Better late than never: antivirals for dengue

Keywords::

• antiviral
• dengue
• dengue fever
• DENV
• DHF/DSS
• vaccine
• virus

With an annual number of infections approaching 50 million worldwide and an increase in disease severity, dengue virus (DENV) has re-emerged as an important pathogen [1,2]. Despite estimates by the WHO that one third of the earth’s population is at risk of dengue infection, there is currently no approved vaccine or antiviral available. What is behind this absence of therapeutics, and how did dengue catch the medical community unprepared?

Over the last several decades, dengue has become the most prevalent mosquito-borne viral disease in the world, and the estimations of infection by the WHO are staggering. Dengue is now endemic in over 100 countries, on every continent except for Antarctica, and primarily afflicts resource-poor countries in the tropical and subtropical regions. Comprised of four distinct serotypes, DENV is transmitted by infected Aedes mosquitoes, primarily Ae. aegypti. Infection produces a wide spectrum of clinical disease ranging from asymptomatic to self-limiting febrile illness. Dengue fever (DF), also known as ‘break bone fever’ [3], includes symptoms of high fever, muscle and joint pain, and rash. A small percentage of individuals will present with the life-threatening severe dengue hemorrhagic fever and shock syndrome (DHF/DSS). Treatment is largely supportive, using either oral or intravenous rehydration and in-patient monitoring, and appropriate medical attention reduces the fatality rate of severe disease to <1% [1]. However, one of the major burdens of the disease is its capacity to overwhelm medical facilities during an outbreak, and in countries where healthcare resources are already stretched thin, this can have catastrophic effects. Better prevention and treatment options are needed.

There are currently five dengue vaccine candidates undergoing clinical trials, including Sanofi Pasteur’s candidate ChimeriVax, which is a live-attenuated tetravalent vaccine. Considered a leading candidate, it is furthest down the regulatory pipeline in Phase III trials, but still at least 2 years from the market [4]. Although vaccines are available for other flaviviruses, development of a dengue vaccine is complicated by the phenomenon known as antibody-dependent enhancement (ADE) [5]. Briefly, non-neutralizing, cross-reactive antibodies produced during a primary infection by one DENV serotype or acquired passively at birth contribute to the development of severe disease upon subsequent infection by one of the other three serotypes [6]. Although any DENV vaccine created would need to protect against all four serotypes of the virus, it remains to be seen whether ADE will affect the safety and efficacy of dengue vaccines. A safe and effective DENV vaccine is clearly the long-term solution, but more immediate strategies are urgently needed to combat the current dengue problem.

A suitable antiviral would not only provide an alternative to potential ADE issues facing vaccines, but it can be given therapeutically, or after a patient has already become symptomatic and is seeking treatment. Despite the potential advantages antiviral drugs possess, their development lags behind vaccines, and none have started clinical trials. Part of the problem can be traced to the lack of attention given to dengue over the last 50 years, particularly in the USA. While the USA has seen only a handful of locally transmitted infections in Hawaii (2002), Texas (2005) and Florida (2010) [7–9], the average number of worldwide cases has nearly doubled every decade since the 1970s, reaching an annual average number of cases close to 1 million between 2000 and 2009 [1]. While these statistics likely reflect a combination of both dengue expansion and better surveillance, the result is that DENV is now recognized as a major threat to global health.

However, in the past, dengue has seen very little of the financial resources distributed for infectious disease research. The total National Institute of Allergy and Infectious Diseases (NIAID) supported funding for DENV in 2000 was only US$4.5 million, while HIV vaccine research alone received US$231.1 million in funding from the National Institutes of Health (NIH) [10]. This difference in financial support had predictable results: by 2004, 20 years and billions of research dollars after the identification of HIV, there were already 19 antiviral compounds approved for treatment in humans [11]. In comparison, there are currently only a handful of anti-dengue drug candidates in the preclinical phase. Clearly there is a strong correlation between funding basic research and drug development. The recognition of DENV as a potential bioterrorism threat (as well as other hemorrhagic viruses) led to its inclusion on the NIAID Category A pathogen list [12], and in 2003, NIAID-sponsored dengue funding had increased to US$15 million. By 2009, the NIH dengue budget had been raised to US$54 million, a dramatic increase from a decade prior, and an open acknowledgement of historically poor funding [13].

