microcephaly, and Guillain-Barrésyndrome. 29 December 2016. Accessed at http://apps.who.int/iris/bitstream/10665/252672/1/zikasitrep29Dec16-eng.pdf?ua=1 on 14 October 2016.
3. Rasmussen SA, Jamieson DJ, Honein MA, Petersen LR. Zika virus and birth defects-reviewing the evidence for causality. N Engl J Med. 2016;374:1981-7. [PMID: 27074377] doi:10.1056/NEJMsr 1604338
4. Costello A, Dua T, Duran P, Gülmezoglu M, Oladapo OT, Perea W, et al. Defining the syndrome associated with congenital Zika virus infection. Bull World Health Organ. 2016;94:406-406A. [PMID: 27274588] doi:10.2471/BLT.16.176990
5. World Health Organization. Zika strategic response framework & joint operations plan: January-June 2016. February 2016. Accessed at www.who.int/emergencies/zika-virus/strategic-response-framework.pdf on 14 October 2016.
6. Sheffield JS, Siegel D, Mirochnick M, Heine RP, Nguyen C, Bergman KL, et al. Designing drug trials: considerations for pregnant women. Clin Infect Dis. 2014;59 Suppl 7:S437-44. [PMID: 25425722] doi:10.1093/cid/ciu709
7. Brasil P, Pereira JP Jr, Moreira ME, Ribeiro Nogueira RM, Damasceno L, Wakimoto M, et al. Zika virus infection in pregnant women in Rio de Janeiro. N Engl J Med. 2016;375:2321-34. [PMID: 26943629]
8. Ekins S, Mietchen D, Coffee M, Stratton TP, Freundlich JS, Freitas-Junior L, et al. Open drug discovery for the Zika virus. F1000Res. 2016;5:150. [PMID: 27134728] doi:10.12688/f1000research.8013.1
9. Kouznetsova J, Sun W, Martínez-Romero C, Tawa G, Shinn P, Chen CZ, et al. Identification of 53 compounds that block Ebola virus-like particle entry via a repurposing screen of approved drugs. Emerg Microbes Infect. 2014;3:e84. [PMID: 26038505] doi:10.1038/emi.2014.88
10. Zmurko J, Marques RE, Schols D, Verbeken E, Kaptein SJF, Neyts J. The viral polymerase inhibitor 7-deaza-2'-Cmethyladenosine is a potent inhibitor of in vitro Zika virus replication and delays disease progression in a robust mouse infection model. PLoS Negl Trop Dis. 2016;10:e0004695. doi:10.1371/journal.pntd.0004695
11. Sacramento CQ, de Melo GR, Rocha N, Hoelz L. The clinically approved antiviral drug sofosbuvir impairs Brazilian Zika virus replication. bioRxivorg. 2016:061671.
12. Xu M, Lee EM, Wen Z, Cheng Y, Huang WK, Qian X, et al. Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen. Nat Med. 2016;22:1101-7. [PMID: 27571349] doi:10.1038/nm.4184
13. Barrows NJ, Campos RK, Powell ST, Prasanth KR, Schott-Lerner G, Soto-Acosta R, et al. A screen of FDA-approved drugs for inhibitors of Zika virus infection. Cell Host Microbe. 2016;20:259-70. [PMID: 27476412] doi:10.1016/j.chom.2016.07.004
14. Driggers RW, Ho CY, Korhonen EM, Kuivanen S, Jääskeläinen AJ, Smura T, et al. Zika virus infection with prolonged maternal viremia and fetal brain abnormalities. N Engl J Med. 2016;374:2142-51. [PMID: 27028667 doi:10.1056/NEJMoa1601824]
15. Adibi JJ, Marques ET Jr, Cartus A, Beigi RH. Teratogenic effects of the Zika virus and the role of the placenta. Lancet. 2016;387:1587-90. [PMID: 26952548] doi:10.1016/S0140-6736 (16) 00650-4
16. Bell TM, Field EJ, Narang HK. Zika virus infection of the central nervous system of mice. Arch Gesamte Virusforsch. 1971;35:183-93. [PMID: 5002906]
17. Hamel R, Dejarnac O, Wichit S, Ekchariyawat P, Neyret A, Luplertlop N, et al. Biology of Zika virus infection in human skin cells. J Virol. 2015;89:8880-96. [PMID: 26085147] doi:10.1128/JVI.00354-15
