{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T17:10:11Z","timestamp":1793293811533,"version":"4.5.0"},"reference-count":208,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,5,16]],"date-time":"2025-05-16T00:00:00Z","timestamp":1747353600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Dengue virus (DENV) threatens public health, especially in regions with tropical and subtropical climates. In 2024, the World Health Organisation reported 3.4 million confirmed dengue cases, with 16,000 severe cases and 3000 dengue-associated fatalities. The first licensed dengue vaccine, CYD-TDV (Dengvaxia\u00ae,Sanofi-Pasteur, Paris, France), is recommended by the WHO only for individuals aged 9\u201345 years with a prior history of dengue infection. However, being vaccinated with Dengvaxia\u00ae increases the risk of developing severe dengue infections in seronegative individuals. Recently, a second licensed dengue vaccine, Qdenga\u00ae,Takeda, Singen, Germany), was approved and recommended by the WHO to be administered only in highly dengue-endemic countries, as it was not shown to elicit a robust immune response against DENV-3 and DENV-4 serotypes in dengue seronegative individuals. Due to an imbalance in immune response against all four DENV serotypes, there is a higher risk of developing the antibody-dependent enhancement (ADE) effect, which could lead to severe dengue. This review has identified mutations throughout the DENV genome that were demonstrated to attenuate the virulence of DENV in either in vitro or in vivo studies. Several amino acid residues within the DENV prM and E proteins were identified to play important roles in ADE and modifying these ADE-linked residues is important in the rational design of novel live-attenuated dengue vaccine candidates. This review provides current insights to guide the development of a novel live-attenuated tetravalent dengue vaccine candidate that is effective against all DENV serotypes and safe from ADE. The efficacy and safety of the live-attenuated vaccine candidate should be further validated in in vivo studies.<\/jats:p>","DOI":"10.3390\/vaccines13050532","type":"journal-article","created":{"date-parts":[[2025,5,16]],"date-time":"2025-05-16T06:57:28Z","timestamp":1747378648000},"page":"532","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Development of New Live-Attenuated Vaccine Candidates Lacking Antibody-Dependent Enhancement (ADE) Against Dengue"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4586-6081","authenticated-orcid":false,"given":"Brandon E. K.","family":"Tan","sequence":"first","affiliation":[{"name":"ALPS Global Holding Berhad, The Icon, East Wing Tower Level 18-01 & Level 18-02, No. 1 Jalan 1\/68F, Off Jalan Tun Razak, Kuala Lumpur 50400, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seng Kong","family":"Tham","sequence":"additional","affiliation":[{"name":"ALPS Global Holding Berhad, The Icon, East Wing Tower Level 18-01 & Level 18-02, No. 1 Jalan 1\/68F, Off Jalan Tun Razak, Kuala Lumpur 50400, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chit Laa","family":"Poh","sequence":"additional","affiliation":[{"name":"ALPS Global Holding Berhad, The Icon, East Wing Tower Level 18-01 & Level 18-02, No. 1 Jalan 1\/68F, Off Jalan Tun Razak, Kuala Lumpur 50400, Malaysia"},{"name":"Nilai University, No.1, Persiaran Universiti, Putra Nilai, Bandar Baru Nilai, Nilai 71800, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,16]]},"reference":[{"key":"ref_1","unstructured":"WHO (2020). Dengue and Severe Dengue Facts Sheets."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Anwar, A., Khan, N., Ayub, M., Nawaz, F., Shah, A., and Flahault, A. (2019). Modeling and predicting dengue incidence in highly vulnerable countries using panel data approach. Int. J. Environ. Res. Public Health, 16.","DOI":"10.3390\/ijerph16132296"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/nature12060","article-title":"The global distribution and burden of dengue","volume":"496","author":"Bhatt","year":"2013","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Tian, N., Zheng, J.-X., Guo, Z.-Y., Li, L.-H., Xia, S., Lv, S., and Zhou, X.-N. (2022). Dengue incidence trends and its burden in major endemic regions from 1990 to 2019. Trop. Med. Infect. Dis., 7.","DOI":"10.3390\/tropicalmed7080180"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1042\/ETLS20180123","article-title":"Climate change and the rising infectiousness of dengue","volume":"3","author":"Tozan","year":"2019","journal-title":"Emerg. Top. Life Sci."},{"key":"ref_6","unstructured":"WHO (2009). Dengue Guidelines for Diagnosis, Treatment, Prevention and Control, World Health Organisation and the Special Programme for Research and Training in Tropical Diseases (TDR)."},{"key":"ref_7","unstructured":"WHO (2024). Disease Outbreaks News. Dengue-Global situation, World Health Organisation."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1186\/s13071-018-2643-9","article-title":"Natural vertical transmission of dengue virus in Aedes aegypti and Aedes albopictus: A systematic review","volume":"11","year":"2018","journal-title":"Parasit. Vectors"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2649","DOI":"10.3390\/v2122649","article-title":"The complexity of antibody-dependent enhancement of dengue virus infection","volume":"2","author":"Guzman","year":"2010","journal-title":"Viruses"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"143","DOI":"10.4269\/ajtmh.1987.36.143","article-title":"Effect of temperature on the vector efficiency of Aedes aegypti for dengue 2 virus","volume":"36","author":"Watts","year":"1987","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1038\/nrmicro2595","article-title":"Fever from the forest: Prospects for the continued emergence of sylvatic dengue virus and its impact on public health","volume":"9","author":"Vasilakis","year":"2011","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1056\/NEJMra1110265","article-title":"Dengue","volume":"366","author":"Simmons","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1146\/annurev-virology-101416-041848","article-title":"The good, the bad, and the shocking: The multiple roles of dengue virus nonstructural protein 1 in protection and pathogenesis","volume":"5","author":"Glasner","year":"2018","journal-title":"Annu. Rev. Virol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1038\/nrmicro1690","article-title":"Prospects for a dengue virus vaccine","volume":"5","author":"Whitehead","year":"2007","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3139","DOI":"10.4049\/jimmunol.147.9.3139","article-title":"Antibody-dependent enhancement of dengue virus infection mediated by bispecific antibodies against cell surface molecules other than Fc gamma receptors","volume":"147","author":"Mady","year":"1991","journal-title":"J. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/S0065-3527(03)60011-4","article-title":"Neutralization and antibody-dependent enhancement of dengue viruses","volume":"60","author":"Halstead","year":"2003","journal-title":"Adv. Virus Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/1742-4690-8-16","article-title":"Extensive complement-dependent enhancement of HIV-1 by autologous non-neutralising antibodies at early stages of infection","volume":"8","author":"Willey","year":"2011","journal-title":"Retrovirology"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Wang, S., Wang, J., Yu, X., Jiang, W., Chen, S., Wang, R., Wang, M., Jiao, S., Yang, Y., and Wang, W. (2022). Antibody-dependent enhancement (ADE) of SARS-CoV-2 pseudoviral infection requires Fc\u03b3RIIB and virus-antibody complex with bivalent interaction. Commun. Biol., 5.","DOI":"10.1038\/s42003-022-03207-0"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.molimm.2022.11.010","article-title":"Antibody-Dependent Enhancement (ADE) and the role of complement system in disease pathogenesis","volume":"152","author":"Thomas","year":"2022","journal-title":"Mol. