Skip to main content
SpringerLink
Log in
Book cover

Dengue and Zika: Control and Antiviral Treatment Strategies pp 63–76Cite as

The Molecular Specificity of the Human Antibody Response to Dengue Virus Infections

  • Chapter
  • First Online:

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1062))

Abstract

Dengue viruses (DENV) are mosquito-borne positive sense RNA viruses in the family Flaviviridae. The four serotypes of DENV (DENV1, DENV2, DENV3, DENV4) are widely distributed and it is estimated over a third of the world’s population is at risk of infection [4]. While the majority of infections are asymptomatic, DENV infection can cause a spectrum of disease, from mild flu-like symptoms, to the more severe DENV hemorrhagic fever and shock syndrome [24]. Over the past 20 years, there have been intense efforts to develop a tetravalent live-attenuated DENV vaccine [36]. The process of vaccine development has been largely empirical, because effective live attenuated vaccines have been developed for other flaviviruses like yellow fever and Japanese encephalitis viruses. However, recent results from phase III live attenuated DENV vaccine efficacy trials are mixed with evidence for efficacy in some populations but not others [20]. In light of unexpected results from DENV vaccine trials, in this chapter we will review recent discoveries about the human antibody response to natural DENV infection and discuss the relevance of this work to understanding vaccine performance.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Amorim JH, Alves RP, Boscardin SB, Ferreira LC (2014) The dengue virus non-structural 1 protein: risks and benefits. Virus Res 181:53–60

    Article  CAS  PubMed  Google Scholar 

  2. Avirutnan P, Punyadee N, Noisakran S, Komoltri C, Thiemmeca S, Auethavornanan K, Jairungsri A, Kanlaya R, Tangthawornchaikul N, Puttikhunt C, Pattanakitsakul SN, Yenchitsomanus PT, Mongkolsapaya J, Kasinrerk W, Sittisombut N, Husmann M, Blettner M, Vasanawathana S, Bhakdi S, Malasit P (2006) Vascular leakage in severe dengue virus infections: a potential role for the nonstructural viral protein NS1 and complement. J Infect Dis 193:1078–1088

    Article  CAS  PubMed  Google Scholar 

  3. Beatty PR, Puerta-Guardo H, Killingbeck SS, Glasner DR, Hopkins K, Harris E (2015) Dengue virus NS1 triggers endothelial permeability and vascular leak that is prevented by NS1 vaccination. Sci Transl Med 7:304ra141

    Article  CAS  PubMed  Google Scholar 

  4. Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, Drake JM, Brownstein JS, Hoen AG, Sankoh O, Myers MF, George DB, Jaenisch T, Wint GR, Simmons CP, Scott TW, Farrar JJ, Hay SI (2013) The global distribution and burden of dengue. Nature 496:504–507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Collins MH, Mcgowan E, Jadi R, Young E, Lopez CA, Baric RS, Lazear HM, De Silva AM (2017) Lack of durable cross-neutralizing antibodies against Zika virus from dengue virus infection. Emerg Infect Dis 23:773–781

    Article  PubMed  PubMed Central  Google Scholar 

  6. Coloma J, Harris E (2015) Broad and strong: the ultimate antibody to dengue virus. Nat Immunol 16:135–137

    Article  CAS  PubMed  Google Scholar 

  7. Corbett KS, Katzelnick L, Tissera H, Amerasinghe A, De Silva AD, De Silva AM (2015) Preexisting neutralizing antibody responses distinguish clinically inapparent and apparent dengue virus infections in a Sri Lankan pediatric cohort. J Infect Dis 211:590–599

    Article  CAS  PubMed  Google Scholar 

  8. De Alwis R, Beltramello M, Messer WB, Sukupolvi-Petty S, Wahala WM, Kraus A, Olivarez NP, Pham Q, Brien JD, Tsai WY, Wang WK, Halstead S, Kliks S, Diamond MS, Baric R, Lanzavecchia A, Sallusto F, De Silva AM (2011) In-depth analysis of the antibody response of individuals exposed to primary dengue virus infection. PLoS Negl Trop Dis 5:e1188

    Article  PubMed  PubMed Central  Google Scholar 

  9. De Alwis R, Smith SA, Olivarez NP, Messer WB, Huynh JP, Wahala WM, White LJ, Diamond MS, Baric RS, Crowe JE Jr, De Silva AM (2012) Identification of human neutralizing antibodies that bind to complex epitopes on dengue virions. Proc Natl Acad Sci U S A 109:7439–7444

