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Dengue is a self limiting systemic infection caused by any one of four dengue virus serotypes and is transmitted between humans by mosquitoes of the genus Aedes aegypti. Infection with any one of the 4 serotypes can produce a broad spectrum of clinical illness, including asymptomatic infection, mild febrile illness, classic Dengue Fever (DF), the fatal dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) . In recent years, the cumulative disease burden caused by dengue virus has reached an unprecedented level with a sharp increase in the size of at risk population . Today 40% of the world's population (2.6 billion) is estimated to be at risk, close to 75% of this exposed global population reside in the Asia-Pacific region . The rapidly increasing global dengue footprint is a public health challenge that presents complex medical, economical and ecological problems not only to dengue endemic countries but also new areas due to re-emergence and spread of Aedes aegypti mosquitoes . Although dengue virus infection is currently unmet by efficient vector-control strategies, specific treatment agents or licensed vaccines, there is a global consensus on the urgent need for effective treatment therapy and safe dengue vaccines not only for the inhabitants of dengue endemic areas, but also for travelers or individuals deployed to work in endemic areas . Is dengue vaccine development approaching the finishing lane? This paper seeks to discuss the current epidemiology of Dengue fever, available preventive methods, the current status of dengue vaccine and challenges faced in its development.
Present dengue epidemiology
Dengue viruses have increased exponentially with intensified research efforts . Over the past five decades, the global incidence and geographical distribution of dengue fever has increased 30 folds making it the most rapidly spreading vector-borne viral disease in the world (Fig 1). Today, Dengue fever threatens almost half of the world's population and causes an estimated ~ 50-100 million new infections annually in more than 100 endemic countries, of which half a million progress to dengue hemorrhagic fever, and approximately 24,000 cases result in death majority of which occur among children below the age of 15 . Annually, an estimated 264 disability adjusted life years per million populations per year are lost ; at an estimated cost of US $ 514 and US$ 1394 for ambulatory and hospitalized cases respectively, especially among poor populations . However, the true values are probably much worse since severe underreporting and misclassification of dengue cases have been reported . Prior to 1970, dengue fever was predominantly reported in less than 10 countries, today the disease is a public health concern in more than 100 endemic countries mainly across Asia, the Pacific, the Americas, Africa, and the Caribbean and the number continues to increase . Furthermore, some isolated cases have also emerged in Texas, Croatia, France and Florida- Hawaii outbreak in 2001.
Figure 1: Average annual number of cases of DF/DHF reported to World Health Organization
Determinant factors of the current global dengue epidemiology trends comprise, but are not restricted to: expanding geographical distribution of Aedes aegypti mosquitoes due to global warming, demographic changes including population growth, economic growth in tropical/subtropical countries and land utilization patterns; increased urbanization and density as a result of rural to urban movement, increased migration of people, animals, merchandise, vectors and pathogens due to modern transportation; and changes in public health infrastructures and policies . With the increasingly global spread of dengue, practicing physicians in Europe, Australia, temperate North America, and Japan are more likely than ever to see returning travelers with dengue infection .
Current control and preventive measures against dengue
Today, dengue fever/DHF control is mainly dependent on the control of Aedes aegypti mosquitoes, since no vaccine is available for the prevention of dengue infectivity and there are no specific agents for its treatment . Currently, symptomatic treatment in the form of analgesic, antipyretics and body fluid management is provided to patients . Prevention and control activities are currently focusing on two main strategies; the first is vector control strategies, which include environmental management to remove mosquito breeding sites through improved water supply, clearing drainage systems, mosquito proofing of overhead tanks; biological control by using fish, bacteria and Cyclopods, and chemical control through insecticide spraying, chemical larviciding, space sprays; the second is personal protection strategies; mainly through the use of protective clothing, mats, coils and aerosol and repellants .
Dengue vaccines: prospects and challenges
Although dengue as a virus was first discovered more than 70 years ago, a licensed vaccine against dengue is still elusive and even today only "candidate" dengue vaccines exist . However, effective vaccines against Yellow fever and Japanese encephalitis which belong to the same family of flaviviruses are currently available . The existence of effective vaccines against other flaviviruses has made scientists to believe in the feasibility of a dengue vaccine .
Is a vaccine for dengue feasible?
Theoretically, development of an effective vaccine against dengue viruses is feasible . Dengue fever is an acute self limiting disease in which replication of the virus is controlled after the initial 3-7 days of viraemia . Studies have indicated that individuals once infected with one serotype of dengue virus develop immunity to re-infection with the same serotype; furthermore short life limited cross immunity has been reported in small percentage populations . Development of a safe, effective and affordable dengue vaccine would therefore represent a major progress in the control of the dengue disease .
What is the current status of dengue vaccine development?
Today, no licensed dengue vaccine is available . Many attempts over the past 60 years to develop a vaccine against dengue have been unsuccessful, only a few candidates could overcome the unusual interaction between human immune system and dengue virus pathogenesis . However, in 2001 WHO undertook an initiative to fasten progress towards dengue vaccine development by bringing together different phase III trial centers under a single entity of pediatric dengue vaccine initiative (PDVI) . As a result, several vaccine candidates are currently at different stages of preclinical or clinical development . Dengue vaccine development today focuses on the creation of a tetravalent vaccine aimed at providing lasting protection against all four dengue virus serotypes but also sufficiently attenuating so as not to cause unacceptable pathogenicity or fail to induce effective immunity , this is key considering the specific complexity of dengue virus known as antibody dependant enhancement (ADE), a phenomenon which many researchers in the field of dengue are reluctant to acknowledge . Indeed the current WHO recommendations on dengue vaccine clinical trials does not include any specific guidelines on ADE, moreover WHO considers ADE a theoretical concern that is yet to be scientifically approved thus should not interfere with current dengue vaccine development . This opinion is also echoed by Claire Huang, a senior infectious disease researcher at CDC's division for vector diseases who has been working for several years on developing an effective dengue vaccine and is currently working on the third dengue vaccine candidate (Chimaeric vaccine) being developed by Inviragen .