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1126\/science.1185181","article-title":"Cross-reacting antibodies enhance dengue virus infection in humans","volume":"328","author":"Dejnirattisai","year":"2010","journal-title":"Science"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Mancardi, D., and Da\u00ebron, M. (2014). Fc receptors in immune responses. Reference Module in Biomedical Research, Elsevier. [3rd ed.].","DOI":"10.1016\/B978-0-12-801238-3.00119-7"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"155","DOI":"10.2217\/17460913.3.2.155","article-title":"Molecular aspects of Dengue virus replication","volume":"3","author":"Bartenschlager","year":"2008","journal-title":"Future Microbiol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Scaturro, P., Cortese, M., Chatel-Chaix, L., Fischl, W., and Bartenschlager, R. (2015). Dengue Virus Non-structural Protein 1 Modulates Infectious Particle Production via Interaction with the Structural Proteins. PLoS Pathog., 11.","DOI":"10.1371\/journal.ppat.1005277"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Nanaware, N., Banerjee, A., Mullick Bagchi, S., Bagchi, P., and Mukherjee, A. (2021). Dengue virus infection: A tale of viral exploitations and host responses. Viruses, 13.","DOI":"10.3390\/v13101967"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/nrmicro1067","article-title":"A structural perspective of the flavivirus life cycle","volume":"3","author":"Mukhopadhyay","year":"2005","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Harapan, H., Michie, A., Sasmono, R.T., and Imrie, A. (2020). Dengue: A minireview. Viruses, 12.","DOI":"10.3390\/v12080829"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"581","DOI":"10.2217\/fvl.09.51","article-title":"Dengue virus markers of virulence and pathogenicity","volume":"4","year":"2009","journal-title":"Future Virol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/S0065-3527(03)59009-1","article-title":"Microevolution and virulence of dengue viruses","volume":"59","year":"2003","journal-title":"Adv. Virus Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0065-3527(08)00401-6","article-title":"The history and evolution of human dengue emergence","volume":"72","author":"Vasilakis","year":"2008","journal-title":"Adv. Virus Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"355","DOI":"10.7150\/ijms.29938","article-title":"The conserved molecular determinants of virulence in dengue virus","volume":"16","author":"Ahmad","year":"2019","journal-title":"Int. J. Med. Sci."},{"key":"ref_31","first-page":"299","article-title":"Epidemiology of dengue: Past, present and future prospects","volume":"20","author":"Murray","year":"2013","journal-title":"Clin. Epidemiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1586\/14760584.2013.815412","article-title":"Dengue vaccines: Recent developments, ongoing challenges and current candidates","volume":"12","author":"McArthur","year":"2013","journal-title":"Expert Rev. Vaccines"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"304ra142","DOI":"10.1126\/scitranslmed.aaa3863","article-title":"Dengue virus NS1 protein activates cells via Toll-like receptor 4 and disrupts endothelial cell monolayer integrity","volume":"7","author":"Modhiran","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Halstead, S.B. (1980). Immunological Parameters of Togavirus Disease Syndromes, Academic Press.","DOI":"10.1016\/B978-0-12-625380-1.50010-2"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Coronel-Ruiz, C., Guti\u00e9rrez-Barbosa, H., Medina-Moreno, S., Velandia-Romero, M.L., Chua, J.V., Castellanos, J.E., and Zapata, J.C. (2020). Humanized mice in dengue research: A comparison with other mouse models. Vaccines, 8.","DOI":"10.3390\/vaccines8010039"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/S0140-6736(18)32560-1","article-title":"Dengue","volume":"393","author":"Ooi","year":"2019","journal-title":"Lancet"},{"key":"ref_37","unstructured":"WHO (2018). The Global Advisory Committee on Vaccine Safety, Dengue Vaccine Safety."},{"key":"ref_38","first-page":"123","article-title":"Infectious disease crisis in the Philippines","volume":"18","author":"Pasteur","year":"2018","journal-title":"Lancet Infect. Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"165","DOI":"10.12688\/wellcomeopenres.15507.1","article-title":"Estimating the proportion of vaccine-induced hospitalized dengue cases among Dengvaxia vaccinees in the Philippines","volume":"4","author":"Flasche","year":"2019","journal-title":"Wellcome Open Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1056\/NEJMoa1411037","article-title":"Efficacy of a tetravalent dengue vaccine in children in Latin America","volume":"372","author":"Villar","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"100604","DOI":"10.1016\/j.jvacx.2024.100604","article-title":"Current status of the development of dengue vaccines","volume":"22","author":"Lee","year":"2025","journal-title":"Vaccine X"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1056\/NEJMoa1800820","article-title":"Effect of dengue serostatus on dengue vaccine safety and efficacy","volume":"379","author":"Sridhar","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.1080\/21645515.2019.1658503","article-title":"A review of Dengvaxia\u00ae: Development to deployment","volume":"15","author":"Thomas","year":"2019","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_44","unstructured":"WHO (2018). Dengue vaccine: WHO position paper. Wkly. Epidemiol. Rec., 36, 457\u2013476."},{"key":"ref_45","unstructured":"WHO (2024). WHO position paper on dengue vaccines. Wkly. Epidemiol. Rec., 99, 203\u2013224."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"11436","DOI":"10.1128\/JVI.77.21.11436-11447.2003","article-title":"Dengue 2 PDK-53 virus as a chimeric carrier for tetravalent dengue vaccine development","volume":"77","author":"Huang","year":"2003","journal-title":"J. Virol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3011","DOI":"10.1128\/JVI.74.7.3011-3019.2000","article-title":"Attenuation markers of a candidate dengue type 2 vaccine virus, strain 16681 (PDK-53), are defined by mutations in the 5\u2032 noncoding region and nonstructural proteins 1 and 3","volume":"74","author":"Butrapet","year":"2000","journal-title":"J. Virol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Hou, J., Ye, W., and Chen, J. (2022). Current development and challenges of tetravalent live-attenuated dengue vaccines. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.840104"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1093\/cid\/ciab864","article-title":"Three-year efficacy and safety of Takeda\u2019s dengue vaccine candidate (TAK-003)","volume":"75","author":"Rivera","year":"2022","journal-title":"Clin. Infect. Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e257","DOI":"10.1016\/S2214-109X(23)00522-3","article-title":"Long-term efficacy and safety of a tetravalent dengue vaccine (TAK-003): 4.5-year results from a phase 3, randomised, double-blind, placebo-controlled trial","volume":"12","author":"Tricou","year":"2024","journal-title":"Lancet Glob. Health"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.virol.2005.06.009","article-title":"Role of RNA structures present at the 3\u2032 UTR of dengue virus on translation, RNA synthesis, and viral replication","volume":"339","author":"Alvarez","year":"2005","journal-title":"Virology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"10342","DOI":"10.1073\/pnas.88.22.10342","article-title":"Construction of intertypic chimeric dengue viruses by substitution of structural protein genes","volume":"88","author":"Bray","year":"1991","journal-title":"Proc. Nat. Acad. Sci. USA"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"405","DOI":"10.4269\/ajtmh.2001.65.405","article-title":"Attenuation and immunogenicity in humans of a live dengue virus type-4 vaccine candidate with a 30 nucleotide deletion in its 3\u2019-untranslated region","volume":"65","author":"Durbin","year":"2001","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1128\/JVI.76.2.525-531.2002","article-title":"Paired charge-to-alanine mutagenesis of dengue virus type 4 NS5 generates mutants with temperature-sensitive, host range, and mouse attenuation phenotypes","volume":"76","author":"Hanley","year":"2002","journal-title":"J. Virol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1128\/JVI.77.2.1653-1657.2003","article-title":"A live, attenuated dengue virus type 1 vaccine candidate with a 30-nucleotide deletion in the 3\u2032 untranslated region is highly attenuated and immunogenic in monkeys","volume":"77","author":"Whitehead","year":"2003","journal-title":"J. Virol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"4307","DOI":"10.1016\/S0264-410X(03)00488-2","article-title":"Substitution of the structural genes of dengue virus type 4 with those of type 2 results in chimeric vaccine candidates which are attenuated for mosquitoes, mice, and rhesus monkeys","volume":"21","author":"Whitehead","year":"2003","journal-title":"Vaccine"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/j.vaccine.2007.11.082","article-title":"Dengue virus type 3 vaccine candidates generated by introduction of deletions in the 3\u2032 untranslated region (3\u2032-UTR) or by exchange of the DENV-3 3\u2032-UTR with that of DENV-4","volume":"26","author":"Blaney","year":"2008","journal-title":"Vaccine"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"678","DOI":"10.4269\/ajtmh.2008.79.678","article-title":"Phase I clinical evaluation of rDEN4\u039430-200,201: A live attenuated dengue 4 vaccine candidate designed for decreased hepatotoxicity","volume":"79","author":"McArthur","year":"2008","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.coviro.2020.09.005","article-title":"Historical discourse on the development of the live attenuated tetravalent dengue vaccine candidate TV003\/TV005","volume":"43","author":"Durbin","year":"2020","journal-title":"Curr. Opin. Virol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1093\/infdis\/jiv082","article-title":"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","volume":"212","author":"Kirkpatrick","year":"2015","journal-title":"J. Infect. Dis."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1093\/infdis\/jiw067","article-title":"A 12-month\u2013interval dosing study in adults indicates that a single dose of the national institute of allergy and infectious diseases tetravalent dengue vaccine induces a robust neutralizing antibody response","volume":"214","author":"Durbin","year":"2016","journal-title":"J. Infect. Dis."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/S1473-3099(20)30023-2","article-title":"Safety and immunogenicity of the tetravalent, live-attenuated dengue vaccine Butantan-DV in adults in Brazil: A two-step, double-blind, randomised placebo-controlled phase 2 trial","volume":"20","author":"Kallas","year":"2020","journal-title":"Lancet Infect. Dis."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1056\/NEJMoa2301790","article-title":"Live, attenuated, tetravalent Butantan\u2013Dengue vaccine in children and adults","volume":"390","author":"Cintra","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/S0065-3527(03)59006-6","article-title":"5\u2032-and 3\u2032-noncoding regions in flavivirus RNA","volume":"59","author":"Markoff","year":"2004","journal-title":"Adv. Vir. Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"249","DOI":"10.4161\/rna.8.2.14992","article-title":"Dynamic RNA structures in the dengue virus genome","volume":"8","author":"Iglesias","year":"2011","journal-title":"RNA Biol."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Ng, W.C., Soto-Acosta, R., Bradrick, S.S., Garcia-Blanco, M.A., and Ooi, E.E. (2017). The 5\u2032 and 3\u2032 untranslated regions of the flaviviral genome. Viruses, 9.","DOI":"10.3390\/v9060137"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"6631","DOI":"10.1128\/JVI.79.11.6631-6643.2005","article-title":"Long-range RNA-RNA interactions circularize the dengue virus genome","volume":"79","author":"Alvarez","year":"2005","journal-title":"J. Virol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1006\/viro.1995.1052","article-title":"Growth-restricted dengue virus mutants containing deletions in the 5\u2032 noncoding region of the RNA genome","volume":"207","author":"Cahour","year":"1995","journal-title":"Virology"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.1099\/vir.0.82455-0","article-title":"Substitution or deletion mutations between nt 54 and 70 in the 5\u2032 non-coding region of dengue type 2 virus produce variable effects on virus viability","volume":"88","author":"Sirigulpanit","year":"2007","journal-title":"J. Gen. Virol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1146\/annurev-virology-110615-042334","article-title":"Properties and functions of the dengue virus capsid protein","volume":"3","author":"Byk","year":"2016","journal-title":"Annu. Rev. Virol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"3414","DOI":"10.1073\/pnas.0305892101","article-title":"Solution structure of dengue virus capsid protein reveals another fold","volume":"101","author":"Ma","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1006\/viro.1997.8608","article-title":"A conserved internal hydrophobic domain mediates the stable membrane integration of the dengue virus capsid protein","volume":"233","author":"Markoff","year":"1997","journal-title":"Virology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2170","DOI":"10.1128\/JVI.80.5.2170-2182.2006","article-title":"RNA secondary structure in the coding region of dengue virus type 2 directs translation start codon selection and is required for viral replication","volume":"80","author":"Clyde","year":"2006","journal-title":"J. Virol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.virol.2008.06.034","article-title":"The capsid-coding region hairpin element (cHP) is a critical determinant of dengue virus and West Nile virus RNA synthesis","volume":"379","author":"Clyde","year":"2008","journal-title":"Virology"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.virusres.2007.03.004","article-title":"Attenuated dengue 2 viruses with deletions in capsid protein derived from an infectious full-length cDNA clone","volume":"126","author":"Zhu","year":"2007","journal-title":"Virus Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1099\/vir.0.83264-0","article-title":"Multiple regions in dengue virus capsid protein contribute to nuclear localization during virus infection","volume":"89","author":"Sangiambut","year":"2008","journal-title":"J. Gen. Virol."