    Article  PubMed  PubMed Central  Google Scholar 

  10. De Souza VA, Tateno AF, Oliveira RR, Domingues RB, Araujo ES, Kuster GW, Pannuti CS (2007) Sensitivity and specificity of three ELISA-based assays for discriminating primary from secondary acute dengue virus infection. J Clin Virol 39:230–233

    Article  CAS  PubMed  Google Scholar 

  11. Dejnirattisai W, Wongwiwat W, Supasa S, Zhang X, Dai X, Rouvinski A, Jumnainsong A, Edwards C, Quyen NT, Duangchinda T, Grimes JM, Tsai WY, Lai CY, Wang WK, Malasit P, Farrar J, Simmons CP, Zhou ZH, Rey FA, Mongkolsapaya J, Screaton GR (2015) A new class of highly potent, broadly neutralizing antibodies isolated from viremic patients infected with dengue virus. Nat Immunol 16:170–177

    Article  CAS  PubMed  Google Scholar 

  12. Dowd KA, Mukherjee S, Kuhn RJ, Pierson TC (2014) Combined effects of the structural heterogeneity and dynamics of flaviviruses on antibody recognition. J Virol 88:11726–11737

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Dowd KA, Demaso CR, Pierson TC (2015) Genotypic differences in dengue virus neutralization are explained by a single amino acid mutation that modulates virus breathing. MBio 6:e01559–e01515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Fibriansah G, Tan JL, Smith SA, De Alwis AR, Ng TS, Kostyuchenko VA, Ibarra KD, Wang JQ, Harris E, De Silva A, Crowe JE, Lok SM (2014) A potent anti-dengue human antibody preferentially recognizes the conformation of E protein monomers assembled on the virus surface. Embo Molecular Medicine 6:358–371

    PubMed  PubMed Central  CAS  Google Scholar 

  15. Fibriansah G, Ibarra KD, Ng TS, Smith SA, Tan JL, Lim XN, Ooi JS, Kostyuchenko VA, Wang J, De Silva AM, Harris E, Crowe JE, Lok SM (2015a) DENGUE VIRUS. Cryo-EM structure of an antibody that neutralizes dengue virus type 2 by locking E protein dimers. Science 349:88–91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Fibriansah G, Tan JL, Smith SA, De Alwis R, Ng TS, Kostyuchenko VA, Jadi RS, Kukkaro P, De Silva AM, Crowe JE, Lok SM (2015b) A highly potent human antibody neutralizes dengue virus serotype 3 by binding across three surface proteins. Nat Commun 6:6341

    Article  CAS  PubMed  Google Scholar 

  17. Gallichotte EN, Widman DG, Yount BL, Wahala WM, Durbin A, Whitehead S, Sariol CA, Crowe JE, De Silva AM, Baric RS (2015) A new quaternary structure epitope on dengue virus serotype 2 is the target of durable type-specific neutralizing antibodies. MBio 6:e01461–e01415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Goo L, Vanblargan LA, Dowd KA, Diamond MS, Pierson TC (2017) A single mutation in the envelope protein modulates flavivirus antigenicity, stability, and pathogenesis. PLoS Pathog 13:e1006178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gromowski GD, Barrett AD (2007) 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 366:349–360

    Article  CAS  PubMed  Google Scholar 

  20. Guy B, Jackson N (2016) Dengue vaccine: hypotheses to understand CYD-TDV-induced protection. Nat Rev Microbiol 14:45–54

    Article  CAS  PubMed  Google Scholar 

  21. Hadinegoro SR, Arredondo-Garcia JL, Capeding MR, Deseda C, Chotpitayasunondh T, Dietze R, Ismail HI, Reynales H, Limkittikul K, Rivera-Medina DM, Tran HN, Bouckenooghe A, Chansinghakul D, Cortes M, Fanouillere K, Forrat R, Frago C, Gailhardou S, Jackson N, Noriega F, Plennevaux E, Wartel TA, Zambrano B, Saville M, CYD-TDV Dengue Vaccine Working Group (2015) Efficacy and long-term safety of a dengue vaccine in regions of endemic disease. N Engl J Med 373:1195–1206

    Article  CAS  PubMed  Google Scholar 

  22. Hadjilaou A, Green AM, Coloma J, Harris E (2015) Single-cell analysis of B cell/antibody cross-reactivity using a novel multicolor FluoroSpot assay. J Immunol 195:3490–3496

