1887

Abstract

Dengue is a disease that poses a significant global public health concern. Although a tetravalent live-attenuated dengue vaccine has been licensed, its efficacy is still debated due to evidence of vaccine breakthrough infection. To avoid this issue, dengue vaccines should stimulate a high degree of serotype-specific response. Thus, envelope domain III (EDIII), which contains serotype-specific neutralizing epitopes, is an attractive target for dengue vaccine development. In this study, we investigated how EDIII encapsidated in N, N, N-trimethyl chitosan chloride nanoparticles (TMC NPs) stimulates a serotype-specific response and whether this response exerts a potential breakthrough infection. The immune response to DENV-2 elicited by EDIII TMC NP-immunized mice was monitored. We demonstrated that immunization with EDIII TMC NPs resulted in a high level of anti-EDIII antibody production. These antibodies included IgG, IgG1, and IgG2a subtypes. Importantly, antibodies from the immunized mice exerted efficient neutralizing activity with undetectable antibody dependent enhancement (ADE) activity. We also found that EDIII TMC NPs activated functional EDIII-specific CD4 and CD8 T cell responses. In conclusion, EDIII TMC NPs stimulated humoral immunity with a strong neutralizing antibody response, as well as a cellular immune response against DENV-2.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.001768
2022-07-14
2024-12-13
Loading full text...

Full text loading...