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Samsa, M.M., Mondotte, J.A., Iglesias, N.G., Assun\u00e7\u00e3o-Miranda, I., Barbosa-Lima, G., Da Poian, A.T., Bozza, P.T., and Gamarnik, A.V. (2009). Dengue virus capsid protein usurps lipid droplets for viral particle formation. PLoS Pathog., 5.","DOI":"10.1371\/journal.ppat.1000632"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1830","DOI":"10.1126\/science.1153263","article-title":"The flavivirus precursor membrane-envelope protein complex: Structure and maturation","volume":"319","author":"Li","year":"2008","journal-title":"Science"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1038\/nsb990","article-title":"Visualization of membrane protein domains by cryo-electron microscopy of dengue virus","volume":"10","author":"Zhang","year":"2003","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"12101","DOI":"10.1128\/JVI.01637-09","article-title":"Association of the pr peptides with dengue virus at acidic pH blocks membrane fusion","volume":"83","author":"Yu","year":"2009","journal-title":"J. Virol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"7290","DOI":"10.1128\/JVI.75.16.7290-7304.2001","article-title":"Construction, safety, and immunogenicity in nonhuman primates of a chimeric yellow fever-dengue virus tetravalent vaccine","volume":"75","author":"Guirakhoo","year":"2001","journal-title":"J. Virol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"3627","DOI":"10.1099\/vir.0.80283-0","article-title":"Histidine 39 in the dengue virus type 2 M protein has an important role in virus assembly","volume":"85","author":"Pryor","year":"2004","journal-title":"J. Gen. Virol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"33149","DOI":"10.1074\/jbc.M114.610428","article-title":"Highly conserved residues in the helical domain of dengue virus type 1 precursor membrane protein are involved in assembly, precursor membrane (prM) protein cleavage, and entry","volume":"289","author":"Hsieh","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"eadk4769","DOI":"10.1126\/scitranslmed.adk4769","article-title":"A prM mutation that attenuates dengue virus replication in human cells enhances midgut infection in mosquitoes","volume":"16","author":"Choi","year":"2024","journal-title":"Sci. Transl. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1002\/jmv.25646","article-title":"Dengue proteins with their role in pathogenesis, and strategies for developing an effective anti-dengue treatment: A review","volume":"92","author":"Nasar","year":"2020","journal-title":"J. Med. Virol."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Slon Campos, J.L., Poggianella, M., Marchese, S., Mossenta, M., Rana, J., Arnoldi, F., Bestagno, M., and Burrone, O.R. (2017). DNA-immunisation with dengue virus E protein domains I\/II, but not domain III, enhances Zika, West Nile and Yellow Fever virus infection. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0181734"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Villala\u00edn, J. (2022). Envelope E protein of dengue virus and phospholipid binding to the late endosomal membrane. Biochim. Biophys. Acta Biomembr., 1864.","DOI":"10.1016\/j.bbamem.2022.183889"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1038\/nature02165","article-title":"Structure of the dengue virus envelope protein after membrane fusion","volume":"427","author":"Modis","year":"2004","journal-title":"Nature"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.virol.2010.07.024","article-title":"Domain-III FG loop of the dengue virus type 2 envelope protein is important for infection of mammalian cells and Aedes aegypti mosquitoes","volume":"406","author":"Erb","year":"2010","journal-title":"Virology"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.virol.2009.10.027","article-title":"The dengue virus type 2 envelope protein fusion peptide is essential for membrane fusion","volume":"396","author":"Huang","year":"2010","journal-title":"Virology"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.virol.2011.01.030","article-title":"Amino acid changes within the E protein hinge region that affect dengue virus type 2 infectivity and fusion","volume":"413","author":"Butrapet","year":"2011","journal-title":"Virology"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"5159","DOI":"10.1128\/JVI.02099-10","article-title":"The helical domains of the stem region of dengue virus envelope protein are involved in both virus assembly and entry","volume":"85","author":"Lin","year":"2011","journal-title":"J. Virol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"7072","DOI":"10.1128\/JVI.00224-12","article-title":"Mutagenesis of the DI\/DIII linker in dengue virus envelope protein impairs viral particle assembly","volume":"86","author":"Yang","year":"2012","journal-title":"J. Virol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"160","DOI":"10.3390\/v3020160","article-title":"Flavivirus cell entry and membrane fusion","volume":"3","author":"Smit","year":"2011","journal-title":"Viruses"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.virol.2014.03.031","article-title":"Molecular determinants of dengue virus 2 envelope protein important for virus entry in Fc\u03b3RIIA-mediated antibody-dependent enhancement of infection","volume":"456","author":"Chotiwan","year":"2014","journal-title":"Virology"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"e01183-24","DOI":"10.1128\/jvi.01183-24","article-title":"Envelope domain III E324, E351, and E380 mutations lever adaptive evolution of DENV-1 genotype I","volume":"98","author":"Jiang","year":"2024","journal-title":"J. Virol."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Rani, N.V., Baig, M.S., Pathak, B., Kapoor, N., and Krishnan, A. (2024). Mutation of conserved histidine residues of dengue virus envelope protein impairs viral like particle maturation and secretion. Biochim. Biophys. Acta Mol. Cell Res., 1871.","DOI":"10.1016\/j.bbamcr.2024.119682"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/0042-6822(88)90408-4","article-title":"Evidence that the mature form of the flavivirus nonstructural protein NS1 is a dimer","volume":"162","author":"Winkler","year":"1988","journal-title":"Virology"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1016\/0042-6822(89)90161-X","article-title":"Maturation of Japanese encephalitis virus glycoproteins produced by infected mammalian and mosquito cells","volume":"169","author":"Mason","year":"1989","journal-title":"Virology"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1006\/viro.1996.0307","article-title":"Immunolocalization of the dengue virus nonstructural glycoprotein NS1 suggests a role in viral RNA replication","volume":"220","author":"Mackenzie","year":"1996","journal-title":"Virology"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"9608","DOI":"10.1128\/jvi.71.12.9608-9617.1997","article-title":"trans-Complementation of yellow fever virus NS1 reveals a role in early RNA replication","volume":"71","author":"Lindenbach","year":"1997","journal-title":"J. Virol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"7270","DOI":"10.1128\/JVI.72.9.7270-7279.1998","article-title":"trans-Complementation of flavivirus RNA polymerase gene NS5 by using Kunjin virus replicon-expressing BHK cells","volume":"72","author":"Khromykh","year":"1998","journal-title":"J. Virol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"10272","DOI":"10.1128\/JVI.73.12.10272-10280.1999","article-title":"Efficient trans-complementation of the flavivirus kunjin NS5 protein but not of the NS1 protein requires its coexpression with other components of the viral replicase","volume":"73","author":"Khromykh","year":"1999","journal-title":"J. Virol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"3253","DOI":"10.1128\/JVI.74.7.3253-3263.2000","article-title":"cis- and trans-acting elements in flavivirus RNA replication","volume":"74","author":"Khromykh","year":"2000","journal-title":"J. Virol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"7360","DOI":"10.1128\/JVI.00157-12","article-title":"Evidence for a genetic and physical interaction between nonstructural proteins NS1 and NS4B that modulates replication of West Nile virus","volume":"86","author":"Youn","year":"2012","journal-title":"J. Virol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1186\/1743-422X-10-339","article-title":"Non-structural protein-1 is required for West Nile virus replication complex formation and viral RNA synthesis","volume":"10","author":"Youn","year":"2013","journal-title":"Virol. J."