Advertisement

Dengue vaccine development: status and future

  • Annelies Wilder-SmithEmail author
Leitthema

Abstract

Dengue, the most common arbovirus, represents an increasingly significant cause of morbidity worldwide, including in travelers. After decades of research, the first dengue vaccine was licensed in 2015: CYD-TDV, a tetravalent live attenuated vaccine with a yellow fever vaccine backbone. Recent analyses have shown that vaccine performance is dependent on serostatus. In those who have had a previous dengue infection, i.e., who are seropositive, the efficacy is high and the vaccine is safe. However, in seronegative vaccinees, approximately 3 years after vaccination the vaccine increases the risk of developing severe dengue when the individual experiences a natural dengue infection.

The World Health Organization recommends that this vaccine be administered only to seropositive individuals. Current efforts are underway to develop rapid diagnostic tests to facilitate prevaccination screening. Two second-generation dengue vaccine candidates, both also live attenuated recombinant vaccines in late-stage development, may not present the same limitations because of differences in the backbone used, but results of phase 3 trials need to be available before firm conclusions can be drawn.

Dengue is increasingly frequent in travelers, but the only licensed dengue vaccine to date can be used only in seropositive individuals. However, the vast majority of travelers are seronegative. Furthermore, the primary series of three doses given 6 months apart renders this vaccine difficult in the travel medicine context.

Keywords

Severe dengue CYD-TDV Antibody-dependent enhancement Travelers Live attenuated chimeric dengue vaccine 

Entwicklung von Impfstoffen gegen Dengue: aktueller Stand und Zukunft

Zusammenfassung

Das Dengue-Virus, das am meisten verbreitete Arbovirus, stellt weltweit eine zunehmende Ursache für Morbidität dar, auch bei Reisenden. Nach jahrzehntelanger Forschung wurde 2015 der erste Impfstoff gegen Dengue-Fieber zugelassen: CYD-TDV, ein tetravalenter, attenuierter Lebendimpfstoff auf Basis des Gelbfieber-Impfvirus („backbone“). Neuste Analysen haben gezeigt, dass die Performance des Impfstoffs vom Serostatus abhängig ist. Bei Menschen, die bereits eine Dengue-Infektion hatten und seropositiv sind, ist die Wirksamkeit hoch und der Impfstoff sicher. Bei seronegativen Impflingen erhöht der Impfstoff jedoch im Fall einer nachfolgenden Dengue-Wildvirusinfektion das Risiko für eine schwere Dengue-Erkrankung etwa 3 Jahre nach der Impfung. Die Weltgesundheitsorganisation empfiehlt daher, den Impfstoff nur an seropositive Menschen zu verabreichen. Derzeit wird intensiv an der Entwicklung von Schnelltests gearbeitet, um das Screening vor der Impfung zu erleichtern. Zwei Dengue-Impfstoffkandidaten der zweiten Generation, beide ebenfalls attenuierte rekombinante Lebendimpfstoffe, befinden sich in der Spätphase der Entwicklungspipeline und könnten aufgrund der Unterschiede der verwendeten „backbones“ nicht dieselben Limitierungen aufweisen; es müssen aber die Ergebnisse der Phase-3-Studien abgewartet werden, um dies sicher beurteilen zu können. Dengue-Fieber tritt immer häufiger bei Reisenden auf. Die überwiegende Mehrheit der Reisenden ist jedoch seronegativ, weshalb bei ihnen der bisher einzige zugelassene Impfstoff gegen Dengue-Fieber nicht eingesetzt werden kann. Darüber hinaus sind für die Grundimmunisierung drei Impfdosen nach dem Schema 0‑6-12 Monate erforderlich, wodurch der Einsatz dieses Impfstoffes im reisemedizinischen Kontext schwierig ist.

Schlüsselwörter

Schweres Dengue-Fieber CYD-TDV Antibody-dependent enhancement Reisende Attenuierter chimärer Dengue-Lebendimpfstoff 

Notes

Compliance with ethical guidelines

Conflict of interest

A. Wilder-Smith serves as a consultant to the World Health Organization with regard to dengue vaccines. The views expressed in this article are those of the author and do not necessarily represent the decisions or policies of the World Health Organization.

For this article no studies with human participants or animals were performed by any of the authors.