    Article  CAS  PubMed  Google Scholar 

  23. Halstead SB (2003) Neutralization and antibody-dependent enhancement of dengue viruses. Adv Virus Res 60:421–467

    Article  CAS  PubMed  Google Scholar 

  24. Halstead SB (2007) Dengue. Lancet 370:1644–1652

    Article  PubMed  Google Scholar 

  25. Halstead SB (2014) Dengue antibody-dependent enhancement: knowns and unknowns. Microbiol Spectr 2

    Google Scholar 

  26. Halstead SB (2015) Pathogenesis of dengue: Dawn of a new era. F1000Res 4

    Google Scholar 

  27. Halstead SB, Rojanasuphot S, Sangkawibha N (1983) Original antigenic sin in dengue. Am J Trop Med Hyg 32:154–156

    Article  CAS  PubMed  Google Scholar 

  28. Hasan SS, Miller A, Sapparapu G, Fernandez E, Klose T, Long F, Fokine A, Porta JC, Jiang W, Diamond MS, Crowe JE Jr, Kuhn RJ, Rossmann MG (2017) A human antibody against Zika virus crosslinks the E protein to prevent infection. Nat Commun 8:14722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. He RT, Innis BL, Nisalak A, Usawattanakul W, Wang S, Kalayanarooj S, Anderson R (1995) Antibodies that block virus attachment to Vero cells are a major component of the human neutralizing antibody response against dengue virus type 2. J Med Virol 45:451–461

    Article  CAS  PubMed  Google Scholar 

  30. Henein S, Swanstrom J, Byers AM, Moser JM, Shaik SF, Bonaparte M, Jackson N, Guy B, Baric R, De Silva AM (2017) Dissecting antibodies induced by a chimeric yellow fever-dengue, live-attenuated, tetravalent dengue vaccine (CYD-TDV) in naive and dengue-exposed individuals. J Infect Dis 215:351–358

    PubMed  Google Scholar 

  31. Kaufmann B, Vogt MR, Goudsmit J, Holdaway HA, Aksyuk AA, Chipman PR, Kuhn RJ, Diamond MS, Rossmann MG (2010) Neutralization of West Nile virus by cross-linking of its surface proteins with fab fragments of the human monoclonal antibody CR4354. Proc Natl Acad Sci U S A 107:18950–18955

    Article  PubMed  PubMed Central  Google Scholar 

  32. Kuhn RJ, Dowd KA, Beth Post C, Pierson TC (2015) Shake, rattle, and roll: impact of the dynamics of flavivirus particles on their interactions with the host. Virology 479–480:508–517

    Article  CAS  PubMed  Google Scholar 

  33. Kurosaki T, Kometani K, Ise W (2015) Memory B cells. Nat Rev Immunol 15:149–159

    Article  CAS  PubMed  Google Scholar 

  34. Kwakkenbos MJ, Diehl SA, Yasuda E, Bakker AQ, Van Geelen CM, Lukens MV, Van Bleek GM, Widjojoatmodjo MN, Bogers WM, Mei H, Radbruch A, Scheeren FA, Spits H, Beaumont T (2010) Generation of stable monoclonal antibody-producing B cell receptor-positive human memory B cells by genetic programming. Nat Med 16:123–128

    Article  CAS  PubMed  Google Scholar 

  35. Libraty DH, Young PR, Pickering D, Endy TP, Kalayanarooj S, Green S, Vaughn DW, Nisalak A, Ennis FA, Rothman AL (2002) High circulating levels of the dengue virus nonstructural protein NS1 early in dengue illness correlate with the development of dengue hemorrhagic fever. J Infect Dis 186:1165–1168

    Article  CAS  PubMed  Google Scholar 

  36. Liu Y, Liu J, Cheng G (2016) Vaccines and immunization strategies for dengue prevention. Emerg Microbes Infect 5:e77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Matheus S, Deparis X, Labeau B, Lelarge J, Morvan J, Dussart P (2005) Discrimination between primary and secondary dengue virus infection by an immunoglobulin G avidity test using a single acute-phase serum sample. J Clin Microbiol 43:2793–2797