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.virol.2017.04.003","article-title":"Sensitive luminescent reporter viruses reveal appreciable release of hepatitis C virus NS5A protein into the extracellular environment","volume":"507","author":"Eyre","year":"2017","journal-title":"Virology"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"8003","DOI":"10.1073\/pnas.1017338108","article-title":"Secreted dengue virus nonstructural protein NS1 is an atypical barrel-shaped high-density lipoprotein","volume":"108","author":"Gutsche","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Tan, B.E.K., Beard, M.R., and Eyre, N.S. (2023). Identification of Key Residues in Dengue Virus NS1 Protein That Are Essential for Its Secretion. Viruses, 15.","DOI":"10.3390\/v15051102"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/0042-6822(89)90544-8","article-title":"Newly synthesized dengue-2 virus nonstructural protein NS1 is a soluble protein but becomes partially hydrophobic and membrane-associated after dimerization","volume":"171","author":"Winkler","year":"1989","journal-title":"Virology"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/0042-6822(89)90162-1","article-title":"Analyses of the terminal sequences of West Nile virus structural proteins and of the in vitro translation of these proteins allow the proposal of a complete scheme of the proteolytic cleavages involved in their synthesis","volume":"169","author":"Nowak","year":"1989","journal-title":"Virology"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"6104","DOI":"10.1128\/JVI.73.7.6104-6110.1999","article-title":"Dengue virus type 1 nonstructural glycoprotein NS1 is secreted from mammalian cells as a soluble hexamer in a glycosylation-dependent fashion","volume":"73","author":"Flamand","year":"1999","journal-title":"J. Virol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.antiviral.2016.02.014","article-title":"The many faces of the flavivirus NS1 protein offer a multitude of options for inhibitor design","volume":"130","author":"Watterson","year":"2016","journal-title":"Antivir. Res."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1126\/science.1247749","article-title":"Flavivirus NS1 structures reveal surfaces for associations with membranes and the immune system","volume":"343","author":"Akey","year":"2014","journal-title":"Science"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1002\/bies.201400182","article-title":"Structure-guided insights on the role of NS1 in flavivirus infection","volume":"37","author":"Akey","year":"2015","journal-title":"Bioessays"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1007\/s12250-014-3459-1","article-title":"Critical role of Dengue Virus NS1 protein in viral replication","volume":"29","author":"Fan","year":"2014","journal-title":"Virol. Sin."},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Plaszczyca, A., Scaturro, P., Neufeldt, C.J., Cortese, M., Cerikan, B., Ferla, S., Brancale, A., Pichlmair, A., and Bartenschlager, R. (2019). A novel interaction between dengue virus nonstructural protein 1 and the NS4A-2K-4B precursor is required for viral RNA replication but not for formation of the membranous replication organelle. PLoS Pathog., 15.","DOI":"10.1371\/journal.ppat.1007736"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1128\/JCM.38.3.1053-1057.2000","article-title":"An antigen capture enzyme-linked immunosorbent assay reveals high levels of the dengue virus protein NS1 in the sera of infected patients","volume":"38","author":"Young","year":"2000","journal-title":"J. Clin. Microbiol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1086\/343813","article-title":"High circulating levels of the dengue virus nonstructural protein NS1 early in dengue illness correlate with the development of dengue hemorrhagic fever","volume":"186","author":"Libraty","year":"2002","journal-title":"J. Infect. Dis."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"eaat7726","DOI":"10.1126\/scitranslmed.aat7726","article-title":"A T164S mutation in the dengue virus NS1 protein is associated with greater disease severity in mice","volume":"11","author":"Chan","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"4609","DOI":"10.1128\/JVI.02424-12","article-title":"Membrane topology and function of dengue virus NS2A protein","volume":"87","author":"Xie","year":"2013","journal-title":"J. Virol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1080\/21505594.2017.1356540","article-title":"NS2A comprises a putative viroporin of Dengue virus 2","volume":"8","author":"Shrivastava","year":"2017","journal-title":"Virulence"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"7232","DOI":"10.1128\/jvi.69.11.7232-7243.1995","article-title":"Evidence that flavivirus NS1-NS2A cleavage is mediated by a membrane-bound host protease in the endoplasmic reticulum","volume":"69","author":"Falgout","year":"1995","journal-title":"J. Virol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/j.chom.2019.09.015","article-title":"Dengue NS2A protein orchestrates virus assembly","volume":"26","author":"Xie","year":"2019","journal-title":"Cell Host Microbe"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1128\/JVI.02882-14","article-title":"Two distinct sets of NS2A molecules are responsible for dengue virus RNA synthesis and virion assembly","volume":"89","author":"Xie","year":"2015","journal-title":"J. Virol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"4281","DOI":"10.1128\/JVI.03011-14","article-title":"Scanning mutagenesis studies reveal a potential intramolecular interaction within the C-terminal half of dengue virus NS2A involved in viral RNA replication and virus assembly and secretion","volume":"89","author":"Wu","year":"2015","journal-title":"J. Virol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"e01836-16","DOI":"10.1128\/JVI.01836-16","article-title":"Mutagenesis of dengue virus protein NS2A revealed a novel domain responsible for virus-induced cytopathic effect and interactions between NS2A and NS2B transmembrane segments","volume":"91","author":"Wu","year":"2017","journal-title":"J. Virol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"2467","DOI":"10.1128\/jvi.65.5.2467-2475.1991","article-title":"Both nonstructural proteins NS2B and NS3 are required for the proteolytic processing of dengue virus nonstructural proteins","volume":"65","author":"Falgout","year":"1991","journal-title":"J. Virol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"2244","DOI":"10.1016\/j.bbamem.2015.06.010","article-title":"Membrane topology of NS2B of dengue virus revealed by NMR spectroscopy","volume":"1848","author":"Li","year":"2015","journal-title":"Biochim. Biophys. Acta."