References

  1. 1.
    Wilder-Smith A, Gubler DJ, Weaver SC, Monath TP, Heymann DL, Scott TW (2017) Epidemic arboviral diseases: priorities for research and public health. Lancet Infect Dis 17(3):e101–e106.  https://doi.org/10.1016/S1473-3099(16)30518-7 CrossRefPubMedGoogle Scholar
  2. 2.
    Jentes ES, Lash RR, Johansson MA, Sharp TM, Henry R, Brady OJ et al (2016) Evidence-based risk assessment and communication: a new global dengue-risk map for travellers and clinicians. J Travel Med.  https://doi.org/10.1093/jtm/taw062 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Masyeni S, Yohan B, Somia IKA, Myint KSA, Sasmono RT (2018) Dengue infection in international travellers visiting Bali, Indonesia. J Travel Med.  https://doi.org/10.1093/jtm/tay061 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Riddell A, Babiker ZO (2017) Imported dengue fever in East London: a 6-year retrospective observational study. J Travel Med.  https://doi.org/10.1093/jtm/tax015 CrossRefPubMedGoogle Scholar
  5. 5.
    Wilder-Smith A, Ooi EE, Horstick O, Wills B (2019) Dengue. Lancet 393(10169):350–363.  https://doi.org/10.1016/S0140-6736(18)32560-1 CrossRefPubMedGoogle Scholar
  6. 6.
    Katzelnick LC, Gresh L, Halloran ME, Mercado JC, Kuan G, Gordon A et al (2017) Antibody-dependent enhancement of severe dengue disease in humans. Science 358(6365):929–932.  https://doi.org/10.1126/science.aan6836 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Andersson N, Arostegui J, Nava-Aguilera E, Harris E, Ledogar RJ (2017) Camino Verde (The Green Way): evidence-based community mobilisation for dengue control in Nicaragua and Mexico: feasibility study and study protocol for a randomised controlled trial. BMC Public Health.  https://doi.org/10.1186/s12889-017-4289-5 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Kittayapong P, Olanratmanee P, Maskhao P, Byass P, Logan J, Tozan Y et al (2017) Mitigating diseases transmitted by aedes mosquitoes: a cluster-randomised trial of permethrin-impregnated school uniforms. PLoS Negl Trop Dis 11(1):e5197–28103255.  https://doi.org/10.1371/journal.pntd.0005197 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Ritchie SA (2018) Wolbachia and the near cessation of dengue outbreaks in Northern Australia despite continued dengue importations via travellers. J Travel Med.  https://doi.org/10.1093/jtm/tay084 CrossRefPubMedGoogle Scholar
  10. 10.
    Stanaway JD, Shepard DS, Undurraga EA, Halasa YA, Coffeng LE, Brady OJ et al (2016) The global burden of dengue: an analysis from the Global Burden of Disease Study. Lancet Infect Dis.  https://doi.org/10.1016/S1473-3099(16)00026-8 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    L’Azou M, Moureau A, Sarti E, Nealon J, Zambrano B, Wartel TA et al (2016) Symptomatic Dengue in children in 10 asian and latin American countries. N Engl J Med 374(12):1155–1166.  https://doi.org/10.1056/NEJMoa1503877 CrossRefPubMedGoogle Scholar
  12. 12.
    Katzelnick LC, Harris E (2017) Participants in the summit on Dengue immune correlates of P. Immune correlates of protection for dengue: state of the art and research agenda. Vaccine 35(36):4659–4669.  https://doi.org/10.1016/j.vaccine.2017.07.045 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Hadinegoro SR, Arredondo-Garcia JL, Capeding MR, Deseda C, Chotpitayasunondh T, Dietze R et al (2015) Efficacy and long-term safety of a dengue vaccine in regions of endemic disease. N Engl J Med.  https://doi.org/10.1056/NEJMoa1506223 CrossRefPubMedGoogle Scholar
  14. 14.
    Guy B, Barban V, Mantel N, Aguirre M, Gulia S, Pontvianne J et al (2009) Evaluation of interferences between dengue vaccine serotypes in a monkey model. Am J Trop Med Hyg 80(2):302–311CrossRefGoogle Scholar
  15. 15.
    Sridhar S, Luedtke A, Langevin E, Zhu M, Bonaparte M, Machabert T et al (2018) Effect of dengue serostatus on Dengue vaccine safety and efficacy. N Engl J Med.  https://doi.org/10.1056/NEJMoa1800820 CrossRefPubMedGoogle Scholar
  16. 16.
    Wilder-Smith A, Hombach J, Ferguson N, Selgelid M, O’Brien K, Vannice K et al (2018) Deliberations of the strategic advisory group of experts on immunization on the use of CYD-TDV dengue vaccine. Lancet Infect Dis.  https://doi.org/10.1016/S1473-3099(18)30494-8 CrossRefPubMedGoogle Scholar
  17. 17.