At present, the most advanced vaccine candidates consist of tetravalent assortment of live attenuated viruses representing each serotype . Varied attenuation mechanisms have been used to develop the three leading candidates . The candidate presently at the most advanced clinical development stage is a live attenuated tetravalent dengue vaccine developed by Sanofi Pasteur (CYD-TDV), which is under evaluation in phase II and III clinical studies; second candidate is a combination of defined chimeras and mutations/deletions, developed by NIH and third candidate involves chimerization with dengue 2 PDK53 virus, attenuated through cell culture passage, developed by Inviragen . Future licensure of any dengue vaccine candidate will depend on the assessment of quality, safety and efficacy data by national regulatory agencies . The CYD-TDV vaccine recently reported a non-statistically significant result of 30.2% (95% confidence interval: -13.4% to 56.6%) in a phase II b clinical trial in Thailand thus an inconclusive vaccine efficacy . The vaccine protected against three of four serotypes, coincidentally it failed to protect against serotype 2 which was the most predominant strain in that region during the vaccine trial . This non-significant result has fueled an intense urge to conduct further larger trials in additional locations with results expected in 2014 . Interestingly, despite the inconclusive vaccine efficacy results, Sanofi Pasteur remains hopeful in their quest to introduce a vaccine to counter dengue infection into the market with the first commercial batches expected to be available in 2015 . However, based on currently available evidence, WHO believes that the public health value of CYD-TDV remains to be demonstrated, and further studies are still required . The other two Chimaeric vaccine candidates being developed by NIH and Inviragen have recently shown promising results in their phase IIa trials and are therefore proceeding to phase IIb .
What are the challenges to vaccine development?
Firstly, the mechanism of protective immunity against dengue is yet to be fully understood. Although there is considerable evidence for a major role of antibody mediated DENV neutralization in protection against dengue infection, it is unclear what quantity of neutralizing antibody is needed for protective immunity . Secondly, infection by any one of the four dengue virus serotypes has been shown to confer long-lasting protection against a similar serotype re-infection, but only a short term protection against a secondary heterotypic infection by any of the three heterogonous serotypes . Moreover, subsequent infection with a different dengue virus serotype has been associated with an increased risk of severe dengue disease . This is a challenge because there can be more than one dengue serotype in circulation at a given time .This and other observations made in studies of the pathogenesis of dengue viruses suggest a specific immune complex known as antibody enhancement of dengue disease . Further challenges are also caused by the lack of an adequate animal disease model for dengue research; ordinary mice do not display significant viraemia or disease when infected with DENV isolates and the resulting doubt around correlates of protection . In spite of these challenges, vaccine development has made incredible evolution in recent times, the current dengue vaccine pipeline is not only advanced, but also varied and overall promising .
A different angle
As the search for dengue vaccine intensifies so should other non vaccine strategies aimed at containing dengue disease . Despite the potential spread of dengue due expanding geographical habitat of Aedes aegypti mosquitoes, more efforts are still focused on developing countries especially the dengue belt rather than a global perspective . Emphasis should be on better dengue diagnostics and reporting, effective and sustainable mosquito vector control strategies and comprehensive guidelines for disease management . Because of the difficulties faced in introducing vaccines to developing countries, some experts are skeptical that a vaccine might not be the solution to the dengue problem . For example if the vaccine will require booster doses, most people in endemic areas will not be able to afford the extra doses . Dengue imposes great demand on health care systems, although severe dengue occurs in only a small percentage of dengue infections, early detection of high-risk patients remains intricate and patients with uncomplicated infections are frequently hospitalized for observation . In the absence of specific treatment agents for dengue patients, doctors have resolved an art of treating the severe disease by compensating for lost fluids . The challenge being to sustain a patient's blood pressure at a level enough to circulate blood without bursting the circulatory system, thus causing life-threatening edemas that inundate vital organs such as brain or lungs . The inability to halt the spread of dengue is a shame, despite the advanced research; dengue is a disease of poor sanitation and water systems, uncontrolled urbanization, and a lack of basic knowledge on how the disease spreads . Ending dengue by immunization without mosquito controls and other preventive strategies will indicate a failure in our public health efforts .
The field of dengue research has been revitalized over the past decade, triggered by the growing recognition of the burden of dengue as a disease coupled with the prospect of an effective dengue vaccine. However, with the current incomplete understanding of dengue virus pathogenesis, we might as well still be in the starting lane of an effective vaccine development. Moreover, no vaccine can be an immediate global solution to the current dengue threat, therefore efforts to improve treatment through application of existing best practices in case diagnosis and management (triage and fluid management), along with efforts to develop new antiviral or other therapeutic drugs, must continue. Similarly, innovative approaches to preventing transmission of the virus, such as through modification of mosquito populations, should be fostered. An improved understanding of the current epidemiology, pathogenesis of the dengue disease and the potential for its future spread would also assist policymakers in allocating resources to combat this global public health challenge.