},{"key":"ref_130","doi-asserted-by":"crossref","unstructured":"Aguirre, S., Luthra, P., Sanchez-Aparicio, M.T., Maestre, A.M., Patel, J., Lamothe, F., Fredericks, A.C., Tripathi, S., Zhu, T., and Pintado-Silva, J. (2017). Dengue virus NS2B protein targets cGAS for degradation and prevents mitochondrial DNA sensing during infection. Nat. Microbiol., 2.","DOI":"10.1038\/nmicrobiol.2017.37"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"2034","DOI":"10.1128\/jvi.67.4.2034-2042.1993","article-title":"Deletion analysis of dengue virus type 4 nonstructural protein NS2B: Identification of a domain required for NS2B-NS3 protease activity","volume":"67","author":"Falgout","year":"1993","journal-title":"J. Virol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"2379","DOI":"10.1074\/jbc.M114.607341","article-title":"The C-terminal 50 amino acid residues of dengue NS3 protein are important for NS3-NS5 interaction and viral replication","volume":"290","author":"Tay","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.virol.2004.07.004","article-title":"The RNA helicase, nucleotide 5\u2032-triphosphatase, and RNA 5\u2032-triphosphatase activities of Dengue virus protein NS3 are Mg2+-dependent and require a functional Walker B motif in the helicase catalytic core","volume":"328","author":"Benarroch","year":"2004","journal-title":"Virology"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1128\/JVI.72.1.624-632.1998","article-title":"Mutagenesis of the NS3 protease of dengue virus type 2","volume":"72","author":"Valle","year":"1998","journal-title":"J. Virol."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"9633","DOI":"10.1128\/JVI.75.20.9633-9643.2001","article-title":"Mutagenesis of the Dengue virus type 2 NS3 protein within and outside helicase motifs: Effects on enzyme activity and virus replication","volume":"75","author":"Matusan","year":"2001","journal-title":"J. Virol."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1006\/viro.2002.1528","article-title":"Genetic basis of attenuation of dengue virus type 4 small plaque mutants with restricted replication in suckling mice and in SCID mice transplanted with human liver cells","volume":"300","author":"Blaney","year":"2002","journal-title":"Virology"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"18817","DOI":"10.1074\/jbc.M109.090936","article-title":"Flexibility between the protease and helicase domains of the dengue virus NS3 protein conferred by the linker region and its functional implications","volume":"285","author":"Luo","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"5451","DOI":"10.1128\/JVI.00206-16","article-title":"A proline-rich N-terminal region of the dengue virus NS3 is crucial for infectious particle production","volume":"90","author":"Gebhard","year":"2016","journal-title":"J. Virol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"12904","DOI":"10.1093\/nar\/gkx1127","article-title":"NS3 helicase from dengue virus specifically recognizes viral RNA sequence to ensure optimal replication","volume":"45","author":"Swarbrick","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"8873","DOI":"10.1074\/jbc.M609919200","article-title":"The non-structural protein 4A of dengue virus is an integral membrane protein inducing membrane alterations in a 2K-regulated manner","volume":"282","author":"Miller","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"2818","DOI":"10.1016\/j.bbamem.2012.06.022","article-title":"NS4A and NS4B proteins from dengue virus: Membranotropic regions","volume":"1818","year":"2012","journal-title":"Biochim. Biophys. Acta."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1016\/j.bbamem.2017.10.016","article-title":"Secondary structure and membrane topology of dengue virus NS4A protein in micelles","volume":"1860","author":"Li","year":"2018","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"4080","DOI":"10.1128\/JVI.01900-12","article-title":"An N-terminal amphipathic helix in dengue virus nonstructural protein 4A mediates oligomerization and is essential for replication","volume":"87","author":"Stern","year":"2013","journal-title":"J. Virol."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"3455","DOI":"10.1128\/JVI.03453-14","article-title":"Characterization of dengue virus NS4A and NS4B protein interaction","volume":"89","author":"Zou","year":"2015","journal-title":"J. Virol."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"6171","DOI":"10.1128\/JVI.00546-15","article-title":"Determinants of dengue virus NS4A protein oligomerization","volume":"89","author":"Lee","year":"2015","journal-title":"J. Virol."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1099\/jgv.0.001462","article-title":"Mutations in the cytoplasmic domain of dengue virus NS4A affect virus fitness and interactions with other non-structural proteins","volume":"101","author":"Tan","year":"2020","journal-title":"J. Gen. Virol."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"e0131021","DOI":"10.1128\/JVI.01310-21","article-title":"Determinants in nonstructural protein 4A of dengue virus required for RNA replication and replication organelle biogenesis","volume":"95","author":"Cortese","year":"2021","journal-title":"J. Virol."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"8854","DOI":"10.1074\/jbc.M512697200","article-title":"Subcellular localization and membrane topology of the dengue virus type 2 non-structural protein 4B","volume":"281","author":"Miller","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"3471","DOI":"10.1128\/JVI.03454-14","article-title":"Mapping the interactions between the NS4B and NS3 proteins of dengue virus","volume":"89","author":"Zou","year":"2015","journal-title":"J. Virol."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"6746","DOI":"10.1128\/JVI.00423-15","article-title":"Mutation of putative N-glycosylation sites on dengue virus NS4B decreases RNA replication","volume":"89","author":"Naik","year":"2015","journal-title":"J. Virol."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"7170","DOI":"10.1128\/JVI.00867-15","article-title":"A combined genetic-proteomic approach identifies residues within Dengue virus NS4B critical for interaction with NS3 and viral replication","volume":"89","author":"Fischl","year":"2015","journal-title":"J. Virol."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1099\/jgv.0.001092","article-title":"A single amino acid substitution in the NS4B protein of Dengue virus confers enhanced virus growth and fitness in human cells in vitro through IFN-dependent host response","volume":"99","author":"Bui","year":"2018","journal-title":"J. Gen. Virol."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"448","DOI":"10.7883\/yoken.JJID.2018.107","article-title":"Single amino acid mutation in dengue virus NS4B protein has opposing effects on viral proliferation in mammalian and mosquito cells","volume":"71","author":"Fujiki","year":"2018","journal-title":"Jpn. J. Infect. Dis."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1128\/JVI.01970-16","article-title":"The many faces of the flavivirus NS5 protein in antagonism of type I interferon signaling","volume":"91","author":"Best","year":"2017","journal-title":"J. Virol."},{"key":"ref_155","doi-asserted-by":"crossref","unstructured":"Lu, G., and Gong, P. (2013). Crystal structure of the full-length Japanese encephalitis virus NS5 reveals a conserved methyltransferase-polymerase interface. PLoS Pathog., 9.","DOI":"10.2210\/pdb4k6m\/pdb"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1146\/annurev.micro.56.012302.160654","article-title":"The molecular biology of West Nile Virus: A new invader of the western hemisphere","volume":"56","author":"Brinton","year":"2002","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"14834","DOI":"10.1073\/pnas.1514978112","article-title":"Molecular basis for specific viral RNA recognition and 2\u2032-O-ribose methylation by the dengue virus nonstructural protein 5 (NS5)","volume":"112","author":"Zhao","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"11642","DOI":"10.1093\/nar\/gku666","article-title":"The methyltransferase domain of dengue virus protein NS5 ensures efficient RNA synthesis initiation and elongation by the polymerase domain","volume":"42","author":"Potisopon","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"5408","DOI":"10.1128\/JVI.02188-08","article-title":"NS5 of dengue virus mediates STAT2 binding and degradation","volume":"83","author":"Ashour","year":"2009","journal-title":"J. Virol."