References

  1. Brady OJ, Gething PW, Bhatt S, Messina JP, Brownstein JS et al. Refining the global spatial limits of dengue virus transmission by evidence-based consensus. PLoS Negl Trop Dis 2012; 6:e1760 [View Article] [PubMed]
    [Google Scholar]
  2. Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW et al. The global distribution and burden of dengue. Nature 2013; 496:504–507 [View Article] [PubMed]
    [Google Scholar]
  3. Shepard DS, Undurraga EA, Halasa YA, Stanaway JD. The global economic burden of dengue: a systematic analysis. Lancet Infect Dis 2016; 16:935–941 [View Article] [PubMed]
    [Google Scholar]
  4. WHO Guidelines Approved by the Guidelines Review Committee Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control, New Edition. Geneva: World Health Organization World Health Organization; 2009
    [Google Scholar]
  5. Halstead SB. Neutralization and antibody-dependent enhancement of dengue viruses. Adv Virus Res 2003; 60:421–467 [View Article] [PubMed]
    [Google Scholar]
  6. Modhiran N, Kalayanarooj S, Ubol S. Subversion of innate defenses by the interplay between DENV and pre-existing enhancing antibodies: TLRs signaling collapse. PLoS Negl Trop Dis 2010; 4:12 [View Article]
    [Google Scholar]
  7. Ubol S, Phuklia W, Kalayanarooj S, Modhiran N. Mechanisms of immune evasion induced by a complex of dengue virus and preexisting enhancing antibodies. J Infect Dis 2010; 201:923–935 [View Article]
    [Google Scholar]
  8. Capeding MR, Tran NH, Hadinegoro SRS, Ismail HIHJM, Chotpitayasunondh T et al. Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial. Lancet 2014; 384:1358–1365 [View Article]
    [Google Scholar]
  9. Villar L, Dayan GH, Arredondo-García JL, Rivera DM, Cunha R et al. Efficacy of a tetravalent dengue vaccine in children in Latin America. N Engl J Med 2015; 372:113–123 [View Article]
    [Google Scholar]
  10. Hadinegoro SR, Arredondo-García JL, Capeding MR, Deseda C, Chotpitayasunondh T et al. Efficacy and long-term safety of a dengue vaccine in regions of endemic disease. N Engl J Med 2015; 373:1195–1206 [View Article]
    [Google Scholar]
  11. Biswal S, Reynales H, Saez-Llorens X, Lopez P, Borja-Tabora C et al. Efficacy of a tetravalent dengue vaccine in healthy children and adolescents. N Engl J Med 2019; 381:2009–2019 [View Article] [PubMed]
    [Google Scholar]
  12. Shukla R, Ramasamy V, Shanmugam RK, Ahuja R, Khanna N. Antibody-dependent enhancement: a challenge for developing a safe dengue vaccine. Front Cell Infect Microbiol 2020; 10:597 [View Article] [PubMed]
    [Google Scholar]
  13. Torresi J, Richmond PC, Heron LG, Qiao M, Marjason J et al. Replication and excretion of the live attenuated tetravalent dengue vaccine CYD-TDV in a flavivirus-naive adult population: assessment of vaccine viremia and virus shedding. J Infect Dis 2017; 216:834–841 [View Article] [PubMed]
    [Google Scholar]
  14. Flasche S, Wilder-Smith A, Hombach J, Smith PG. Estimating the proportion of vaccine-induced hospitalized dengue cases among Dengvaxia vaccinees in the Philippines. Wellcome Open Res 2019; 4:165 [View Article] [PubMed]
    [Google Scholar]
  15. Rabaa MA, Girerd-Chambaz Y, Duong Thi Hue K, Vu Tuan T, Wills B et al. Genetic epidemiology of dengue viruses in phase III trials of the CYD tetravalent dengue vaccine and implications for efficacy. Elife 2017; 6:e24196 [View Article] [PubMed]
    [Google Scholar]
  16. Juraska M, Magaret CA, Shao J, Carpp LN, Fiore-Gartland AJ et al. Viral genetic diversity and protective efficacy of a tetravalent dengue vaccine in two phase 3 trials. Proc Natl Acad Sci U S A 2018; 115:E8378–E8387 [View Article] [PubMed]
    [Google Scholar]
  17. Gallichotte EN, Baric TJ, Nivarthi U, Delacruz MJ, Graham R et al. Genetic variation between dengue virus type 4 strains impacts human antibody binding and neutralization. Cell Rep 2018; 25:1214–1224 [View Article] [PubMed]
    [Google Scholar]
  18. Martinez DR, Yount B, Nivarthi U, Munt JE, Delacruz MJ et al. Antigenic variation of the dengue virus 2 genotypes impacts the neutralization activity of human antibodies in vaccinees. Cell Rep 2020; 33:108226 [View Article] [PubMed]
    [Google Scholar]
  19. Zhang X, Jia R, Shen H, Wang M, Yin Z et al. Structures and functions of the envelope glycoprotein in flavivirus infections. Viruses 2017; 9:E338 [View Article] [PubMed]
    [Google Scholar]
  20. Sukupolvi-Petty S, Austin SK, Purtha WE, Oliphant T, Nybakken GE et al. Type- and subcomplex-specific neutralizing antibodies against domain III of dengue virus type 2 envelope protein recognize adjacent epitopes. J Virol 2007; 81:12816–12826 [View Article] [PubMed]
    [Google Scholar]
  21. Gromowski GD, Barrett ADT. 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; 366:349–360 [View Article] [PubMed]
    [Google Scholar]
  22. Crill WD, Hughes HR, Delorey MJ, Chang G-JJ. Humoral immune responses of dengue fever patients using epitope-specific serotype-2 virus-like particle antigens. PLoS One 2009; 4:e4991 [View Article] [PubMed]
    [Google Scholar]
  23. Lin T-H, Chen H-W, Hsiao Y-J, Yan J-Y, Chiang C-Y et al. Immunodomination of serotype-specific CD4+ T-cell epitopes contributed to the biased immune responses induced by a tetravalent measles-vectored dengue vaccine. Front Immunol 2020; 11:546 [View Article] [PubMed]