18. Nowakowski TJ, Pollen AA, Di Lullo E, Sandoval-Espinosa C, Bershteyn M, Kriegstein AR. Expression analysis highlights AXL as a candidate Zika virus entry receptor in neural stem cells. Cell Stem Cell. 2016;18:591-6. [PMID: 27038591] doi:10.1016/j.stem.2016.03.012
19. Tang H, Hammack C, Ogden SC, Wen Z, Qian X, Li Y, et al. Zika virus infects human cortical neural progenitors and attenuates their growth. Cell Stem Cell. 2016;18:587-90. [PMID: 26952870] doi:10.1016/j.stem.2016.02.016
20. Li C, Xu D, Ye Q, Hong S, Jiang Y, Liu X, et al. Zika virus disrupts neural progenitor development and leads to microcephaly in mice. Cell Stem Cell. 2016;19:120-6. [PMID: 27179424] doi:10.1016/j.stem.2016.04.017
21. Solozobova V, Wyvekens N, Pruszak J. Lessons from the embryonic neural stem cell niche for neural lineage differentiation of pluripotent stem cells. Stem Cell Rev. 2012;8:813-29. [PMID: 22628111] doi:10.1007/s12015-012-9381-8
22. Barkovich AJ, Guerrini R, Kuzniecky RI, Jackson GD, Dobyns WB. A developmental and genetic classification for malformations of cortical development: update 2012. Brain. 2012;135:1348-69. [PMID: 22427329] doi:10.1093/brain/aws019
23. Ji R, Tian S, Lu HJ, Lu Q, Zheng Y, Wang X, et al. TAM receptors affect adult brain neurogenesis by negative regulation of microglial cell activation. J Immunol. 2013;191:6165-77. [PMID: 24244024] doi: 10.4049/jimmunol.1302229
24. Pierce AM, Keating AK. TAM receptor tyrosine kinases: expression, disease and oncogenesis in the central nervous system. Brain Res. 2014;1542:206-20. [PMID: 24184575] doi:10.1016/j.brainres.2013.10.049
25. Knuesel I, Chicha L, Britschgi M, Schobel SA, Bodmer M, Hellings JA, et al. Maternal immune activation and abnormal brain development across CNS disorders. Nat Rev Neurol. 2014;10:643-60. [PMID: 25311587] doi:10.1038/nrneurol.2014.187
26. Boksa P. Effects of prenatal infection on brain development and behavior: a review of findings from animal models. Brain Behav Immun. 2010;24:881-97. [PMID: 20230889] doi:10.1016/j.bbi.2010.03.005
27. Holt PG, Jones CA. The development of the immune system during pregnancy and early life. Allergy. 2000;55:688-97. [PMID: 10955693]
28. Dang J, Tiwari SK, Lichinchi G, Qin Y, Patil VS, Eroshkin AM, et al. Zika virus depletes neural progenitors in human cerebral organoids through activation of the innate immune receptor TLR3. Cell Stem Cell. 2016;19:258-65. [PMID: 27162029] doi:10.1016/j.stem.2016.04.014
29. Carty M, Reinert L, Paludan SR, Bowie AG. Innate antiviral signalling in the central nervous system. Trends Immunol. 2014;35:79-87. [PMID: 24316012] doi:10.1016/j.it.2013.10.012
30. Okun E, Griffioen KJ, Mattson MP. Toll-like receptor signaling in neural plasticity and disease. Trends Neurosci. 2011;34:269-81. [PMID: 21419501] doi:10.1016/j.tins.2011.02.005
31. Miner JJ, Cao B, Govero J, Smith AM, Fernandez E, Cabrera OH, et al. Zika virus infection during pregnancy in mice causes placental damage and fetal demise. Cell. 2016;165:1081-91. [PMID: 271 80225] doi:10.1016/j.cell.2016.05.008
32. Delorme-Axford E, Bayer A, Sadovsky Y, Coyne CB. Autophagy as a mechanism of antiviral defense at the maternal-fetal interface. Autophagy. 2013;9:2173-4. [PMID: 24231730] doi:10.4161/auto.26558
33. Robbins JR, Bakardjiev AI. Pathogens and the placental fortress. Curr Opin Microbiol. 2012;15:36-43. [PMID: 22169833] doi:10.1016/j.mib.2011.11.006
34. Johansson MA, Mier-y-Teran-Romero L, Reefhuis J, Gilboa SM, Hills SL. Zika and the risk of microcephaly. N Engl J Med. 2016;375:1-4. [PMID: 27222919] doi:10.1056/NEJMp1605367
35. Gude NM, Roberts CT, Kalionis B, King RG. Growth and function of the normal human placenta. Thromb Res. 2004;114:397-407. [PMID: 15507270]
