The Recombinant NS3 Protein a Potential Antigen for Dengue Vaccine Development

Rosa Ramirez Bartutis*

Rosa Ramirez Bartutis*

Volume5-Issue4
Dates: Received: 2023-12-15 | Accepted: 2024-04-05 | Published: 2024-04-05
Pages: 290-295

Abstract

The NS3 protein is a multifunctional non-structural protein involved in dengue virus polyprotein processing. This protein is also target in the immune response against dengue virus infection. The predominance of cytotoxic T-cell lymphocytes epitopes in the NS3 structure suggests the participation of this protein in limiting virus replication and in the protection against dengue disease. A brief presentation on aspects related to antigenic characteristics and immunogenicity of the recombinant NS3 protein is reported in this work. A reduced number of studies have assessed the NS3 protein in a dengue vaccine formulation. Researches carried out in mice shown that DNA vaccines based on NS3 protein induced a protective response evaluated by their ability to produce IFNγ. Moreover, the incorporation of recombinant subunit NS3 in a purified inactivated vaccine significantly increased the immune response induced by this inactivated vaccine. Likewise, recent studies demonstrated that the combination of the recombinant modified-NS1 and NS3 proteins from dengue 2 virus induced higher immune responses and protection in mice. The immunological studies discussed herein support the possible inclusion of the NS3 protein in a dengue vaccine formulation.

FullText HTML FullText PDF DOI: 10.37871/jbres1894

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How to cite this article

Bartutis RR. The Recombinant NS3 Protein a Potential Antigen for Dengue Vaccine Development. J Biomed Res Environ Sci. 2024 Apr 06; 5(4): 290-295. doi: 10.37871/jbres1894, Article ID: JBRES1894, Available at: https://www.jelsciences.com/ articles/jbres1894.pdf

Subject area(s)

