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Zika virus vaccines

Nature Reviews Microbiology (2018) | Download Citation


The recent epidemic of Zika virus (ZIKV) in the Americas has revealed the devastating consequences of ZIKV infection, particularly in pregnant women. Congenital Zika syndrome, characterized by malformations and microcephaly in neonates as well as developmental challenges in children, highlights the need for the development of a safe and effective vaccine. Multiple vaccine candidates have been developed and have shown promising results in both animal models and phase I clinical trials. However, important challenges remain for the clinical development of these vaccines. In this Progress article, we discuss recent preclinical studies and lessons learned from first-in-human clinical trials with ZIKV vaccines.

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Nature Reviews Microbiology thanks J. Miner, P.-Y. Shi and the other anonymous reviewer(s) for their contribution to the peer review of this work.


  1. 1.

    Dick, G. W., Kitchen, S. F. & Haddow, A. J. Zika virus. I. Isolations and serological specificity. Trans. R. Soc. Trop. Med. Hyg. 46, 509–520 (1952).

  2. 2.

    Petersen, L. R., Baden, L. R., Jamieson, D. J., Powers, A. M. & Honein, M. A. Zika virus. N. Engl. J. Med. 374, 1552–1563 (2016).

  3. 3.

    Duffy, M. R. et al. Zika virus outbreak on Yap Island, Federated States of Micronesia. N. Engl. J. Med. 360, 2536–2543 (2009).

  4. 4.

    Oehler, E. et al. Zika virus infection complicated by Guillain-Barré syndrome — case report, French Polynesia, December 2013. Euro Surveill. 19, 20720 (2014).

  5. 5.

    Kindhauser, M. K., Allen, T., Frank, V., Santhana, R. S. & Dye, C. Zika: the origin and spread of a mosquito-borne virus. Bull. World Health Organ. 94, 675–686C (2016).

  6. 6.

    Tognarelli, J. et al. A report on the outbreak of Zika virus on Easter Island, South Pacific, 2014. Arch. Virol. 161, 665–668 (2016).

  7. 7.

    Carteaux, G. et al. Zika virus associated with meningoencephalitis. N. Engl. J. Med. 374, 1595–1596 (2016).

  8. 8.

    de Araújo, T. V. B. et al. Association between microcephaly, Zika virus infection, and other risk factors in Brazil: final report of a case-control study. Lancet Infect. Dis. 18, 328–336 (2018).

  9. 9.

    de Oliveira, C. S. & da Costa Vasconcelos, P. F. Microcephaly and Zika virus. J. Pediatr. (Rio J.) 92, 103–105 (2016).

  10. 10.

    Martines, R. B. et al. Notes from the field: evidence of Zika virus infection in brain and placental tissues from two congenitally infected newborns and two fetal losses — Brazil, 2015. MMWR Morb. Mortal. Wkly Rep. 65, 159–160 (2016).

  11. 11.

    de Oliveira, W. K. et al. Infection-related microcephaly after the 2015 and 2016 Zika virus outbreaks in Brazil: a surveillance-based analysis. Lancet 390, 861–870 (2017).

  12. 12.

    Valladeau, J. et al. The monoclonal antibody DCGM4 recognizes Langerin, a protein specific of Langerhans cells, and is rapidly internalized from the cell surface. Eur. J. Immunol. 29, 2695–2704 (1999).

  13. 13.

    Sirohi, D. & Kuhn, R. J. Zika virus structure, maturation, and receptors. J. Infect. Dis. 216, S935–S944 (2017).

  14. 14.

    Faye, O. et al. Molecular evolution of Zika virus during its emergence in the 20(th) century. PLoS Negl. Trop. Dis. 8, e2636 (2014).

  15. 15.

    Cunha, M. S. et al. First complete genome sequence of Zika Virus (flaviviridae, flavivirus) from an autochthonous transmission in Brazil. Genome Announc. 4, e00032-16 (2016).

  16. 16.

    Aid, M. et al. Zika virus persistence in the central nervous system and lymph nodes of rhesus monkeys. Cell 169, 610–620.e14 (2017).

  17. 17.

    Kostyuchenko, V. A. et al. Structure of the thermally stable Zika virus. Nature 533, 425–428 (2016).

  18. 18.

    Song, H., Qi, J., Haywood, J., Shi, Y. & Gao, G. F. Zika virus NS1 structure reveals diversity of electrostatic surfaces among flaviviruses. Nat. Struct. Mol. Biol. 23, 456–458 (2016).