36. Ilekis JV, Tsilou E, Fisher S, Abrahams VM, Soares MJ, Cross JC, et al. Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Am J Obstet Gynecol. 2016;215:S1-S46. [PMID: 26972897] doi:10.1016/j.ajog.2016.03.001
37. Keller MA, Stiehm ER. Passive immunity in prevention and treatment of infectious diseases. Clin Microbiol Rev. 2000;13:602-14. [PMID: 11023960]
38. McLean HQ, Fiebelkorn AP, Temte JL, Wallace GS; Centers for Disease Control and Prevention. Prevention of measles, rubella, congenital rubella syndrome, and mumps, 2013: summary recommendations of the Advisory Committee on Immunization Practices (ACIP) [erratum in: MMWR Recomm Rep. 2015;64:259]. MMWR Recomm Rep. 2013;62:1-34. [PMID: 23760231]
39. Centers for Disease Control and Prevention (CDC). Updated recommendations for use of VariZIG-United States, 2013. MMWR Morb Mortal Wkly Rep. 2013;62:574-6. [PMID: 23863705]
40. Nigro G, Adler SP, La Torre R, Best AM; Congenital Cytomegalovirus Collaborating Group. Passive immunization during pregnancy for congenital cytomegalovirus infection. N Engl J Med. 2005;353:1350-62. [PMID: 16192480]
41. Nigro G, Adler SP, Parruti G, Anceschi MM, Coclite E, Pezone I, et al. Immunoglobulin therapy of fetal cytomegalovirus infection occurring in the first half of pregnancy-a case-control study of the outcome in children. J Infect Dis. 2012;205:215-27. [PMID: 22140265] doi:10.1093/infdis/jir718
42. Visentin S, Manara R, Milanese L, Da Roit A, Forner G, Salviato E, et al. Early primary cytomegalovirus infection in pregnancy: maternal hyperimmunoglobulin therapy improves outcomes among infants at 1 year of age. Clin Infect Dis. 2012;55:497-503. [PMID: 22539662] doi:10.1093/cid/cis423
43. Revello MG, Lazzarotto T, Guerra B, Spinillo A, Ferrazzi E, Kustermann A, et al; CHIP Study Group. A randomized trial of hyperimmune globulin to prevent congenital cytomegalovirus. N Engl J Med. 2014;370:1316-26. [PMID: 24693891] doi:10.1056/NEJMoa 1310214
44. A randomized trial to prevent congenital cytomegalovirus (CMV). ClinicalTrials.gov: NCT01376778. Accessed at https://clinicaltrials.gov/ct2/show/NCT01376778 on 14 October 2016.
45. Prevention of congenital CMV infection in infants of mothers with primary CMV infection during pregnancy. EudraCT Number: 2007-004692-19. Accessed at https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-004692-19/IT on 14 October 2016.
46. Stricker RB, Steinleitner A, Winger EE. Intravenous immunoglobulin (IVIG) therapy for immunologic abortion. Clin Appl Immunol Rev. 2002;2:187-99.
47. Dejnirattisai W, Supasa P, Wongwiwat W, Rouvinski A, Barba-Spaeth G, Duangchinda T, et al. Dengue virus sero-cross-reactivity drives antibody-dependent enhancement of infection with zika virus. Nat Immunol. 2016;17:1102-8.
48. Teixeira MG, Siqueira JB Jr, Ferreira GL, Bricks L, Joint G. Epidemiological trends of dengue disease in Brazil (2000-2010): a systematic literature search and analysis. PLoS Negl Trop Dis. 2013;7:e2520. [PMID: 24386496] doi:10.1371/journal.pntd.0002520
49. Costantine MM. Physiologic and pharmacokinetic changes in pregnancy. Front Pharmacol. 2014;5:65. [PMID: 24772083] doi:10.3389/fphar.2014.00065
50. Griffiths SK, Campbell JP. Placental structure, function and drug transfer. Continuing Education in Anaesthesia, Critical Care & Pain. 2015;15:84-9.
51. Ala-Kokko TI, Myllynen P, Vahakangas K. Ex vivo perfusion of the human placental cotyledon: implications for anesthetic pharmacology. Int J Obstet Anesth. 2000;9:26-38.