Vaccines

Biology

References

Katzelnick LC, Montoya M, Gresh L, Balmaseda A, E H. Neutralizing antibody titers against dengue virus correlate with protection from symptomatic infection in a longitudinal cohort. . Proceedings of the National Academy of Sciences of the United States of America. 2016 113(3):728-33. doi: 10.1073/pnas.1522136113. PubMed PMID: 26729879; PubMed Central PMCID: PMC4725482
Bos S, Graber AL, Cardona-Ospina JA, Duarte EM, Zambrana JV, Ruíz Salinas JA, et al. The association of neutralizing antibodies with protection against symptomatic dengue virus infection varies by serotype, prior infection history, and assay condition. medRxiv [Preprint]. 2023:2023.06.20.23291522. doi: 10.1101/2023.06.20.23291522. . PubMed PMID: 37502957; PubMed Central PMCID: PMC10371115.
Nivarthi UK, Swanstrom J, Delacruz MJ, Patel B, Durbin AP, Whitehead SS, Kirkpatrick BD, Pierce KK, Diehl SA, Katzelnick L, Baric RS, de Silva AM. A tetravalent live attenuated dengue virus vaccine stimulates balanced immunity to multiple serotypes in humans. Nat Commun. 2021 Feb 17;12(1):1102. doi: 10.1038/s41467-021-21384-0. PMID: 33597521; PMCID: PMC7889627.
Kirkpatrick BD, Durbin AP, Pierce KK, Carmolli MP, Tibery CM, Grier PL, et al. Robust and Balanced Immune Responses to All 4 Dengue Virus Serotypes Following Administration of a Single Dose of a Live Attenuated Tetravalent Dengue Vaccine to Healthy, Flavivirus-Naive Adults. The Journal of infectious diseases. 2015;212(5):702-10. Epub 03/22. doi: 10.1093/infdis/jiv082. PubMed PMID: 25801652; PubMed Central PMCID: PMC4612392.
Capeding MR, Tran NH, Hadinegoro SR, Ismail HI, Chotpitayasunondh T, Chua MN, 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(9951):1358-65. Epub 2014/07/16. doi: 10.1016/s0140-6736(14)61060-6. PubMed PMID: 25018116.
Villar L, Dayan GH, Arredondo-García JL, Rivera DM, Cunha R, Deseda C, et al. Efficacy of a tetravalent dengue vaccine in children in Latin America. The New England journal of medicine. 2015;372(2):113-23. Epub 2014/11/05. doi: 10.1056/NEJMoa1411037. PubMed PMID: 25365753.
Yang Y, Meng Y, Halloran ME, Longini IM, Jr. Dependency of Vaccine Efficacy on Preexposure and Age: A Closer Look at a Tetravalent Dengue Vaccine. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2018;66(2):178-84. Epub 2017/10/12. doi: 10.1093/cid/cix766. PubMed PMID: 29020332; PubMed Central PMCID: PMCPMC5850009.
Guy B, Jackson N. Dengue vaccine: hypotheses to understand CYD-TDV-induced protection. Nat Rev Microbiol. 2016 Jan;14(1):45-54. doi: 10.1038/nrmicro.2015.2. Epub 2015 Dec 7. PMID: 26639777.
Thomas SJ, Yoon I-K. A review of Dengvaxia®: development to deployment. Human vaccines & immunotherapeutics. 2019;15(10):2295-314. Epub 10/07. doi: 10.1080/21645515.2019.1658503. PubMed PMID: 31589551.
Wichmann O, Vannice K, Asturias EJ, de Albuquerque Luna EJ, Longini I, Lopez AL, et al. Live-attenuated tetravalent dengue vaccines: The needs and challenges of post-licensure evaluation of vaccine safety and effectiveness. Vaccine. 2017;35(42):5535-42. Epub 2017/09/13. doi: 10.1016/j.vaccine.2017.08.066. PubMed PMID: 28893477.
Arredondo-García JL, Hadinegoro SR, Reynales H, Chua MN, Rivera Medina DM, Chotpitayasunondh T, Tran NH, Deseda CC, Wirawan DN, Cortés Supelano M, Frago C, Langevin E, Coronel D, Laot T, Perroud AP, Sanchez L, Bonaparte M, Limkittikul K, Chansinghakul D, Gailhardou S, Noriega F, Wartel TA, Bouckenooghe A, Zambrano B; CYD-TDV Dengue Vaccine Study Group. Four-year safety follow-up of the tetravalent dengue vaccine efficacy randomized controlled trials in Asia and Latin America. Clin Microbiol Infect. 2018 Jul;24(7):755-763. doi: 10.1016/j.cmi.2018.01.018. Epub 2018 Feb 8. PMID: 29408333.
Yauch LE, Prestwood TR, May MM, Morar MM, Zellweger RM, Peters B, 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. Journal of immunology. 2010;185(9):5405-16. doi: 10.4049/jimmunol.1001709. PubMed PMID: 20870934; PubMed Central PMCID: PMC2962919.
Zellweger RM, Tang WW, Eddy WE, King K, Sanchez MC, Shresta S. CD8+ T Cells Can Mediate Short-Term Protection against Heterotypic Dengue Virus Reinfection in Mice. J Virol. 2015 Jun;89(12):6494-505. doi: 10.1128/JVI.00036-15. Epub 2015 Apr 8. PMID: 25855749; PMCID: PMC4474296.
