Dengue Vaccine Development: Status and Future
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Leitthema Bundesgesundheitsbl 2020 · 63:40–44 Annelies Wilder-Smith1,2 https://doi.org/10.1007/s00103-019-03060-3 1 Department of Disease Control, London School of Hygiene and Tropical Medicine, London, UK Published online: 29 November 2019 2 Heidelberg Institute of Global Health, University of Heidelberg, Heidelberg, Germany © Springer-Verlag GmbH Deutschland, ein Teil von Springer Nature 2019 Dengue vaccine development: status and future Introduction Rationale for a dengue vaccine serotypes. As a tetravalent immune re- sponse is desired, when a mixture of all Dengue is globally the most frequent ar- According to modeling estimates, about four serotypes in a tetravalent live at- boviral disease, present in more than 128 50–100 million dengue cases occur every tenuated vaccine is given, each compo- countries in the tropics and subtropics year [10]. Te incidence of dengue has nent would need to independently result and poised to increase even further in increased greatly, with the number of in four different monotypic immune re- terms of incidence and continued geo- cases more than doubling every decade, sponses that are solid to each serotype. graphic expansion [1, 2], thereby also af- from 8.3 million (3.3–17.2 million) ap- Tis has, unfortunately, proven to be dif- fecting international travelers [3, 4]. Te parent cases in 1990 to 58.4 million ficult to achieve. four dengue virus serotypes belong to the (23.6–121.9 million) apparent cases in family of Flaviviridae and are genetically 2013, responsible for 1.14 million disabil- Dengue vaccine development distinct but still closely related. Infec- ity-adjusted life-years [10]. In dengue- tion with any of the four dengue virus endemic countries, approximately 10% Despite more than 30 years of efforts serotypes may be asymptomatic or may offebrileepisodesinchildrenandado- using various vaccine platforms includ- result in clinical manifestations ranging lescents are due to dengue, with a higher ing inactivated, DNA, and live vaccines, from a mild undifferentiated febrile syn- incidence in Asia (4.6 episodes per 100 only live attenuated vaccines have en- drome to severe dengue. Severe dengue person-years) compared to Latin Amer- tered phase 3 trials. Tree live attenu- is characterized by plasma leakage, hem- ica (2.9 episodes per 100 person-years); ateddenguevaccinesarenowinlate-stage orrhagic tendencies, organ failure, shock, the percentage of dengue infections re- development, with one candidate having and, occasionally,death[5]. Patientswith quiring hospitalization was 19% in Asia completed phase 3 trials including long- a second dengue infection with a dengue versus 11% in Latin America [11]. Many term follow-up of 5 years: CYD-TDV serotype different from the first are at dengue infections lead to hospitaliza- by Sanofi Pasteur, Lyon, France, with the increased risk for severe dengue. Te tions, which can overwhelm weak health trade name of Dengvaxia. hallmark of severe dengue is capillary carestructures, inparticularduringtimes leakage leading to shock and, if not man- of outbreaks. Given the unpredictability CYD-TDV dengue vaccine aged well, death. Te pathomechanism of outbreaks, the increasing magnitude of severe dengue is still poorly under- and frequency of such outbreaks, and CYD-TDV, a tetravalent live attenuated stood, although the most plausible hy- the current lack of highly effective and vaccine with a yellow fever 17D back- pothesisisantibody-dependentenhance- sustainable vector-control interventions, bone, is the first dengue vaccine to be li- ment in secondary infections [6]. Be- there is a clear indication for a dengue censed. Phase 3 trials revealed a vaccine cause effective vector-control measures vaccine for endemic populations. efficacy that depended on age, serosta- are not scalable or sustainable, commu- tus, and serotype but also showed a pop- nity-based approaches have led to mixed Challenges and hurdles in ulation-level benefit [13]. Interference results [7, 8], and promising novel strate- the development of dengue manifested by asymmetric immunolog- gies such as Wolbachia are still under de- vaccines ical responses to the mixtures of four velopment [9], a dengue vaccine would dengue vaccine viruses was recognized appear to be the best intervention. Te Severaldifficultieshave hampered the de- as a possible reason for this varied vac- purpose of this review is to elaborate on velopment of a dengue vaccine. One cine performance [14]. Post hoc retro- the first licensed dengue vaccine and re- challenge is the lack of an appropriate spective analyses of the long-term safety viewsecond-generationdenguevaccines, animal model and poor knowledge of data using a novel nonstructural protein both in the context of endemic popula- correlates, both for protection and dis- (NS1) antibody assay revealed an excess tions as well as international travelers. ease enhancement [12]. But the biggest risk of severe dengue in those who were hurdle is the interaction among the four seronegative at baseline, which means 40 Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz 1 · 2020 those who were dengue-naïve at the time cination screening strategy [22]. In May and phase 2 clinical trials, with high of administration of the first dose [15]. 