The G-FINDER report, an annual survey of global funding for neglected diseases commissioned by the Bill & Melinda Gates Foundation, reveals additional information about the distribution of funding for dengue research. This survey is compiled from 110 public and private sector entities worldwide, and details both monetary sources and research focus [14]. When one considers that there are five vaccine candidates and zero drug candidates currently in clinical trials, it is not surprising to discover that funding for drug development lags well behind vaccine development. While over 56% of global dengue research and development funding went to vaccine development (US$93.6 million), only 9.5% (US$15.7 million) of this funding was dedicated to antiviral drug development in 2009 [13].

As the pursuit of a HIV vaccine has demonstrated, even substantial resources do not guarantee solutions, and the complex pathology of dengue is a considerable challenge to therapeutics. Our understanding of its basic biology has progressed enough that multiple strategies to disrupt DENV infection have been identified and examined in vitro, including inhibition of viral entry and specific targeting of viral replication machinery [15]. However, the major hurdle currently facing drug development remains our incomplete understanding of mechanisms of dengue pathogenesis, and this is in large part due to the lack of an appropriate animal model. Non-human primates support limited replication of DENV, but display little or no clinical signs of disease. Several mouse models that utilize mice deficient in components of the innate immune system (notably mice lacking type I and/or type II interferon receptors) are currently being used to investigate dengue pathogenesis and evaluate antiviral candidates, but to date, no immunocompetent mouse model exists [16]. A consensus opinion released by the WHO offers clues about why an animal model may be so hard to develop: ‘Dengue is one disease entity with different clinical presentations and often with unpredictable clinical evolution and outcome’ [1]. Further studies using human clinical samples, tissue culture and existing in vivo models will help push forward the innovation of an appropriate animal model of disease suitable to elucidate mechanisms of dengue pathogenesis and to test preclinical drugs.

There is reason to be optimistic about the future of dengue antivirals, and funding of dengue research in general. The 2010 G-FINDER report revealed over US$165 million in total global funding to dengue research in 2009, which included US$54 million from the NIH, US$10.5 million from the Department of Defense, and US$1.4 million from the CDC. Approximately 9.5% (US$15.7 million) of global funding was focused on drug development, a 106% increase from even 2008, and a step in the right direction considering this amount is three times the total amount what the NIH dengue budget was in 2000. Another positive indicator is the revelation that 38% of 2009 funding was provided by the private sector, demonstrating that international pharmaceutical companies are also investing in drug development. On the other hand, the US Division of Vector-Borne Infectious Diseases narrowly escaped funding cuts in the 2011 budget proposed by the Obama administration (from US$39 million to US$12 million), which would have dramatically affected the CDC Puerto Rico Dengue branch and the Colorado State Division of vector-borne diseases [17]. The big question remains whether funding levels will be sustained, and how susceptible dengue research is to government cost cutting.

Clearly, the history of poor funding is not the only factor contributing to the absence of antiviral drugs against dengue, but there can be no argument that money is the driving force in advancing research and development, regardless of its source. There is a logical progression from awareness, to allocation of financial resources, to funding basic research, to the development of therapeutics. Others have voiced a similar sentiment: “The staggering success in developing drugs against HIV is an example of how efficiently effective antivirals can be developed given appropriate funding” [18]. It is unreasonable to think that the level of funding for dengue research will ever approach that of HIV. Nevertheless, we hope the attention dengue is currently receiving across the globe, both financially and otherwise, will eventually lead to a pipeline of successful therapeutics.

Financial & competing interests disclosure

The Shresta laboratory (Sujan Shresta, Stuart Perry and Michael Buck) receives some financial support for research from private sector entities that are developing dengue therapeutics (Conatus Pharmaceuticals and AVI BioPharma). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.