Lam JH, Chua YL, Lee PX, Martínez Gómez JM, Ooi EE, Alonso S. Dengue vaccine-induced CD8+ T cell immunity confers protection in the context of enhancing, interfering maternal antibodies. JCI Insight. 2017 Dec 21;2(24):e94500. doi: 10.1172/jci.insight.94500. PMID: 29263304; PMCID: PMC5752305.
Weiskopf D, Bangs DJ, Sidney J, Kolla RV, De Silva AD, de Silva AM, Crotty S, Peters B, Sette A. Dengue virus infection elicits highly polarized CX3CR1+ cytotoxic CD4+ T cells associated with protective immunity. Proc Natl Acad Sci U S A. 2015 Aug 4;112(31):E4256-63. doi: 10.1073/pnas.1505956112. Epub 2015 Jul 20. PMID: 26195744; PMCID: PMC4534238.
Yauch LE, Zellweger RM, Kotturi MF, Qutubuddin A, Sidney J, Peters B, et al. A protective role for dengue virus-specific CD8+ T cells. Journal of immunology. 2009;182(8):4865-73. doi: 10.4049/jimmunol.0801974. PubMed PMID: 19342665; PubMed Central PMCID: PMC2674070.
Chiang CY, Huang MH, Pan CH, Hsieh CH, Chen MY, Liu HH, et al. Induction of robust immunity by the emulsification of recombinant lipidated dengue-1 envelope protein domain III. Microbes and infection / Institut Pasteur. 2013;15(10-11):719-28. doi: 10.1016/j.micinf.2013.06.002. PubMed PMID: 23774693.
Chiang CY, Huang MH, Hsieh CH, Chen MY, Liu HH, Tsai JP, et al. Dengue-1 envelope protein domain III along with PELC and CpG oligodeoxynucleotides synergistically enhances immune responses. PLoS neglected tropical diseases. 2012;6(5):e1645. doi: 10.1371/journal.pntd.0001645. PubMed PMID: 22616020; PubMed Central PMCID: PMC3352863.
Janssen EM, Lemmens EE, Wolfe T, Christen U, von Herrath MG, Schoenberger SP. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature. 2003;421(6925):852-6. Epub 2003/02/21. doi: 10.1038/nature01441. PubMed PMID: 12594515.
Jellison ER, Kim SK, Welsh RM. Cutting edge: MHC class II-restricted killing in vivo during viral infection. Journal of immunology. 2005;174(2):614-8. Epub 2005/01/07. doi: 10.4049/jimmunol.174.2.614. PubMed PMID: 15634878.
Moris P, Bauer KM, Currier JR, Friberg H, Eckels KH, Esquilin IO, et al. Cell-mediated immune responses to different formulations of a live-attenuated tetravalent dengue vaccine candidate in subjects living in dengue endemic and non-endemic regions. Human vaccines & immunotherapeutics. 2019;15(9):2090-105. Epub 2019/03/05. doi: 10.1080/21645515.2019.1581536. PubMed PMID: 30829100; PubMed Central PMCID: PMCPMC6773406.
Livingston PG, Kurane I, Dai LC, Okamoto Y, Lai CJ, Men R, et al. Dengue virus-specific, HLA-B35-restricted, human CD8+ cytotoxic T lymphocyte (CTL) clones. Recognition of NS3 amino acids 500 to 508 by CTL clones of two different serotype specificities. Journal of immunology. 1995;154(3):1287-95. PubMed PMID: 7529799.
Spaulding AC, Kurane I, Ennis FA, Rothman AL. Analysis of murine CD8(+) T-cell clones specific for the Dengue virus NS3 protein: flavivirus cross-reactivity and influence of infecting serotype. Journal of virology. 1999;73(1):398-403. PubMed PMID: 9847344; PubMed Central PMCID: PMC103845.
Duangchinda T, Dejnirattisai W, Vasanawathana S, Limpitikul W, Tangthawornchaikul N, Malasit P, et al. Immunodominant T-cell responses to dengue virus NS3 are associated with DHF. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(39):16922-7. doi: 10.1073/pnas.1010867107. PubMed PMID: 20837518; PubMed Central PMCID: PMC2947904.
Rivino L, Kumaran EA, Jovanovic V, Nadua K, Teo EW, Pang SW, et al. Differential targeting of viral components by CD4+ versus CD8+ T lymphocytes in dengue virus infection. Journal of virology. 2013;87(5):2693-706. doi: 10.1128/JVI.02675-12. PubMed PMID: 23255803; PubMed Central PMCID: PMC3571409.
Simmons CP, Dong T, Chau NV, Dung NT, Chau TN, Thao le TT, et al. Early T-cell responses to dengue virus epitopes in Vietnamese adults with secondary dengue virus infections. Journal of virology. 2005;79(9):5665-75. doi: 10.1128/JVI.79.9.5665-5675.2005. PubMed PMID: 15827181; PubMed Central PMCID: PMC1082776.
Mladinich KM, Piaskowski SM, Rudersdorf R, Eernisse CM, Weisgrau KL, Martins MA, et al. Dengue virus-specific CD4+ and CD8+ T lymphocytes target NS1, NS3 and NS5 in infected Indian rhesus macaques. Immunogenetics. 2012;64(2):111-21. doi: 10.1007/s00251-011-0566-0. PubMed PMID: 21881953.