    Larson HJ, Hartigan-Go K, de Figueiredo A (2019) Vaccine confidence plummets in the Philippines following dengue vaccine scare: why it matters to pandemic preparedness. Hum Vaccin Immunother 15(3):625–627.  https://doi.org/10.1080/21645515.2018.1522468 CrossRefPubMedGoogle Scholar
  18. 18.
    Leong WY (2018) Measles cases hit record high in Europe in 2018. J Travel Med.  https://doi.org/10.1093/jtm/tay080 CrossRefPubMedGoogle Scholar
  19. 19.
    Massad E (2018) Measles and human movement in Europe. J Travel Med.  https://doi.org/10.1093/jtm/tay091 CrossRefPubMedGoogle Scholar
  20. 20.
    Cousins S (2019) Measles: a global resurgence. Lancet Infect Dis 19(4):362–363.  https://doi.org/10.1016/S1473-3099(19)30129-X CrossRefPubMedGoogle Scholar
  21. 21.
    Dengue vaccine (2018) WHO position paper-September 2018. Wkly Epidemiol Rec 93:457–476Google Scholar
  22. 22.
    Wilder-Smith A, Smith PG, Luo R, Kelly-Cirino C, Curry D, Larson H et al (2019) Pre-vaccination screening strategies for the use of the CYD-TDV dengue vaccine: A meeting report. Vaccine.  https://doi.org/10.1016/j.vaccine.2019.07.016 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Vannice KS, Wilder-Smith A, Barrett ADT, Carrijo K, Cavaleri M, de Silva A et al (2018) Clinical development and regulatory points for consideration for second-generation live attenuated dengue vaccines. Vaccine 36(24):3411–3417.  https://doi.org/10.1016/j.vaccine.2018.02.062 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Jaenisch T, Hendrickx K, Erpicum M, Agulto L, Tomashek KM, Dempsey W et al (2018) Development of standard clinical endpoints for use in dengue interventional trials: introduction and methodology. BMC Med Res Methodol 18(1):134.  https://doi.org/10.1186/s12874-018-0601-z CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Osorio JE, Wallace D, Stinchcomb DT (2016) A recombinant, chimeric tetravalent dengue vaccine candidate based on a dengue virus serotype 2 backbone. Expert Rev Vaccines 15(4):497–508.  https://doi.org/10.1586/14760584.2016.1128328 CrossRefPubMedGoogle Scholar
  26. 26.
    Saez-Llorens X, Tricou V, Yu D, Rivera L, Jimeno J, Villarreal AC et al (2018) Immunogenicity and safety of one versus two doses of tetravalent dengue vaccine in healthy children aged 2–17 years in Asia and Latin America: 18-month interim data from a phase 2, randomised, placebo-controlled study. Lancet Infect Dis 18(2):162–170.  https://doi.org/10.1016/S1473-3099(17)30632-1 CrossRefPubMedGoogle Scholar
  27. 27.
    Kirkpatrick BD, Durbin AP, Pierce KK, Carmolli MP, Tibery CM, Grier PL et al (2015) 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. J Infect Dis 212(5):702–710.  https://doi.org/10.1093/infdis/jiv082 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Whitehead SS (2016) Development of TV003/TV005, a single dose, highly immunogenic live attenuated dengue vaccine; what makes this vaccine different from the Sanofi-Pasteur CYD vaccine? Expert Rev Vaccines 15(4):509–517.  https://doi.org/10.1586/14760584.2016.1115727 CrossRefPubMedGoogle Scholar
  29. 29.
    Weiskopf D, Angelo MA, Bangs DJ, Sidney J, Paul S, Peters B et al (2015) The human CD8+ T cell responses induced by a live attenuated tetravalent dengue vaccine are directed against highly conserved epitopes. J Virol 89(1):120–128.  https://doi.org/10.1128/JVI.02129-14 CrossRefPubMedGoogle Scholar
  30. 30.
    Angelo MA, Grifoni A, O’Rourke PH, Sidney J, Paul S, Peters B et al (2017) Human CD4+ T cell responses to an attenuated tetravalent Dengue vaccine parallel those induced by natural infection in magnitude, HLA restriction, and antigen specificity. J Virol.  https://doi.org/10.1128/JVI.02147-16 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Halstead S, Wilder-Smith A (2019) Severe dengue in travellers: pathogenesis, risk and clinical management. J Travel Med.  https://doi.org/10.1093/jtm/taz062 CrossRefPubMedGoogle Scholar
  32. 32.
    Streit JA, Yang M, Cavanaugh JE, Polgreen PM (2011) Upward trend in Dengue incidence among hospitalized patients, United States. Emerg Infect Dis 17(5):914–916.  https://doi.org/10.3201/eid1705.101023 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Rocklov J, Lohr W, Hjertqvist M, Wilder-Smith A (2014) Attack rates of dengue fever in Swedish travellers. J INFECT DIS 46(6):412–417.  https://doi.org/10.3109/00365548.2014.887222 CrossRefGoogle Scholar
  34. 34.
