Dengue: Update on Clinically Relevant Therapeutic Strategies and Vaccines

Dengue human infection model: introduction.

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Dengue is a mosquito-borne disease which is currently an expanding global health problem. The disease is caused by four closely related viruses, the dengue virus. There are no specific dengue therapeutics and prevention is currently limited to vector control measures. Development of an effective tetravalent dengue vaccine would therefore represent a major advance in the control of the disease and is considered a high public health priority. While a licensed dengue vaccine is not yet available, the scope and intensity of dengue vaccine development has increased dramatically in the last decade. The uniqueness of the dengue viruses and the spectrum of disease resulting from infection have made dengue vaccine development difficult. Several vaccine candidates are currently being evaluated in clinical studies. The candidate currently at the most advanced clinical development stage, a live-attenuated tetravalent vaccine based on chimeric yellow fever dengue virus, has progressed to phase III efficacy studies. Several other live-attenuated vaccines, as well as subunit, DNA and purified inactivated vaccine candidates, are at earlier stages of clinical development. Additional technological approaches, such as virus-vectored and virus-like particle-based vaccines, are under evaluation in preclinical studies.

ABSTRACTIntroduction: Dengue is an emerging viral disease that affects the human population around the globe. Recent advancements in dengue virus research have opened new avenues for the development of vaccines against dengue. The development of a vaccine against dengue is a challenging task because any of the four serotypes of dengue viruses can cause disease. The development of a dengue vaccine aims to provide balanced protection against all the serotypes. Several dengue vaccine candidates are in the developmental stages such as inactivated, live attenuated, recombinant subunit, and plasmid DNA vaccines.Area covered: The authors provide an overview of the progress made in the development of much needed dengue vaccines. The authors include their expert opinion and their perspectives for future developments.Expert opinion: Human trials of a live attenuated tetravalent chimeric vaccine have clearly demonstrated its potential as a dengue vaccine. Other vaccine candidate molecules such as DENVax, a recombinant chimeric vaccine andTetraVax, are at different stages of development at this time. The authors believe that the novel strategies for testing and improving the immune response of vaccine candidates in humans will eventually lead to the development of a successful dengue vaccine in future.

Long-term safety assessment of live attenuated tetravalent dengue vaccines: Deliberations from a WHO technical consultation

Dengue is among the most prevalent and important arbovirus diseases of humans. To effectively control this rapidly spreading disease, control of the vector mosquito and a safe and efficacious vaccine are critical. Despite considerable efforts, the development of a successful vaccine has remained elusive. Multiple factors have complicated the creation of a successful vaccine, not the least of which are the complex, immune-mediated responses against four antigenically distinct serotypes necessitating a tetravalent vaccine providing long-lasting protective immunity. Despite the multiple impediments, there are currently many promising vaccine candidates in preclinical and clinical development. Here, the recent advances in dengue virus vaccine development are reviewed and the challenges associated with the use of these vaccines as a public health tool are briefly discussed.

Dengue has become a major public health problem over the world,and there are no specific dengue therapeutics available so far.At present,several candidate vaccines have entered clinical trials.The second generation dengue vaccines may arise from the present preclinical candidates.In this review,technological approaches to dengue vaccine are described,specifically focusing on the preclinical vaccines. Key words: Dengue virus; Domain Ⅲ protein; Dengue vaccines

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Despite 70 years of research that has intensified in the past decade, a safe and efficacious dengue vaccine has yet to be available. In addition to the expected challenges such as identifying immune correlates of protection, the dengue vaccine field has faced additional hurdles including the necessity to design a tetravalent formulation and the risk of antibody-mediated disease enhancement. Nevertheless, tetravalent live attenuated vaccine candidates have reached efficacy trials and demonstrated some benefit, despite imbalanced immunogenicity and incomplete protection against the four serotypes. Meanwhile, the development of sub-unit dengue vaccines has gained momentum. As the target of most of the neutralizing antibodies so far reported, the virus envelope E protein has been the focus of much effort and represents the leading dengue sub-unit vaccine candidate. However, its notorious poor immunogenicity has prompted the development of innovative approaches to make E-derived constructs part of the second generation dengue vaccines portfolio.