2019, the U.S. Food and Drug Adminis- titers of neutralizing antibody to all four Tisincreasedriskwasobservedstart- tration (FDA) approved CYD-TDV for serotypes in nonhuman primates and ing from 30 months afer administration use in seropositive individuals 9–16 years humans, including cross-reactive T-cell- of the first dose. Te reasons for the of age living in endemic areas of the mediated responses that may be neces- excess cases are not fully understood, United States. Te European Medicines sary for broad protection against dengue but a plausible hypothesis is that Deng- Agency also endorsed the use of this vac- fever [25, 26]. Te vaccine efficacy is vaxia may trigger an immune response cine in seropositive individuals only. currently being tested in approximately to dengue in seronegative persons that Te World Health Organization has 20,000 recipients in phase 3 trials in predisposes them to a higher risk of se- published guidance on evaluating the Asia and Latin America using a two- vere disease, analogous to what is seen quality, safety, and efficacy of live at- dose regimen given 3 months apart. in natural secondary dengue infections. tenuated dengue tetravalent vaccines, Efficacy data for the first 18 months are In other words, it is plausible that Deng- including the need for baseline blood imminent. vaxia results in a “primary-like” silent samples from all participants for a priori Te other tetravalent live attenuated infection (which live attenuated vaccines analysis plans stratified by serostatus, as dengue vaccine was developed by the U.S. ofen elicit) [16]. A subsequent infection well as long-term follow-up for 3–5 years National Institutes of Health (NIH) and with the first true wild-type dengue virus afer the first dose [23]. Tis document is currently in a phase 3 trial in Brazil, but would then be a “secondary-like”, clin- will guide vaccine developers in trial itwasalsolicensedtoMerckandvarious ically more severe dengue illness. It is design and facilitate regulatory review other vaccine manufacturers for further not the vaccine itself that causes excess to enable broader public health rec- development outside Brazil. Tis vac- cases, but rather the vaccine’s induction ommendations for second-generation cine consists of three full-length dengue of an immune status that increases the dengue vaccines. Indeed, the phase 3 virus (DENV) serotypes attenuated by ′ risk that subsequent infections will be efficacy trials of the two second-genera- one or more deletions in the 3 untrans- more severe. tion dengue vaccines have incorporated lated region with DEN1Δ30, DEN2Δ30, Despite licensure in 20 dengue-en- all these requirements. Furthermore, and DEN4Δ30, while the fourth com- demic countries to date, CYD-TDV has there is a need for the development ponent is a chimeric virus in which the been introduced in only two subnational of standardized end points for vaccine prM and E proteins of DENV-2 replace public health programs: those in the and other interventional trials, includ- thoseofDENV-4intheDEN4Δ30back- Philippines and in Brazil. Afer a me- ing the need for subsequent validation ground[27]. Tisvaccineperformedwell dia release in November 2017 about the with prospective data sets [24]. Te and was safe in phase 1 and phase 2 tri- safety concern for seronegative persons, complexity of developing moderate dis- als [28]. A single dose induced robust the Philippines decided to suspend its ease research end points for dengue is tetravalent antibody and cellular T-cell program, while Brazil completed its pro- particularly challenging. responsesandresultedin100%efficacyin grambuthasnotexpandedit.Temedia ahumanchallengestudy[29]. Tecapac- release resulted in a major public outcry Second-generation dengue ity to elicit CD4+ cell responses closely in the Philippines, with heightened anx- vaccines mirrored those observed in a population iety and lack of confidence around vac- associated with natural immunity [30]. cines in general [17], which led to the Two live attenuated dengue vaccines are Teadvantagesofthesesecond-gener- subsequent resurgence of measles in the nowinphase3trials.Onesuchliveatten- ationdenguevaccinesaretheinclusionof Philippines, reflecting the global resur- uated dengue vaccine is being developed NS proteins of the dengue backbone and