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"19410","DOI":"10.1074\/jbc.M800613200","article-title":"Mutagenesis of the dengue virus type 2 NS5 methyltransferase domain","volume":"283","author":"Kroschewski","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"5745","DOI":"10.1128\/JVI.02343-10","article-title":"The F1 motif of dengue virus polymerase NS5 is involved in promoter-dependent RNA synthesis","volume":"85","author":"Iglesias","year":"2011","journal-title":"J. Virol."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.antiviral.2013.06.002","article-title":"Nuclear localization of dengue virus (DENV) 1\u20134 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin","volume":"99","author":"Tay","year":"2013","journal-title":"Antivir. Res."},{"key":"ref_163","doi-asserted-by":"crossref","unstructured":"Tay, M.Y., Smith, K., Ng, I.H., Chan, K.W., Zhao, Y., Ooi, E.E., Lescar, J., Luo, D., Jans, D.A., and Forwood, J.K. (2016). The C-terminal 18 amino acid region of dengue virus NS5 regulates its subcellular localization and contains a conserved arginine residue essential for infectious virus production. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005886"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"10717","DOI":"10.1128\/JVI.01239-15","article-title":"Flexibility of NS5 methyltransferase-polymerase linker region is essential for dengue virus replication","volume":"89","author":"Zhao","year":"2015","journal-title":"J. Virol."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"3930","DOI":"10.1128\/jvi.70.6.3930-3937.1996","article-title":"Dengue type 4 virus mutants containing deletions in the 3\u2019noncoding region of the RNA genome: Analysis of growth restriction in cell culture and altered viremia pattern and immunogenicity in rhesus monkeys","volume":"70","author":"Men","year":"1996","journal-title":"J. Virol."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1093\/nar\/25.6.1194","article-title":"Secondary structure of the 3\u2032 untranslated region of flaviviruses: Similarities and differences","volume":"25","author":"Proutski","year":"1997","journal-title":"Nucleic Acids Res."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"7510","DOI":"10.1128\/JVI.72.9.7510-7522.1998","article-title":"Identification of specific nucleotide sequences within the conserved 3\u2032-SL in the dengue type 2 virus genome required for replication","volume":"72","author":"Zeng","year":"1998","journal-title":"J. Virol."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.tim.2016.01.002","article-title":"RNA structure duplications and flavivirus host adaptation","volume":"24","author":"Villordo","year":"2016","journal-title":"Trends Microbiol."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"11407","DOI":"10.1128\/JVI.01159-10","article-title":"RNA structures required for production of subgenomic flavivirus RNA","volume":"84","author":"Funk","year":"2010","journal-title":"J. Virol."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"30497","DOI":"10.1074\/jbc.M705755200","article-title":"Y box-binding protein-1 binds to the dengue virus 3\u2032-untranslated region and mediates antiviral effects","volume":"282","author":"Paranjape","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"e01892","DOI":"10.7554\/eLife.01892","article-title":"RNA structures that resist degradation by Xrn1 produce a pathogenic Dengue virus RNA","volume":"3","author":"Chapman","year":"2014","journal-title":"Elife"},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"13486","DOI":"10.1128\/JVI.01104-12","article-title":"Noncoding flavivirus RNA displays RNA interference suppressor activity in insect and Mammalian cells","volume":"86","author":"Schnettler","year":"2012","journal-title":"J. Virol."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.virol.2003.08.012","article-title":"Translation efficiency determines differences in cellular infection among dengue virus type 2 strains","volume":"317","author":"Edgil","year":"2003","journal-title":"Virology"},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"817","DOI":"10.4269\/ajtmh.2009.08-0595","article-title":"Translational regulation by the 3\u2032 untranslated region of the dengue type 2 virus genome","volume":"81","author":"Wei","year":"2009","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"22521","DOI":"10.1074\/jbc.M111.234302","article-title":"Identification of cis-acting elements in the 3\u2032-untranslated region of the dengue virus type 2 RNA that modulate translation and replication","volume":"286","author":"Manzano","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_176","doi-asserted-by":"crossref","unstructured":"Filomatori, C.V., Carballeda, J.M., Villordo, S.M., Aguirre, S., Pallar\u00e9s, H.M., Maestre, A.M., S\u00e1nchez-Vargas, I., Blair, C.D., Fabri, C., and Morales, M.A. (2017). Dengue virus genomic variation associated with mosquito adaptation defines the pattern of viral non-coding RNAs and fitness in human cells. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006265"},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"e3297","DOI":"10.1002\/jgm.3297","article-title":"Antibody-dependent enhancement (ADE) of dengue virus: Identification of the key amino acid that is vital in DENV vaccine research","volume":"23","author":"Cui","year":"2021","journal-title":"J. Gene Med."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.tim.2011.02.002","article-title":"Partial maturation: An immune-evasion strategy of dengue virus?","volume":"19","author":"Wilschut","year":"2011","journal-title":"Trends Microbiol."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1128\/9781555817411.ch15","article-title":"Dengue antibody-dependent enhancement: Knowns and unknowns","volume":"2","author":"Halstead","year":"2015","journal-title":"Antibodies Infect. Dis."},{"key":"ref_180","doi-asserted-by":"crossref","unstructured":"Luo, Y.-Y., Feng, J.-J., Zhou, J.-M., Yu, Z.-Z., Fang, D.-Y., Yan, H.-J., Zeng, G.-C., and Jiang, L.-F. (2013). Identification of a novel infection-enhancing epitope on dengue prM using a dengue cross-reacting monoclonal antibody. BMC Microbiol., 13.","DOI":"10.1186\/1471-2180-13-194"},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1128\/JVI.01805-15","article-title":"Dengue virus prM-specific human monoclonal antibodies with virus replication-enhancing properties recognize a single immunodominant antigenic site","volume":"90","author":"Smith","year":"2016","journal-title":"J. Virol."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"6631","DOI":"10.1128\/JVI.00316-08","article-title":"Antibodies to envelope glycoprotein of dengue virus during the natural course of infection are predominantly cross-reactive and recognize epitopes containing highly conserved residues at the fusion loop of domain II","volume":"82","author":"Lai","year":"2008","journal-title":"J. Virol."},{"key":"ref_183","doi-asserted-by":"crossref","unstructured":"Crill, W.D., Hughes, H.R., Delorey, M.J., and Chang, G.-J.J. (2009). Humoral immune responses of dengue fever patients using epitope-specific serotype-2 virus-like particle antigens. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0004991"},{"key":"ref_184","doi-asserted-by":"crossref","unstructured":"Crill, W.D., Hughes, H.R., Trainor, N.B., Davis, B.S., Whitney, M.T., and Chang, G.