  19. 19.

    Sirohi, D. et al. The 3.8 A resolution cryo-EM structure of Zika virus. Science 352, 467–470 (2016).

  20. 20.

    Osuna, C. E. et al. Zika viral dynamics and shedding in rhesus and cynomolgus macaques. Nat. Med. 22, 1448–1455 (2016).

  21. 21.

    Chen, J. et al. AXL promotes Zika virus infection in astrocytes by antagonizing type I interferon signalling. Nat. Microbiol. 3, 302–309 (2018).

  22. 22.

    Cugola, F. R. et al. The Brazilian Zika virus strain causes birth defects in experimental models. Nature 534, 267–271 (2016).

  23. 23.

    Tang, H. et al. Zika virus infects human cortical neural progenitors and attenuates their growth. Cell Stem Cell 18, 587–590 (2016).

  24. 24.

    Lin, M.-Y. et al. Zika virus infects intermediate progenitor cells and post-mitotic committed neurons in human fetal brain tissues. Sci. Rep. 7, 14883 (2017).

  25. 25.

    Nowakowski, T. J. et al. Expression analysis highlights AXL as a candidate Zika virus entry receptor in neural stem cells. Cell Stem Cell 18, 591–596 (2016).

  26. 26.

    Retallack, H. et al. Zika virus cell tropism in the developing human brain and inhibition by azithromycin. Proc. Natl Acad. Sci. USA 113, 14408–14413 (2016).

  27. 27.

    Meertens, L. et al. Axl mediates ZIKA virus entry in human glial cells and modulates innate immune responses. Cell Rep. 18, 324–333 (2017).

  28. 28.

    Hastings, A. K. et al. TAM receptors are not required for Zika virus infection in mice. Cell Rep. 19, 558–568 (2017).

  29. 29.

    Putnak, R. et al. Development of a purified, inactivated, dengue-2 virus vaccine prototype in vero cells: immunogenicity and protection in mice and rhesus monkeys. J. Infect. Dis. 174, 1176–1184 (1996).

  30. 30.

    Monath, T. P. et al. Chimeric live, attenuated vaccine against Japanese encephalitis (ChimeriVax-JE): phase 2 clinical trials for safety and immunogenicity, effect of vaccine dose and schedule, and memory response to challenge with inactivated Japanese encephalitis antigen. J. Infect. Dis. 188, 1213–1230 (2003).

  31. 31.

    Davis, B. S. et al. West Nile virus recombinant DNA vaccine protects mouse and horse from virus challenge and expresses in vitro a noninfectious recombinant antigen that can be used in enzyme-linked immunosorbent assays. J. Virol. 75, 4040–4047 (2001).

  32. 32.

    Brasil, P. et al. Zika virus infection in pregnant women in Rio de Janeiro. N. Engl. J. Med. 375, 2321–2334 (2016).

  33. 33.

    Guillemette-Artur, P., Besnard, M., Eyrolle-Guignot, D., Jouannic, J. M. & Garel, C. Prenatal brain MRI of fetuses with Zika virus infection. Pediatr. Radiol. 46, 1032–1039 (2016).

  34. 34.

    Mlakar, J. et al. Zika virus associated with microcephaly. N. Engl. J. Med. 374, 951–958 (2016).

  35. 35.

    Martinot, A. J. et al. Fetal neuropathology in Zika virus-infected pregnant female rhesus monkeys. Cell 173, 1111–1122.e10 (2018).

  36. 36.

    Satterfield-Nash, A. et al. Health and development at age 19–24 months of 19 children who were born with microcephaly and laboratory evidence of congenital Zika virus infection during the 2015 Zika virus outbreak — Brazil, 2017. MMWR Morb. Mortal. Wkly Rep. 66, 1347–1351 (2017).

  37. 37.

    Durkin, M. Systematic review of neuromotor impairments in infancy following congenital Zika virus infection. Dev. Med. Child Neurol. 59, 13–13 (2017).

  38. 38.

    Ventura, C. V., Maia, M., Bravo-Filho, V., Gois, A. L. & Belfort, R. Jr. Zika virus in Brazil and macular atrophy in a child with microcephaly. Lancet 387, 228 (2016).

  39. 39.

    Schuler-Faccini, L. et al. Possible association between Zika virus infection and microcephaly — Brazil, 2015. MMWR Morb. Mortal. Wkly Rep. 65, 59–62 (2016).