52. Hutson JR, Garcia-Bournissen F, Davis A, Koren G. The human placental perfusion model: a systematic review and development of a model to predict in vivo transfer of therapeutic drugs. Clin Pharmacol Ther. 2011;90:67-76. [PMID: 21562489] doi:10.1038/clpt.2011.66
53. Ben-Hur H, Gurevich P, Elhayany A, Avinoach I, Schneider DF, Zusman I. Transport of maternal immunoglobulins through the human placental barrier in normal pregnancy and during inflammation. Int J Mol Med. 2005;16:401-7. [PMID: 16077946]
54. Abbott NJ. Inflammatory mediators and modulation of bloodbrain barrier permeability. Cell Mol Neurobiol. 2000;20:131-47. [PMID: 10696506]
55. Clancy B, Finlay BL, Darlington RB, Anand KJ. Extrapolating brain development from experimental species to humans. Neurotoxicology. 2007;28:931-7. [PMID: 17368774]
56. Schachter AD, Kohane IS. Drug target-gene signatures that predict teratogenicity are enriched for developmentally related genes. Reprod Toxicol. 2011;31:562-9. [PMID: 21115113] doi:10.1016/j.reprotox.2010.11.008
57. Furtado JM, Espósito DL, Klein TM, Teixeira-Pinto T, da Fonseca BA. Uveitis associated with Zika virus infection [Letter]. N Engl J Med. 2016;375:394-6. [PMID: 27332784] doi:10.1056/NEJMc1603618
58. Simeone RM, Shapiro-Mendoza CK, Meaney-Delman D, Petersen EE, Galang RR, Oduyebo T, et al; Zika and Pregnancy Working Group. Possible Zika virus infection among pregnant women-United States and Territories, May 2016. MMWR Morb Mortal Wkly Rep. 2016;65:514-9. [PMID: 27248295] doi:10.15585/mmwr.mm 6520e1
59. Centers for Disease Control and Prevention. Revised diagnostic testing for Zika, chikungunya, and dengue viruses in US Public Health Laboratories. 7 February 2016. Accessed at www.cdc.gov/zika/pdfs/denvchikvzikv-testing-algorithm.pdf on 14 October 2016.
60. Casadevall A, Pirofski LA. Antibody-mediated regulation of cellular immunity and the inflammatory response. Trends Immunol. 2003;24:474-8. [PMID: 12967670]
61. Gilmore EC, Walsh CA. Genetic causes of microcephaly and lessons for neuronal development. Wiley Interdiscip Rev Dev Biol. 2013;2:461-78. [PMID: 24014418] doi:10.1002/wdev. 89
62. Mankarious S, Lee M, Fischer S, Pyun KH, Ochs HD, Oxelius VA, et al. The half-lives of IgG subclasses and specific antibodies in patients with primary immunodeficiency who are receiving intravenously administered immunoglobulin. J Lab Clin Med. 1988;112:634-40. [PMID: 3183495]
63. Robinson DP, Klein SL. Pregnancy and pregnancy-associated hormones alter immune responses and disease pathogenesis. Horm Behav. 2012;62:263-71. [PMID: 22406114] doi:10.1016/j.yhbeh.2012.02.023
64. World Health Organization. Screening, assessment and management of neonates and infants with complications associated with Zika virus exposure in utero: interim guidance. 2016. Accessed at http://apps.who.int/iris/bitstream/10665/204475/1/WHO-ZIKV-MOC-16.3-eng.pdf?ua=1 on 14 October 2016.
65. Leviton A, Holmes LB, Allred EN, Vargas J. Methodologic issues in epidemiologic studies of congenital microcephaly. Early Hum Dev. 2002;69:91-105. [PMID: 12324187]
66. Sells CJ. Microcephaly in a normal school population. Pediatrics. 1977;59:262-5. [PMID: 834509]
67. Custer DA, Vezina LG, Vaught DR, Brasseux C, Samango-Sprouse CA, Cohen MS, et al. Neurodevelopmental and neuroimaging correlates in nonsyndromal microcephalic children. J Dev Behav Pediatr. 2000;21:12-8. [PMID: 10706344]
68. de Fatima Vasco Aragao M, van der Linden V, Brainer-Lima AM, Coeli RR, Rocha MA, Sobral da Silva P, et al. Clinical features and neuroimaging (CT and MRI) findings in presumed Zika virus related congenital infection and microcephaly: retrospective case series study. BMJ. 2016;353:i1901. [PMID: 27075009] doi:10.1136/bmj.i1901
69. Rasmussen SA, Hernandez-Diaz S, Abdul-Rahman OA, Sahin L, Petrie CR, Keppler-Noreuil KM, et al. Assessment of congenital anomalies in infants born to pregnant women enrolled in clinical trials. Clin Infect Dis. 2014;59 Suppl 7:S428-36. [PMID: 25425721] doi:10.1093/cid/ciu738
70. Lazzarotto T, Varani S, Guerra B, Nicolosi A, Lanari M, Landini MP. Prenatal indicators of congenital cytomegalovirus infection. J Pediatr. 2000;137:90-5. [PMID: 10891828]