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Messer WB, Yount BL, Royal SR, De Alwis R, Widman DG, Smith SA, Crowe JE Jr, Pfaff JM, Kahle KM, Doranz BJ, Ibarra KD, Harris E, De Silva AM, Baric RS (2016) Functional transplant of a dengue virus serotype 3 (DENV3)-specific human monoclonal antibody epitope into DENV1. J Virol 90:5090–5097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Mukherjee S, Sirohi D, Dowd KA, Chen Z, Diamond MS, Kuhn RJ, Pierson TC (2016) Enhancing dengue virus maturation using a stable furin over-expressing cell line. Virology 497:33–40

    Article  CAS  PubMed  Google Scholar 

  40. Muller DA, Young PR (2013) The flavivirus NS1 protein: molecular and structural biology, immunology, role in pathogenesis and application as a diagnostic biomarker. Antivir Res 98:192–208

    Article  CAS  PubMed  Google Scholar 

  41. Nivarthi UK, Kose N, Sapparapu G, Widman D, Gallichotte E, Pfaff JM, Doranz BJ, Weiskopf D, Sette A, Durbin AP, Whitehead SS, Baric R, Crowe JEJ, De Silva AM (2017) Mapping the human memory B cell and serum neutralizing antibody responses to dengue virus serotype 4 infection and vaccination. J Virol 91:e02041–e02016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Olkowski S, Forshey BM, Morrison AC, Rocha C, Vilcarromero S, Halsey ES, Kochel TJ, Scott TW, Stoddard ST (2013) Reduced risk of disease during postsecondary dengue virus infections. J Infect Dis 208:1026–1033

    Article  PubMed  PubMed Central  Google Scholar 

  43. Patel B, Longo P, Miley MJ, Montoya M, Harris E, De Silva AM (2017) Dissecting the human serum antibody response to secondary dengue virus infections. PLoS Negl Trop Dis 11:e0005554

    Article  PubMed  PubMed Central  Google Scholar 

  44. Robinson WH (2015) Sequencing the functional antibody repertoire—diagnostic and therapeutic discovery. Nat Rev Rheumatol 11:171–182

    Article  CAS  PubMed  Google Scholar 

  45. Roehrig JT (2003) Antigenic structure of flavivirus proteins. Adv Virus Res 59:141–175

    Article  CAS  PubMed  Google Scholar 

  46. Rothman AL (2011) Immunity to dengue virus: a tale of original antigenic sin and tropical cytokine storms. Nat Rev Immunol 11:532–543

    Article  CAS  PubMed  Google Scholar 

  47. Rouvinski A, Guardado-Calvo P, Barba-Spaeth G, Duquerroy S, Vaney MC, Kikuti CM, Navarro Sanchez ME, Dejnirattisai W, Wongwiwat W, Haouz A, Girard-Blanc C, Petres S, Shepard WE, Despres P, Arenzana-Seisdedos F, Dussart P, Mongkolsapaya J, Screaton GR, Rey FA (2015) Recognition determinants of broadly neutralizing human antibodies against dengue viruses. Nature 520:109–113

    Article  CAS  PubMed  Google Scholar 

  48. Smith SA, Crowe JE Jr (2015) Use of human Hybridoma technology to isolate human monoclonal antibodies. Microbiol Spectr 3, AID-0027-2014

    Google Scholar 

  49. Smith K, Garman L, Wrammert J, Zheng NY, Capra JD, Ahmed R, Wilson PC (2009) Rapid generation of fully human monoclonal antibodies specific to a vaccinating antigen. Nat Protoc 4:372–384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Smith SA, De Alwis AR, Kose N, Harris E, Ibarra KD, Kahle KM, Pfaff JM, Xiang X, Doranz BJ, De Silva AM, Austin SK, Sukupolvi-Petty S, Diamond MS, Crowe JE Jr (2013) The potent and broadly neutralizing human dengue virus-specific monoclonal antibody 1C19 reveals a unique cross-reactive epitope on the bc loop of domain II of the envelope protein. MBio 4:e00873–e00813

    PubMed  PubMed Central  Google Scholar 

  51. Smith SA, Nivarthi UK, De Alwis R, Kose N, Sapparapu G, Bombardi R, Kahle KM, Pfaff JM, Lieberman S, Doranz BJ, De Silva AM, Crowe JE Jr (2015) Dengue virus prM-specific human monoclonal antibodies with virus replication-enhancing properties recognize a single Immunodominant antigenic site. J Virol 90:780–789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Stettler K, Beltramello M, Espinosa DA, Graham V, Cassotta A, Bianchi S, Vanzetta F, Minola A, Jaconi S, Mele F, Foglierini M, Pedotti M, Simonelli L, Dowall S, Atkinson B, Percivalle E, Simmons CP, Varani L, Blum J, Baldanti F, Cameroni E, Hewson R, Harris E, Lanzavecchia A, Sallusto F, Corti D (2016) Specificity, cross-reactivity, and function of antibodies elicited by Zika virus infection. Science 353:823–826