  40. 40.

    Plotkin, S. A. Rubella eradication. Vaccine 19, 3311–3319 (2001).

  41. 41.

    van Wouwe, J. P. et al. Women’s reproductive health knowledge, attitudes and practices in relation to the Zika virus outbreak in northeast Brazil. PLoS ONE 13, e0190024 (2018).

  42. 42.

    Saiz, J.-C. & Martín-Acebes, M. A. The race to find antivirals for Zika virus. Antimicrob. Agents Chemother. 61, e00411-17 (2017).

  43. 43.

    Shiryaev, S. A. et al. Repurposing of the anti-malaria drug chloroquine for Zika Virus treatment and prophylaxis. Sci. Rep. 7, 15771 (2017).

  44. 44.

    Barrett, A. D. T. Zika vaccine candidates progress through nonclinical development and enter clinical trials. NPJ Vaccines 1, 16023 (2016).

  45. 45.

    Ferraro, B. et al. Clinical applications of DNA vaccines: current progress. Clin. Infect. Dis. 53, 296–302 (2011).

  46. 46.

    Tebas, P. et al. Safety and immunogenicity of an anti–Zika virus DNA vaccine — preliminary report. N. Engl. J. Med. (2017).

  47. 47.

    Aliota, M. T. et al. Characterization of lethal Zika virus infection in AG129 mice. PLoS Negl. Trop. Dis. 10, e0004682 (2016).

  48. 48.

    Gaudinski, M. R. et al. Safety, tolerability, and immunogenicity of two Zika virus DNA vaccine candidates in healthy adults: randomised, open-label, phase 1 clinical trials. Lancet 391, 552–562 (2018).

  49. 49.

    Yousafzai, M. T. et al. Feasibility of conducting intradermal vaccination campaign with inactivated poliovirus vaccine using Tropis intradermal needle free injection system, Karachi, Pakistan. Heliyon 3, e00395 (2017).

  50. 50.

    Modjarrad, K. et al. Preliminary aggregate safety and immunogenicity results from three trials of a purified inactivated Zika virus vaccine candidate: phase 1, randomised, double-blind, placebo-controlled clinical trials. Lancet 391, 563–571 (2018).

  51. 51.

    Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018).

  52. 52.

    Reichmuth, A. M., Oberli, M. A., Jaklenec, A., Langer, R. & Blankschtein, D. mRNA vaccine delivery using lipid nanoparticles. Ther. Deliv. 7, 319–334 (2016).

  53. 53.

    Richner, J. M. et al. Modified mRNA vaccines protect against Zika virus infection. Cell 168, 1114–1125.e10 (2017).

  54. 54.

    Pardi, N. et al. Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination. Nature 543, 248–251 (2017).

  55. 55.

    Richner, J. M. et al. Vaccine mediated protection against Zika virus-induced congenital disease. Cell 170, 273–283.e12 (2017).

  56. 56.

    Ura, T., Okuda, K. & Shimada, M. Developments in viral vector-based vaccines. Vaccines 2, 624–641 (2014).

  57. 57.

    Lauer, K. B., Borrow, R., Blanchard, T. J. & Papasian, C. J. Multivalent and multipathogen viral vector vaccines. Clin. Vaccine Immunol. 24, e00298-16 (2017).

  58. 58.

    Combredet, C. et al. A molecularly cloned schwarz strain of measles virus vaccine induces strong immune responses in macaques and transgenic mice. J. Virol. 77, 11546–11554 (2003).

  59. 59.

    ZIKAVAX. ZIKAVAX. (2018).

  60. 60.

    Barouch, D. H. et al. Characterization of humoral and cellular immune responses elicited by a recombinant adenovirus serotype 26 HIV-1 env vaccine in healthy adults (IPCAVD 001). J. Infect. Dis. 207, 248–256 (2013).

  61. 61.

    Baden, L. R. et al. Assessment of the safety and immunogenicity of 2 novel vaccine platforms for HIV-1 prevention. Ann. Intern. Med. 164, 313 (2016).

  62. 62.

    Milligan, I. D. et al. Safety and immunogenicity of novel adenovirus type 26– and modified vaccinia Ankara–vectored Ebola vaccines. JAMA 315, 1610 (2016).

  63. 63.

    Winslow, R. L. et al. Immune responses to novel adenovirus type 26 and modified vaccinia virus Ankara–vectored Ebola vaccines at 1 year. JAMA 317, 1075 (2017).

