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Abstract

Purpose. Hantavirus infections cause severe haemorrhagic fever with renal syndrome (HFRS) in humans and are associated with high fatality rates. In 2017, numerous outbreaks were reported in China and Germany. This represents a significant public-healthcare issue with no effective HFRS vaccines that offer a long-term immune response. In this study, we investigated the long-term humoral and cellular immune responses and protective immunity of Hantaan virus (HTNV) granulocyte-macrophage colony stimulating factor (GM-CSF) and CD40 ligand (CD40L) virus-like particles (VLPs) in mice.

Methodology. GM-CSF and CD40L VLPs were constructed via co-transfection of pCI-S and pCI-M-CD40L, and pCI-S and pCI-M-GM-CSF, into dihydrofolatereductase (dhfr)-deficient Chinese hamster ovary cells, respectively. Mice were immunized with HTNV VLPs 2 weeks apart. The animals were challenged 6 months after immunization. Specific and neutralizing antibodies were assessed by ELISA; IFN-γ was measured by enzyme-linked immunospot (ELISpot) assay and effectiveness by cytotoxic T lymphocyte (CTL) cytotoxicity assays. Nucleic acid loads of HTNV were tested by quantitative real-time PCR and viral antigen was detected via indirect ELISA. Pathological alterations were detected via haematoxylin–eosin staining.

Results. GM-CSF and CD40L VLPs provided stable, long-term protection with a high titre of neutralizing antibody in mice 6 months after immunization. Furthermore, VLPs increased HTNV-specific cellular immune responses via higher expression of IFN-γ and CTL responses. HTNV challenge assay results showed long-term protection against HFRS. No significant pathological alteration was observed in the organs of mice after immunization.

Conclusion. This is, to the best of our knowledge, the first report demonstrating the long-term potency of HTNV VLP vaccines against HTNV infection and offers new insights into HTNV vaccine development.

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/content/journal/jmm/10.1099/jmm.0.000897
2019-01-18
2019-12-09
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References