    Neumayr A, Munoz J, Schunk M, Bottieau E, Cramer J, Calleri G et al (2017) Sentinel surveillance of imported dengue via travellers to Europe 2012 to 2014: tropnet data from the denguetools research initiative. Euro Surveill.  https://doi.org/10.2807/1560-7917.ES.2017.22.1.30433 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Wilder-Smith A, Boggild AK (2018) Sentinel surveillance in travel medicine: 20 years of geosentinel publications (1999–2018). J Travel Med.  https://doi.org/10.1093/jtm/tay139 CrossRefPubMedGoogle Scholar
  36. 36.
    Leder K, Torresi J, Libman MD, Cramer JP, Castelli F, Schlagenhauf P et al (2013) GeoSentinel surveillance of illness in returned travelers, 2007–2011. Ann Intern Med 158(6):456–468.  https://doi.org/10.7326/0003-4819-158-6-201303190-00005 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Chen LH, Leder K, Barbre KA, Schlagenhauf P, Libman M, Keystone J et al (2018) Business travel-associated illness: a GeoSentinel analysis. J Travel Med.  https://doi.org/10.1093/jtm/tax097 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Neuberger A, Turgeman A, Lustig Y, Schwartz E (2016) Dengue fever among Israeli expatriates in Delhi, 2015: implications for dengue incidence in Delhi, India. J Travel Med.  https://doi.org/10.1093/jtm/taw003 CrossRefPubMedGoogle Scholar
  39. 39.
    Leder K, Tong S, Weld L, Kain KC, Wilder-Smith A, von Sonnenburg F et al (2006) Illness in travelers visiting friends and relatives: a review of the GeoSentinel Surveillance Network. Clin Infect Dis 43(9):1185–1193.  https://doi.org/10.1086/507893 CrossRefPubMedGoogle Scholar
  40. 40.
    Diagne CT, Barry MA, Ba Y, Faye O, Sall AA (2019) Dengue epidemic in Touba, Senegal: implications for the grand Magal pilgrimage for travelers. J Travel Med.  https://doi.org/10.1093/jtm/tay123 CrossRefPubMedGoogle Scholar
  41. 41.
    Poddighe D, Bonomelli I, Giardinetti S, Nedbal M, Bruni P (2016) Paediatric Dengue Fever diagnosed through parents’ epidemiologic report and preventive strategy during the acute phase of infection. J Travel Med.  https://doi.org/10.1093/jtm/tav013 CrossRefPubMedGoogle Scholar
  42. 42.
    Rabinowicz S, Schwartz E (2017) Morbidity among Israeli paediatric travellers. J Travel Med.  https://doi.org/10.1093/jtm/tax062 CrossRefPubMedGoogle Scholar
  43. 43.
    Tozan Y, Headley TY, Sewe MO, Schwartz E, Shemesh T, Cramer JP et al (2019) A prospective study on the impact and out-of-pocket costs of dengue illness in international travelers. Am J Trop Med Hyg 100(6):1525–1533.  https://doi.org/10.4269/ajtmh.18-0780 CrossRefPubMedGoogle Scholar
  44. 44.
    Steffen R (2018) Travel vaccine preventable diseases-updated logarithmic scale with monthly incidence rates. J Travel Med.  https://doi.org/10.1093/jtm/tay046 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Angelo KM, Kozarsky PE, Ryan ET, Chen LH, Sotir MJ (2017) What proportion of international travellers acquire a travel-related illness? A review of the literature. J Travel Med.  https://doi.org/10.1093/jtm/tax046 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Torresi J, Steffen R (2017) Redefining priorities towards graded travel-related infectious disease research. J Travel Med.  https://doi.org/10.1093/jtm/tax064 CrossRefPubMedGoogle Scholar
  47. 47.
    Wilder-Smith A (2018) Serostatus-dependent performance of the first licensed dengue vaccine: implications for travellers. J Travel Med.  https://doi.org/10.1093/jtm/tay057 CrossRefPubMedGoogle Scholar
  48. 48.
    Wilder-Smith A (2019) The first licensed dengue vaccine: can it be used in travelers? Curr Opin Infect Dis 32(5):394–400.  https://doi.org/10.1097/QCO.0000000000000573 CrossRefPubMedGoogle Scholar
  49. 49.
    Durbin AP, Gubler DJ (2019) What is the prospect of a safe and effective dengue vaccine for travelers? J Travel Med.  https://doi.org/10.1093/jtm/tay153 CrossRefPubMedGoogle Scholar
  50. 50.
    Goodyer L, Schofield S (2018) Mosquito repellents for the traveller: does picaridin provide longer protection than DEET? J Travel Med 25(suppl_1):S10–S15.  https://doi.org/10.1093/jtm/tay005 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Deutschland, ein Teil von Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Disease ControlLondon School of Hygiene and Tropical MedicineLondonUK
  2. 2.Heidelberg Institute of Global HealthUniversity of HeidelbergHeidelbergGermany

Personalised recommendations