    [Google Scholar]
  24. Mota J, Acosta M, Argotte R, Figueroa R, Méndez A et al. Induction of protective antibodies against dengue virus by tetravalent DNA immunization of mice with domain III of the envelope protein. Vaccine 2005; 23:3469–3476 [View Article] [PubMed]
    [Google Scholar]
  25. Zaneti AB, Yamamoto MM, Sulczewski FB, Almeida B da S, Souza HFS et al. Dendritic cell targeting using a DNA vaccine induces specific antibodies and CD4+ T cells to the dengue virus envelope protein domain III. Front Immunol 2019; 10:59 [View Article] [PubMed]
    [Google Scholar]
  26. Tian Y, Grifoni A, Sette A, Weiskopf D. Human T cell response to dengue virus infection. Front Immunol 2019; 10:2125 [View Article] [PubMed]
    [Google Scholar]
  27. Weiskopf D, Angelo MA, de Azeredo EL, Sidney J, Greenbaum JA et al. Comprehensive analysis of dengue virus-specific responses supports an HLA-linked protective role for CD8+ T cells. Proc Natl Acad Sci U S A 2013; 110:E2046–53 [View Article] [PubMed]
    [Google Scholar]
  28. Weiskopf D, Bangs DJ, Sidney J, Kolla RV, De Silva AD et al. Dengue virus infection elicits highly polarized CX3CR1+ cytotoxic CD4+ T cells associated with protective immunity. Proc Natl Acad Sci U S A 2015; 112:E4256–63 [View Article] [PubMed]
    [Google Scholar]
  29. Yauch LE, Prestwood TR, May MM, Morar MM, Zellweger RM et al. CD4+ T cells are not required for the induction of dengue virus-specific CD8+ T cell or antibody responses but contribute to protection after vaccination. J Immunol 2010; 185:5405–5416 [View Article]
    [Google Scholar]
  30. Yauch LE, Zellweger RM, Kotturi MF, Qutubuddin A, Sidney J et al. A protective role for dengue virus-specific CD8+ T cells. J Immunol 2009; 182:4865–4873 [View Article] [PubMed]
    [Google Scholar]
  31. Nantachit N, Sunintaboon P, Ubol S. EDIII-DENV3 nanospheres drive immature dendritic cells into a mature phenotype in an in vitro model. Microbiol Immunol 2017; 61:305–317 [View Article] [PubMed]
    [Google Scholar]
  32. Jearanaiwitayakul T, Sunintaboon P, Chawengkittikul R, Limthongkul J, Midoeng P et al. Nanodelivery system enhances the immunogenicity of dengue-2 nonstructural protein 1, DENV-2 NS1. Vaccine 2020; 38:6814–6825 [View Article] [PubMed]
    [Google Scholar]
  33. Jearanaiwitayakul T, Sunintaboon P, Chawengkittikul R, Limthongkul J, Midoeng P et al. Whole inactivated dengue virus-loaded trimethyl chitosan nanoparticle-based vaccine: immunogenic properties in ex vivo and in vivo models. Hum Vaccin Immunother 2021; 17:2793–2807 [View Article] [PubMed]
    [Google Scholar]
  34. Jearanaiwitayakul T, Seesen M, Chawengkirttikul R, Limthongkul J, Apichirapokey S et al. Intranasal Administration of RBD Nanoparticles Confers Induction of Mucosal and Systemic Immunity against SARS-CoV-2. Vaccines (Basel) 2021; 9:768 [View Article] [PubMed]
    [Google Scholar]
  35. Jearanaiwitayakul T, Apichirapokey S, Chawengkirttikul R, Limthongkul J, Seesen M et al. Peritoneal administration of a subunit vaccine encapsulated in a nanodelivery system not only augments systemic responses against SARS-CoV-2 but also stimulates responses in the respiratory tract. Viruses 2021; 13:2202 [View Article] [PubMed]
    [Google Scholar]
  36. Dabaghian M, Latifi AM, Tebianian M, NajmiNejad H, Ebrahimi SM. Nasal vaccination with r4M2e.HSP70c antigen encapsulated into N-trimethyl chitosan (TMC) nanoparticulate systems: Preparation and immunogenicity in a mouse model. Vaccine 2018; 36:2886–2895 [View Article]
    [Google Scholar]
  37. Frey A, Di Canzio J, Zurakowski D. A statistically defined endpoint titer determination method for immunoassays. J Immunol Methods 1998; 221:35–41 [View Article]
    [Google Scholar]
  38. Stevens TL, Bossie A, Sanders VM, Fernandez-Botran R, Coffman RL et al. Regulation of antibody isotype secretion by subsets of antigen-specific helper T cells. Nature 1988; 334:255–258 [View Article]
    [Google Scholar]
  39. Tang C-T, Liao M-Y, Chiu C-Y, Shen W-F, Chiu C-Y et al. Generation of monoclonal antibodies against dengue virus type 4 and identification of enhancing epitopes on envelope protein. PLoS One 2015; 10:e0136328 [View Article]
    [Google Scholar]
  40. Rungrojcharoenkit K, Sunintaboon P, Ellison D, Macareo L, Midoeng P et al. Development of an adjuvanted nanoparticle vaccine against influenza virus, an in vitro study. PLoS One 2020; 15:e0237218 [View Article]
    [Google Scholar]
  41. Zhang P, Liu W, Peng Y, Han B, Yang Y. Toll like receptor 4 (TLR4) mediates the stimulating activities of chitosan oligosaccharide on macrophages. Int Immunopharmacol 2014; 23:254–261 [View Article]
    [Google Scholar]
  42. Carroll EC, Jin L, Mori A, Muñoz-Wolf N, Oleszycka E et al. The vaccine adjuvant chitosan promotes cellular immunity via DNA sensor cGAS-STING-dependent induction of type I interferons. Immunity 2016; 44:597–608 [View Article]
    [Google Scholar]
/content/journal/jgv/10.1099/jgv.0.001768
Loading
/content/journal/jgv/10.1099/jgv.0.001768
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error