  1. Nava A, Shimabukuro JS, Chmura AA, Luz SLB. The impact of global environmental changes on infectious disease emergence with a focus on risks for Brazil. Ilar J 2017;58:393–400
    [Google Scholar]
  2. Cunze S, Kochmann J, Kuhn T, Frank R, Dörge DD et al. Spatial and temporal patterns of human Puumala virus (PUUV) infections in Germany. PeerJ 2018;6:e4255
    [Google Scholar]
  3. Chang B, Crowley M, Campen M, Koster F. Hantavirus cardiopulmonary syndrome. Semin Respir Crit Care Med 2007;28:193–200 [CrossRef][PubMed]
    [Google Scholar]
  4. Jiang H, Du H, Wang LM, Wang PZ, Bai XF et al. Hemorrhagic fever with renal syndrome: pathogenesis and clinical picture. Front Cell Infect Microbiol 2016;6:1
    [Google Scholar]
  5. Jonsson CB, Figueiredo LT, Vapalahti O. A global perspective on hantavirus ecology, epidemiology, and disease. Clin Microbiol Rev 2010;23:412–441
    [Google Scholar]
  6. Zhang YZ, Zou Y, Fu ZF, Plyusnin A. Hantavirus infections in humans and animals, China. Emerg Infect Dis 2010;16:1195–1203
    [Google Scholar]
  7. Schmaljohn CS. Vaccines for hantaviruses: progress and issues. Expert Rev Vaccines 2012;11:511–513
    [Google Scholar]
  8. Lu Q, Zhu Z, Weng J. Immune responses to inactivated vaccine in people naturally infected with hantaviruses. J Med Virol 1996;49:333–335
    [Google Scholar]
  9. Macartney KK, Chiu C, Georgousakis M, Brotherton JM. Safety of human papillomavirus vaccines: a review. Drug Saf 2013;36:393–412
    [Google Scholar]
  10. Mohsen MO, Zha L, Cabral-Miranda G, Bachmann MF. Major findings and recent advances in virus-like particle (VLP)-based vaccines. Semin Immunol 2017;34:123–132
    [Google Scholar]
  11. Alon D, Stein GY, Hadas-Golan V, Tau L, Brosh T et al. Immunogenicity of Sci-B-Vac (a third-generation hepatitis B vaccine) in HIV-positive adults. Isr Med Assoc J 2017;19:143–146
    [Google Scholar]
  12. Calazans A, Boggiano C, Lindsay R. A DNA inducing VLP vaccine designed for HIV and tested in mice. PLoS One 2017;12:e0183803
    [Google Scholar]
  13. Changotra H, Vij A. Rotavirus virus-like particles (RV-VLPs) vaccines: an update. Rev Med Virol 2017;27:e1954
    [Google Scholar]
  14. Ying Q, Ma T, Cheng L, Zhang X, Truax AD et al. Construction and immunological characterization of CD40L or GM-CSF incorporated hantaan virus like particle. Oncotarget 2016;7:63488–63503
    [Google Scholar]
  15. Skountzou I, Quan FS, Gangadhara S, Ye L, Vzorov A et al. Incorporation of glycosylphosphatidylinositol-anchored granulocyte-macrophage colony-stimulating factor or CD40 ligand enhances immunogenicity of chimeric simian immunodeficiency virus-like particles. J Virol 2007;81:1083–1094
    [Google Scholar]
  16. Zhang R, Zhang S, Li M, Chen C, Yao Q et al. Incorporation of CD40 ligand into SHIV virus-like particles (VLP) enhances SHIV-VLP-induced dendritic cell activation and boosts immune responses against HIV. Vaccine 2010;28:5114–5127
    [Google Scholar]
  17. Chiodoni C, Paglia P, Stoppacciaro A, Rodolfo M, Parenza M et al. Dendritic cells infiltrating tumors cotransduced with granulocyte/macrophage colony-stimulating factor (GM-CSF) and CD40 ligand genes take up and present endogenous tumor-associated antigens, and prime naive mice for a cytotoxic T lymphocyte response. J Exp Med 1999;190:125–134
    [Google Scholar]
  18. Cheng LF, Wang F, Zhang L, Yu L, Ye W et al. Incorporation of GM-CSF or CD40L enhances the immunogenicity of hantaan virus-like particles. Front Cell Infect Microbiol 2016;6:185
    [Google Scholar]
  19. Laboratory biosafety manual. World Health Organization. Ann Ist Super Sanita 1995;31:1–121
    [Google Scholar]
  20. Xu Z, Wei L, Wang L, Wang H, Jiang S et al. The in vitro and in vivo protective activity of monoclonal antibodies directed against hantaan virus: potential application for immunotherapy and passive immunization. Biochem Biophys Res Commun 2002;298:552–558
    [Google Scholar]
  21. Ma RX, Cheng LF, Ying QK, Liu RR, Ma TJ et al. Screening and identification of an H-2Kb-restricted CTL epitope within the glycoprotein of hantaan virus. Front Cell Infect Microbiol 2016;6:151
    [Google Scholar]
  22. Jiang DB, Sun LJ, Cheng LF, Zhang JP, Xiao SB et al. Recombinant DNA vaccine of hantavirus Gn and LAMP1 induced long-term immune protection in mice. Antiviral Res 2017;138:32–39
    [Google Scholar]
  23. Li G, Pan L, Mou D, Chen Y, Zhang Y et al. Characterization of truncated hantavirus nucleocapsid proteins and their application for serotyping. J Med Virol 2006;78:926–932
    [Google Scholar]
  24. Yi J, Xu Z, Zhuang R, Wang J, Zhang Y et al. Hantaan virus RNA load in patients having hemorrhagic fever with renal syndrome: correlation with disease severity. J Infect Dis 2013;207:1457–1461
    [Google Scholar]
  25. Jennings GT, Bachmann MF. The coming of age of virus-like particle vaccines. Biol Chem 2008;389:521–536
    [Google Scholar]
  26. Fiedler JD, Higginson C, Hovlid ML, Kislukhin AA, Castillejos A et al. Engineered mutations change the structure and stability of a virus-like particle. Biomacromolecules 2012;13:2339–2348
    [Google Scholar]
  27. Mohsen MO, Gomes AC, Cabral-Miranda G, Krueger CC, Leoratti FM et al. Delivering adjuvants and antigens in separate nanoparticles eliminates the need of physical linkage for effective vaccination. J Control Release 2017;251:92–100
    [Google Scholar]
  28. Cai X, Zheng W, Pan S, Zhang S, Xie Y et al. A virus-like particle of the hepatitis B virus preS antigen elicits robust neutralizing antibodies and T cell responses in mice. Antiviral Res 2018;149:48–57
    [Google Scholar]
  29. Kang SM, Yoo DG, Lipatov AS, Song JM, Davis CT et al. Induction of long-term protective immune responses by influenza H5N1 virus-like particles. PLoS One 2009;4:e4667
    [Google Scholar]
  30. Harper DM, Demars LR. HPV vaccines - a review of the first decade. Gynecol Oncol 2017;146:196–204
    [Google Scholar]
  31. Landry N, Pillet S, Favre D, Poulin JF, Trépanier S et al. Influenza virus-like particle vaccines made in Nicotiana benthamiana elicit durable, poly-functional and cross-reactive T cell responses to influenza HA antigens. Clin Immunol 2014;154:164–177
    [Google Scholar]
  32. Schmidt MR, McGinnes LW, Kenward SA, Willems KN, Woodland RT et al. Long-term and memory immune responses in mice against Newcastle disease virus-like particles containing respiratory syncytial virus glycoprotein ectodomains. J Virol 2012;86:11654–11662
    [Google Scholar]
  33. Song JY, Woo HJ, Cheong HJ, Noh JY, Baek LJ et al. Long-term immunogenicity and safety of inactivated hantaan virus vaccine (Hantavax™) in healthy adults. Vaccine 2016;34:1289–1295
    [Google Scholar]
  34. Borhani K, Ajorloo M, Bamdad T, Mozhgani SH, Ghaderi M et al. A comparative approach between heterologous prime-boost vaccination strategy and DNA vaccinations for rabies. Arch Iran Med 2015;18:223–227
    [Google Scholar]
  35. Mitchell RE, Hassan M, Burton BR, Britton G, Hill EV et al. IL-4 enhances IL-10 production in Th1 cells: implications for Th1 and Th2 regulation. Sci Rep 2017;7:11315
    [Google Scholar]
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