  64. 64.

    Ledgerwood, J. E. et al. Chimpanzee adenovirus vector Ebola vaccine — preliminary report. N. Engl. J. Med. 373, 776 (2015).

  65. 65.

    Abbink, P. et al. Rapid cloning of novel rhesus adenoviral vaccine vectors. J. Virol. 92, e01924-17 (2018).

  66. 66.

    Larocca, R. A. et al. Vaccine protection against Zika virus from Brazil. Nature 536, 474–478 (2016).

  67. 67.

    Abbink, P. et al. Protective efficacy of multiple vaccine platforms against Zika virus challenge in rhesus monkeys. Science 353, 1129–1132 (2016).

  68. 68.

    Abbink, P. et al. Durability and correlates of vaccine protection against Zika virus in rhesus monkeys. Sci. Transl Med. 9, eaao4163 (2017).

  69. 69.

    Dowd, K. A. et al. Rapid development of a DNA vaccine for Zika virus. Science 354, 237–240 (2016).

  70. 70.

    Xu, K. et al. Recombinant chimpanzee adenovirus vaccine AdC7-M/E protects against Zika virus infection and testis damage. J. Virol. 92, e01722-17 (2018).

  71. 71.

    Larocca, R. A. et al. Adenovirus serotype 5 vaccine vectors trigger IL-27-dependent inhibitory CD4 + T cell responses that impair CD8 + T cell function. Sci. Immunol. 1, eaaf7643 (2016).

  72. 72.

    Brault, A. C. et al. A Zika vaccine targeting NS1 protein protects immunocompetent adult mice in a lethal challenge model. Sci. Rep. 7, 14769 (2017).

  73. 73.

    Shan, C. et al. A live-attenuated Zika virus vaccine candidate induces sterilizing immunity in mouse models. Nat. Med. 23, 763–767 (2017).

  74. 74.

    Kwek, S. S. et al. A systematic approach to the development of a safe live attenuated Zika vaccine. Nat. Commun. 9, 1031 (2018).

  75. 75.

    Li, X.-F. et al. Development of a chimeric Zika vaccine using a licensed live-attenuated flavivirus vaccine as backbone. Nat. Commun. 9, 673 (2018).

  76. 76.

    Austin, S. K. & Dowd, K. A. B cell response and mechanisms of antibody protection to West Nile virus. Viruses 6, 1015–1036 (2014).

  77. 77.

    Xu, M. et al. A potent neutralizing antibody with therapeutic potential against all four serotypes of dengue virus. NPJ Vaccines 2, 2 (2017).

  78. 78.

    Larena, M., Prow, N. A., Hall, R. A., Petrovsky, N. & Lobigs, M. JE-ADVAX vaccine protection against Japanese encephalitis virus mediated by memory B cells in the absence of CD8+ T cells and pre-exposure neutralizing antibody. J. Virol. 87, 4395–4402 (2013).

  79. 79.

    Wen, J. et al. Identification of Zika virus epitopes reveals immunodominant and protective roles for dengue virus cross-reactive CD8+ T cells. Nat. Microbiol. 2, 17036 (2017).

  80. 80.

    Elong Ngono, A. et al. Mapping and role of the CD8 + T cell response during primary Zika virus infection in mice. Cell Host Microbe 21, 35–46 (2017).

  81. 81.

    Driggers, R. W. et al. Zika virus infection with prolonged maternal viremia and fetal brain abnormalities. N. Engl. J. Med. 374, 2142–2151 (2016).

  82. 82.

    El Costa, H. et al. ZIKA virus reveals broad tissue and cell tropism during the first trimester of pregnancy. Sci. Rep. 6, 35296 (2016).

  83. 83.

    Osuna, C. E. & Whitney, J. B. Nonhuman primate models of Zika virus infection, immunity, and therapeutic development. J. Infect. Dis. 216, S928–S934 (2017).

  84. 84.

    Bhatnagar, J. et al. Zika virus RNA replication and persistence in brain and placental tissue. Emerg. Infect. Dis. 23, 405–414 (2017).

  85. 85.

    Miner, J. J. et al. Zika virus infection during pregnancy in mice causes placental damage and fetal demise. Cell 165, 1081–1091 (2016).

  86. 86.

    Nguyen, S. M. et al. Highly efficient maternal-fetal Zika virus transmission in pregnant rhesus macaques. PLoS Pathog. 13, e1006378 (2017).