Dengue is considered the most important emerging, human arboviruses, with worldwide distribution in the tropics. Unfortunately, there are no licensed dengue vaccines available or specific anti-viral drugs. The development of a dengue vaccine faces unique challenges. The four serotypes co-circulate in endemic areas, and pre-existing immunity to one serotype does not protect against infection with other serotypes, and actually may enhance severity of disease. One foremost constraint to test the efficacy of a dengue vaccine is the lack of an animal model that adequately recapitulates the clinical manifestations of a dengue infection in humans. In spite of this limitation, non-human primates (NHP) are considered the best available animal model to evaluate dengue vaccine candidates due to their genetic relatedness to humans and their ability to develop a viremia upon infection and a robust immune response similar to that in humans. Therefore, most dengue vaccines candidates are tested in primates before going into clinical trials. In this article, we present a comprehensive review of published studies on dengue vaccine evaluations using the NHP model, and discuss critical parameters affecting the usefulness of the model. In the light of recent clinical data, we assess the ability of the NHP model to predict immunological parameters of vaccine performances in humans and discuss parameters that should be further examined as potential correlates of protection. Finally, we propose some guidelines toward a more standardized use of the model to maximize its usefulness and to better compare the performance of vaccine candidates from different research groups.

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BackgroundDengue virus (DENV) causes up to 390 million infections yearly, of which 96 million are clinically manifested.Approximately 500,000 people with severe dengue require hospitalization each year and there are at least 25,000 deaths among children from Asian and Latin American countries.DENV is endemic in more than 100 countries.Chemical and biological controls have been implemented in targeting Aedes aegypti and Aedes albopictus mosquitoes, but these control practices failed to stem the dengue transmission.As a result, dengue vaccine has become a potential option recommended by WHO to be implemented in dengue endemic regions.Currently, several vaccine candidates are being evaluated in clinical studies.Amongst the vaccine candidates, live attenuated vaccines (LAV) are the furthest along the development pipeline.The most advanced vaccine, CYD-TDV (Dengvaxia) has been licensed in 19 countries.Several other live attenuated vaccines, as well as DNA, subunit, inactivated virus, viral-vectored and subunit-based vaccines, are under development and evaluation in preclinical or clinical studies.Each of the liveattenuated vaccine candidates targets on molecular determinants of virulence in DENV, with the emphasis on attenuating the DENV and inducing a balanced tetravalent immune response against all the four dengue serotypes. AimsThis review presents several different vaccine approaches and their construction strategies, providing an insight into the development of future dengue vaccines such as live attenuated vaccines, DNA vaccines, sub-unit protein vaccines and viral vectored vaccines. MethodsRecent development status of dengue vaccine candidates was reviewed based on the published data and an online registry for clinical trials (ClinicalTrials.gov)which is run by the U.S.

Recent discordance between measured levels of serotypes of dengue virus neutralizing antibody and clinical outcomes suggests a need to reevaluate the process of prescreening dengue vaccine candidates to better predict their clinical benefit before initiation of large-scale human vaccine trials. In the absence of a reliable animal model for dengue, a human dengue virus challenge model (ie, a controlled live dengue virus infectious challenge study) may prove useful and timely to elucidate mechanisms that underlie protection (as well as virulence), thus facilitating down-selection of vaccine candidates before beginning advanced field trials. Dengue challenge studies were safely used in prior decades to study the vector biology, clinical spectrum of illness, and reactogenicity of candidate live dengue virus vaccines of uncertain attenuation. Redeveloping the human dengue challenge model following current regulatory guidance, good manufacturing practice, and good clinical practice could streamline and accelerate vaccine development by offering a time- and resource-efficient method to evaluate the safety and potential efficacy of dengue vaccine and therapeutic candidates. In this article, the development of such a challenge model and its subsequent application is summarized from 2 recent reports.

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