    Article  CAS  PubMed  Google Scholar 

  53. Sukupolvi-Petty S, Austin SK, Purtha WE, Oliphant T, Nybakken GE, Schlesinger JJ, Roehrig JT, Gromowski GD, Barrett AD, Fremont DH, Diamond MS (2007) Type- and subcomplex-specific neutralizing antibodies against domain III of dengue virus type 2 envelope protein recognize adjacent epitopes. J Virol 81:12816–12826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Teoh EP, Kukkaro P, Teo EW, Lim AP, Tan TT, Yip A, Schul W, Aung M, Kostyuchenko VA, Leo YS, Chan SH, Smith KG, Chan AH, Zou G, Ooi EE, Kemeny DM, Tan GK, Ng JK, Ng ML, Alonso S, Fisher D, Shi PY, Hanson BJ, Lok SM, Macary PA (2012) The structural basis for serotype-specific neutralization of dengue virus by a human antibody. Sci Transl Med 4:139ra83

    Article  CAS  PubMed  Google Scholar 

  55. Tsai WY, Lai CY, Wu YC, Lin HE, Edwards C, Jumnainsong A, Kliks S, Halstead S, Mongkolsapaya J, Screaton GR, Wang WK (2013) High-avidity and potently neutralizing cross-reactive human monoclonal antibodies derived from secondary dengue virus infection. J Virol 87:12562–12575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Tsai WY, Durbin A, Tsai JJ, Hsieh SC, Whitehead S, Wang WK (2015) Complexity of neutralizing antibodies against multiple dengue virus serotypes after heterotypic immunization and secondary infection revealed by in-depth analysis of cross-reactive antibodies. J Virol 89:7348–7362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wahala WM, Kraus AA, Haymore LB, Accavitti-Loper MA, De Silva AM (2009) Dengue virus neutralization by human immune sera: role of envelope protein domain III-reactive antibody. Virology 392:103–113

    Article  CAS  PubMed  Google Scholar 

  58. Wang Q, Yang H, Liu X, Dai L, Ma T, Qi J, Wong G, Peng R, Liu S, Li J, Li S, Song J, Liu J, He J, Yuan H, Xiong Y, Liao Y, Li J, Yang J, Tong Z, Griffin BD, Bi Y, Liang M, Xu X, Qin C, Cheng G, Zhang X, Wang P, Qiu X, Kobinger G, Shi Y, Yan J, Gao GF (2016) Molecular determinants of human neutralizing antibodies isolated from a patient infected with Zika virus. Sci Transl Med 8:369ra179

    Article  CAS  PubMed  Google Scholar 

  59. Yu IM, Zhang W, Holdaway HA, Li L, Kostyuchenko VA, Chipman PR, Kuhn RJ, Rossmann MG, Chen J (2008) Structure of the immature dengue virus at low pH primes proteolytic maturation. Science 319:1834–1837

    Article  CAS  PubMed  Google Scholar 

  60. Yu IM, Holdaway HA, Chipman PR, Kuhn RJ, Rossmann MG, Chen J (2009) Association of the pr peptides with dengue virus at acidic pH blocks membrane fusion. J Virol 83:12101–12107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zompi S, Harris E (2013) Original antigenic sin in dengue revisited. Proc Natl Acad Sci U S A 110:8761–8762

    Article  PubMed  PubMed Central  Google Scholar 

  62. Zompi S, Montoya M, Pohl MO, Balmaseda A, Harris E (2012) Dominant cross-reactive B cell response during secondary acute dengue virus infection in humans. PLoS Negl Trop Dis 6:e1568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zybert IA, Van Der Ende-Metselaar H, Wilschut J, Smit JM (2008) Functional importance of dengue virus maturation: infectious properties of immature virions. J Gen Virol 89:3047–3051

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC, USA

    Emily N. Gallichotte, Ralph S. Baric & Aravinda M. de Silva

  2. Department of Epidemiology, University of North Carolina School of Public Health, Chapel Hill, NC, USA

    Ralph S. Baric

Authors
  1. Emily N. Gallichotte
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ralph S. Baric
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aravinda M. de Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Aravinda M. de Silva .