Masaki H, Fujii Y, Wakasa-Morimoto C, Toyosaki-Maeda T, Irimajiri K, Tomura TT, et al. Induction of specific and flavivirus--Cross-reactive CTLs by immunization with a single dengue virus-derived CTL epitope peptide. Virus research. 2009;144(1-2):188-94. doi: 10.1016/j.virusres.2009.04.024. PubMed PMID: 19427342.
Rothman AL. Immunity to dengue virus: a tale of original antigenic sin and tropical cytokine storms. Nature reviews Immunology. 2011;11(8):532-43. doi: 10.1038/nri3014. PubMed PMID: 21760609.
Chua JJ, Ng MM, Chow VT. The non-structural 3 (NS3) protein of dengue virus type 2 interacts with human nuclear receptor binding protein and is associated with alterations in membrane structure. Virus research. 2004;102(2):151-63. doi: 10.1016/j.virusres.2004.01.025. PubMed PMID: 15084397.
Nunes PC, Viana-Paes M, Basilio-de Oliveira CA, Gomes-Soares AC, Bispo-de Filippis AM, da Rocha Queiroz -Lima M, \Maria de BAA, Fernandes ASJ, Chicarino de JMOC, Chagas deFCR, Rita Maria RN, Barreto dos SF. Detection of dengue NS1 and NS3 proteins in placenta and umbilical cord in fetal and maternal death. Journal of medical virology. 2016. doi: 10.1002/jmv.24479.
Ramírez R, Falcón R, Izquierdo A, García A, Alvarez M, Pérez AB, Soto Y, Muné M, da Silva EM, Ortega O, Mohana-Borges R, Guzmán MG. Recombinant dengue 2 virus NS3 protein conserves structural antigenic and immunological properties relevant for dengue vaccine design. Virus Genes. 2014 Oct;49(2):185-95. doi: 10.1007/s11262-014-1087-3. Epub 2014 May 23. PMID: 24854144.
Tan CH, Yap EH, Singh M, Deubel V, Chan YC. Passive protection studies in mice with monoclonal antibodies directed against the non-structural protein NS3 of dengue 1 virus. The Journal of general virology. 1990;71 ( Pt 3):745-9. PubMed PMID: 2138211.
Garcia G, Vaughn DW, Del Angel RM. Recognition of synthetic oligopeptides from nonstructural proteins NS1 and NS3 of dengue-4 virus by sera from dengue virus-infected children. The American journal of tropical medicine and hygiene. 1997;56(4):466-70. PubMed PMID: 9158059.
Churdboonchart V, Bhamarapravati N, Peampramprecha S, Sirinavin S. Antibodies against dengue viral proteins in primary and secondary dengue hemorrhagic fever. The American journal of tropical medicine and hygiene. 1991;44(5):481-93. PubMed PMID: 2063952.
Valdes K, Alvarez M, Pupo M, Vazquez S, Rodriguez R, Guzman MG. Human Dengue antibodies against structural and nonstructural proteins. Clinical and diagnostic laboratory immunology. 2000;7(5):856-7. PubMed PMID: 10973471; PubMed Central PMCID: PMC95972.
Chen Z, Tian Y, Liu L, An J. Production of a monoclonal antibody against non-structural protein 3 of dengue-2 virus by intrasplenic injection. Hybridoma. 2008;27(6):467-71. doi: 10.1089/hyb.2008.0048. PubMed PMID: 19108619.
Alvarez-Rodriguez LM, Ramos-Ligonio A, Rosales-Encina JL, Martinez-Cazares MT, Parissi-Crivelli A, Lopez-Monteon A. Expression, purification, and evaluation of diagnostic potential and immunogenicity of a recombinant NS3 protein from all serotypes of dengue virus. Journal of tropical medicine. 2012;2012:956875. doi: 10.1155/2012/956875. PubMed PMID: 23258983; PubMed Central PMCID: PMC3518973.
Costa SM, Yorio AP, Goncalves AJ, Vidale MM, Costa EC, Mohana-Borges R, et al. Induction of a protective response in mice by the dengue virus NS3 protein using DNA vaccines. PloS one. 2011;6(10):e25685. doi: 10.1371/journal.pone.0025685. PubMed PMID: 22031819; PubMed Central PMCID: PMC3198735.
Hurtado-Melgoza ML, Ramos-Ligonio A, Álvarez-Rodríguez LM, Meza-Menchaca T, López-Monteon A. Differential humoral and cellular immunity induced by vaccination using plasmid DNA and protein recombinant expressing the NS3 protein of dengue virus type 3. J Biomed Sci. 2016 Dec 1;23(1):85. doi: 10.1186/s12929-016-0302-z. PMID: 27903271; PMCID: PMC5131448.
Simmons M, Sun P, Putnak R. Recombinant Dengue 2 Virus NS3 Helicase Protein Enhances Antibody and T-Cell Response of Purified Inactivated Vaccine. PLoS One. 2016 Apr 1;11(4):e0152811. doi: 10.1371/journal.pone.0152811. PMID: 27035715; PMCID: PMC4818016.