-J.J. (2012). Sculpting humoral immunity through dengue vaccination to enhance protective immunity. Front. Immunol., 3.","DOI":"10.3389\/fimmu.2012.00334"},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"e01181-17","DOI":"10.1128\/JVI.01181-17","article-title":"An envelope-modified tetravalent dengue virus-like-particle vaccine has implications for flavivirus vaccine design","volume":"91","author":"Urakami","year":"2017","journal-title":"J. Virol."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1038\/s41541-016-0003-3","article-title":"A potent neutralizing antibody with therapeutic potential against all four serotypes of dengue virus","volume":"2","author":"Xu","year":"2017","journal-title":"NPJ Vaccines"},{"key":"ref_187","doi-asserted-by":"crossref","unstructured":"Sarker, A., Dhama, N., and Gupta, R.D. (2023). Dengue virus neutralizing antibody: A review of targets, cross-reactivity, and antibody-dependent enhancement. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1200195"},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1016\/j.bbrc.2012.06.057","article-title":"Human monoclonal antibodies to neutralize all dengue virus serotypes using lymphocytes from patients at acute phase of the secondary infection","volume":"423","author":"Setthapramote","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"e4021","DOI":"10.7717\/peerj.4021","article-title":"Generation and characterization of cross neutralizing human monoclonal antibody against 4 serotypes of dengue virus without enhancing activity","volume":"5","author":"Injampa","year":"2017","journal-title":"PeerJ"},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.jviromet.2007.05.012","article-title":"Application of a focus formation assay for detection and titration of porcine epidemic diarrhea virus","volume":"145","author":"Cruz","year":"2007","journal-title":"J. Virol. Methods"},{"key":"ref_191","first-page":"52065","article-title":"Viral concentration determination through plaque assays: Using traditional and novel overlay systems","volume":"93","author":"Baer","year":"2014","journal-title":"J Vis Exp."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"e116","DOI":"10.1002\/cpim.116","article-title":"Development of a rapid focus reduction neutralization test assay for measuring SARS-CoV-2 neutralizing antibodies","volume":"131","author":"Vanderheiden","year":"2020","journal-title":"Curr. Protoc. Immunol."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"962","DOI":"10.4269\/ajtmh.12-0461","article-title":"Optimization and validation of a plaque reduction neutralization test for the detection of neutralizing antibodies to four serotypes of dengue virus used in support of dengue vaccine development","volume":"88","author":"Timiryasova","year":"2013","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/978-1-62703-484-5_17","article-title":"High-throughput screening using dengue virus reporter genomes","volume":"1030","author":"Fischl","year":"2013","journal-title":"Methods Mol. Biol."},{"key":"ref_195","doi-asserted-by":"crossref","unstructured":"Santiago, G.A., Vergne, E., Quiles, Y., Cosme, J., Vazquez, J., Medina, J.F., Medina, F., Col\u00f3n, C., Margolis, H., and Mu\u00f1oz-Jord\u00e1n, J.L. (2013). Analytical and clinical performance of the CDC real time RT-PCR assay for detection and typing of dengue virus. PLoS Negl. Trop. Dis., 7.","DOI":"10.1371\/annotation\/ae27d48b-025f-47ce-8427-4af59f821ad7"},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/j.omtm.2020.07.013","article-title":"Modified mRNA-LNP vaccines confer protection against experimental DENV-2 infection in mice","volume":"18","author":"Zhang","year":"2020","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"e02482-20","DOI":"10.1128\/JVI.02482-20","article-title":"A dengue virus serotype 1 mRNA-LNP vaccine elicits protective immune responses","volume":"95","author":"Wollner","year":"2021","journal-title":"J. Virol."},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1016\/j.virs.2022.07.003","article-title":"A multiple-target mRNA-LNP vaccine induces protective immunity against experimental multi-serotype DENV in mice","volume":"37","author":"He","year":"2022","journal-title":"Virol. Sin."},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"2404159","DOI":"10.1080\/22221751.2024.2404159","article-title":"Progress and challenges in development of animal models for dengue virus infection","volume":"13","author":"Yuya","year":"2024","journal-title":"Emerg. Microbes Infect."},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1146\/annurev-ento-011019-024918","article-title":"The global expansion of dengue: How Aedes aegypti mosquitoes enabled the first pandemic arbovirus","volume":"65","author":"Brady","year":"2020","journal-title":"Annu. Rev. Entomol."},{"key":"ref_201","doi-asserted-by":"crossref","unstructured":"Murugesan, A., and Manoharan, M. (2020). Dengue virus. Emerging and Re-Emerging Viral Pathogens, Elsevier.","DOI":"10.1016\/B978-0-12-819400-3.00016-8"},{"key":"ref_202","first-page":"001831","article-title":"Challenges on the development of a dengue vaccine: A comprehensive review of the state of the art","volume":"104","year":"2023","journal-title":"J. Gen. Virol."},{"key":"ref_203","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/s40794-024-00231-2","article-title":"The role of antibody-dependent enhancement in dengue vaccination","volume":"10","author":"Langerak","year":"2024","journal-title":"Trop. Dis. Trav. Med. Vaccines"},{"key":"ref_204","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1093\/infdis\/jiz081","article-title":"Magnitude and functionality of the NS1-specific antibody response elicited by a live-attenuated tetravalent dengue vaccine candidate","volume":"221","author":"Sharma","year":"2020","journal-title":"J. Infect. Dis."},{"key":"ref_205","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s12985-025-02645-6","article-title":"Revolutionizing immunization: A comprehensive review of mRNA vaccine technology and applications","volume":"22","author":"Leong","year":"2025","journal-title":"Virol. J."},{"key":"ref_206","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1016\/S1473-3099(10)70166-3","article-title":"Intrinsic antibody-dependent enhancement of microbial infection in macrophages: Disease regulation by immune complexes","volume":"10","author":"Halstead","year":"2010","journal-title":"Lancet Infect. Dis."},{"key":"ref_207","doi-asserted-by":"crossref","unstructured":"Wang, W.-H., Urbina, A.N., Lin, C.-Y., Yang, Z.-S., Assavalapsakul, W., Thitithanyanont, A., Lu, P.-L., Chen, Y.-H., and Wang, S.-F. (2021). Targets and strategies for vaccine development against dengue viruses. Biomed. Pharmacother., 144.","DOI":"10.1016\/j.biopha.2021.112304"},{"key":"ref_208","doi-asserted-by":"crossref","unstructured":"Al Fayez, N., Nassar, M.S., Alshehri, A.A., Alnefaie, M.K., Almughem, F.A., Alshehri, B.Y., Alawad, A.O., and Tawfik, E.A. (2023). Recent advancement in mRNA vaccine development and applications. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15071972"}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/13\/5\/532\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:33:50Z","timestamp":1760031230000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/13\/5\/532"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,16]]},"references-count":208,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["vaccines13050532"],"URL":"https:\/\/doi.org\/10.3390\/vaccines13050532","relation":{},"ISSN":["2076-393X"],"issn-type":[{"value":"2076-393X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,16]]}}}