Editor information

Editors and Affiliations

  1. Institute of Biochemistry, University of Lübeck, Lübeck, Germany

    Rolf Hilgenfeld

  2. Emerging Infectious Diseases Program, Duke-NUS Medical School Singapore, Singapore, Singapore

    Subhash G. Vasudevan

Discussion of Chapter 5 in Dengue and Zika: Control and Antiviral Treatment Strategies

Discussion of Chapter 5 in Dengue and Zika: Control and Antiviral Treatment Strategies

This discussion was held at the 2nd Advanced Study Week on Emerging Viral Diseases at Praia do Tofo, Mozambique.Transcribed by Hilgenfeld R and Vasudevan SG (Eds); approved by Dr. Aravinda de Silva.

  • Félix Rey: So you will be calling to question the fact that antibodies against Dengue would neutralize Zika?

  • Aravinda de Silva: No. But what I am saying is that in people who have recovered from Dengue – when they are in the late convalescent stage – they do not have circulating antibodies that neutralize Zika. I think in people who have secondary Dengue, when you isolate antibodies from their plasmablast, you can certainly find monoclonals that cross-neutralize Zika or even cross-protective against Zika, but it looks like they are not persisting into memory.

  • Félix Rey: How do you know that?

  • Aravinda de Silva: So in those people who have repeated Dengue infections – when we bleed them 6 months out from their infection, there is no neutralizing antibody against Zika. And I think that even in some of the other studies that are coming out to say that Zika and Dengue cross-neutralize, many of these studies have been done with samples within the first 3 or 4 weeks of an acute secondary Dengue infection. We know that one of the hallmarks of Dengue is that soon after they recover from Dengue during the convalescence period, there are very high levels of cross-neutralizing antibodies. This is even the case with primary Dengue infection, where we get a lot of cross-neutralizing antibodies during the convalescence period. But that is transient and it goes down and the response becomes more monotypic.

  • Paul Young: Can I just explore that further, because we have known that for a very long time. Why does the cross-neutralizing activity go down yet the serotype-specificity stays on. What is driving it?

  • Aravinda de Silva: So one of the obvious things is that IgM plays a role in cross-neutralization. But the second possibility is that there is an extrafollicular reaction. These cells are activated but they don’t get into the germinal centers and differenciate into plasmablast. They make a transcient antibody response but the cells do not persist. So a lot of the cross-neutralizing antibody is coming from extrafollicular reactions.

  • Paul Young: But why? I’m still a little confused. But I understand that’s why it happened. But why are those selectively lost?

  • Aravinda de Silva: Yes. That’s a good question. What is it about those epitopes that are getting lost, why are type-specific ones being maintained?

  • George Gao: Can we have a big picture for those three domains [of the envelope protein]? Which domain contributes the most to neutralizing antibodies? Can we say that now?

  • Aravinda de Silva: I think you have to really ask that question in the context of primary infection. In someone who has only had Dengue once or Zika once and no other flavivirus exposures, then what epitope is responsible for durable neutralization? We find in these cases there are defined epitopes responsible and they are the quaternary structure type-specific epitopes. But in someone with repeated infections – at least repeated Dengue infections – it could be ADE antibodies, it could be other antibodies that we haven’t discovered. But after natural infection, I don’t think that there is evidence that there are these long-lasting memory responses that are cross-neutralizing multiple flaviviruses.

  • Félix Rey: You would say that if it does not bind recombinant E protein, it has to bind some super-organization between dimers or something, but the recombinant E is monomeric unless you have it at a very high concentration.

  • Aravinda de Silva: Yes I agree that it could be binding dimers because the recombinant E protein test would not pick dimers.

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Gallichotte, E.N., Baric, R.S., de Silva, A.M. (2018). The Molecular Specificity of the Human Antibody Response to Dengue Virus Infections. In: Hilgenfeld, R., Vasudevan, S. (eds) Dengue and Zika: Control and Antiviral Treatment Strategies. Advances in Experimental Medicine and Biology, vol 1062. Springer, Singapore. https://doi.org/10.1007/978-981-10-8727-1_5

Download citation

Publish with us

Policies and ethics

Search

Navigation