  87. 87.

    Li, C. et al. Zika virus disrupts neural progenitor development and leads to microcephaly in mice. Cell Stem Cell 19, 120–126 (2016).

  88. 88.

    Vermillion, M. S. et al. Intrauterine Zika virus infection of pregnant immunocompetent mice models transplacental transmission and adverse perinatal outcomes. Nat. Commun. 8, 14575 (2017).

  89. 89.

    Mysorekar, I. U., Phimister, E. G. & Diamond, M. S. Modeling Zika virus infection in pregnancy. N. Engl. J. Med. 375, 481–484 (2016).

  90. 90.

    Shan, C. et al. A single-dose live-attenuated vaccine prevents Zika virus pregnancy transmission and testis damage. Nat. Commun. 8, 676 (2017).

  91. 91.

    van der Linden, V. et al. Description of 13 infants born during October 2015–January 2016 with congenital Zika virus infection without microcephaly at birth — Brazil. MMWR Morb. Mortal. Wkly Rep. 65, 1343–1348 (2016).

  92. 92.

    Malassine, A., Frendo, J. L. & Evain-Brion, D. A comparison of placental development and endocrine functions between the human and mouse model. Hum. Reprod. Update 9, 531–539 (2003).

  93. 93.

    Grigsby, P. Animal models to study placental development and function throughout normal and dysfunctional human pregnancy. Semin. Reprod. Med. 34, 011–016 (2016).

  94. 94.

    Adams Waldorf, K. M. et al. Fetal brain lesions after subcutaneous inoculation of Zika virus in a pregnant nonhuman primate. Nat. Med. 22, 1256–1259 (2016).

  95. 95.

    Lissauer, D., Smit, E. & Kilby, M. D. Zika virus and pregnancy. BJOG 123, 1258–1263 (2016).

  96. 96.

    Rather, I. A., Lone, J. B., Bajpai, V. K. & Park, Y.-H. Zika virus infection during pregnancy and congenital abnormalities. Front. Microbiol. 8, 581 (2017).

  97. 97.

    Ulmer, J. B., Deck, R. R., Dewitt, C. M., Donnhly, J. I. & Liu, M. A. Generation of MHC class I-restricted cytotoxic T lymphocytes by expression of a viral protein in muscle cells: antigen presentation by non-muscle cells. Immunology 89, 59–67 (1996).

  98. 98.

    van Ballegooijen, M., Bogaards, J. A., Weverling, G. J., Boerlijst, M. C. & Goudsmit, J. AIDS vaccines that allow HIV-1 to infect and escape immunologic control: a mathematic analysis of mass vaccination. J. Acquir. Immune Defic. Syndr. 34, 214–220 (2003).

  99. 99.

    Feasey, N. A. & Levine, M. M. Typhoid vaccine development with a human challenge model. Lancet 390, 2419–2421 (2017).

  100. 100.

    Memoli, M. J. et al. Validation of the wild-type influenza A human challenge model H1N1pdMIST: an A(H1N1)pdm09 dose-finding investigational new drug study. Clin. Infect. Dis. 60, 693–702 (2015).

  101. 101.

    Shah, S. K. et al. Ethical considerations for Zika virus human challenge trials. NIH (2017).

  102. 102.

    US Food and Drug Administration. Product development under the animal rule. Guidance for industry. FDA (2015).

  103. 103.

    Beasley, D. W. C., Brasel, T. L. & Comer, J. E. First vaccine approval under the FDA Animal Rule. NPJ Vaccines 1, 16013 (2016).

  104. 104.

    Hokey, D. A. TB vaccines: the (human) challenge ahead. Mycobact. Dis. 4, e128 (2014).

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Author notes

  1. These authors contributed equally: Peter Abbink, Kathryn E. Stephenson, Dan H. Barouch.


  1. Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    • Peter Abbink
    • , Kathryn E. Stephenson
    •  & Dan H. Barouch
  2. Ragon Institute of MGH, MIT and Harvard, Boston, MA, USA

    • Kathryn E. Stephenson
    •  & Dan H. Barouch


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P.A., K.E.S. and D.H.B. researched data for the article, made substantial contributions to discussions of the content, wrote the article and reviewed and edited the manuscript before submission.

Competing interests statement

P.A. and D.H.B. are co-inventors on ZIKV vaccine patents that have been licensed to Janssen Vaccines & Prevention B.V.

Corresponding author

Correspondence to Dan H. Barouch.

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