Dengue has been striking India, usually in the post-monsoon season, with unfailing regularity. The disease which is spread to humans by the Aedes aegypti mosquito, doesn't usually make headline news like AIDS and SARS do. The 2006 dengue epidemic in India became newsworthy because it affected the Indian prime minister's family.
According to the National Vector Borne Disease Control Programme, India's central nodal agency for the prevention and control of vector-borne diseases, nearly 12,000 people were affected, of which about 1.5% succumbed to the disease. More than eighty dengue outbreaks have been recorded throughout the country since the early sixties.
The disease, prevalent in most of our metropolitan cities, has begun spreading to rural areas as well. The population in India accounts for approximately half the 2.5 billion people in the world estimated to be at risk of contracting dengue. The International Health Regulations were recently revised to include dengue as a potential international public health emergency. Ironically, India has done precious little to address the dengue problem.
The menace
Dengue is caused by four distinct varieties or serotypes of dengue viruses. Infection in the majority of cases may be either non-symptomatic or produce high fever and debilitating joint pain, known as dengue fever. In the rest it can produce a potentially fatal disease, dengue haemorrhagic fever (DHF), characterized by plasma leakage from blood vessels to tissues, a drop in platelet counts and bleeding. If the patient is not hospitalized in time, leakage and/or bleeding can lead to fatal dengue shock syndrome (DSS).
Oftentimes DHF/DSS has been correlated with re-infection with a second dengue virus serotype. A report from All India Institute of Medical Sciences, New Delhi, in January this year, which found evidence of the presence all four types of dengue viruses in the 2006 outbreak, has established India as truly hyperendemic. The study which found several patients with dual dengue virus infections, many of whom were diagnosed to be DHF cases, may have only uncovered the tip of the iceberg. All ingredients necessary to trigger a dengue nightmare, the four dengue virus serotypes, the dense human population, and the high prevalence of the mosquito vector, are present in our cities.
Taming the hydra heads
What makes dengue such a daunting problem? Foremost is the lack of an effective vaccine against all four serotypes. Moreover, there is neither a clinically useful diagnostic test to identify dengue infection, nor specific antiviral drugs to treat dengue patients. We also lack adequate healthcare facilities and trained personnel for effective clinical management of such patients. The failure to implement effective vector control measures has made the dream of eradicating the disease-spreading mosquitoes an elusive one. Finally, the government has failed to assess the reality of the dengue problem, realize its enormity, and formulate a meaningful public heath response.
A comprehensive multi-pronged strategy that addresses each facet of the dengue problem is necessary to tackle dengue effectively. A panel of dengue experts from around the world which met in Geneva recently, identified the factors outlined above as the cornerstones on which the global community must base its efforts in developing an effective strategy to combat the dengue menace.
A vaccine would provide the most effective means to combat the threat posed to public health by dengue viruses. Epidemiologic evidence from Cuba indicates that immunity to dengue infection is serotype-specific and that such immunity would not only fail to protect against a different serotype, but may also trigger fatal DHF/DSS. To ensure that a dengue vaccine does not predispose a recipient to fatal dengue disease it must be tetravalent, conferring solid and durable immunity against all four dengue virus serotypes.
Live attenuated vaccines are currently the front runners in the dengue vaccine pipeline, but the tendency of the attenuated strains in the tetravalent vaccine to interfere with each other is not well understood. According to the US Centers for Disease Control and Prevention, an effective dengue vaccine will not be available for the next 5 to 10 years. This warrants the development of new generation non-infectious sub-unit vaccine approaches such as those based on the host receptor-binding domain of the dengue virus envelope protein. Importantly, the emphasis in the Indian context, besides safety and efficacy, must be affordability.
With dedicated dengue wards in hospitals staffed by trained personnel, case fatality rates in dengue epidemics can be significantly reduced. Experienced doctors must get together to determine clinical indicators of different levels of disease severity and formulate simple case management guidelines for implementation at peripheral health units.
Reliable diagnostic tools can aid in timely treatment. It is necessary to develop a diagnostic test capable of identifying dengue infections with a high degree of sensitivity and specificity against the background of other co-prevalent infections. These tests will be useful for epidemiological surveillance and vaccine efficacy trials as well. Scott Halstead, Senior Advisor and R&D Director of the Seoul-based Pediatric Dengue Vaccine Initiative (PDVI), opines that such tests in future could also be used to screen blood before transfusion to minimize the risk to recipients in areas of hyperendemicity, such as India, where all serotypes co-circulate.
Access to effective antiviral drugs will be important in dealing with periodic dengue outbreaks. The recent unraveling of the structures of dengue enzymes, particularly the protease and polymerase, should permit the application of the structure-based design strategy to the development of drugs for dengue. India has the added advantage of having access to a large herbal bioresource. It has been estimated that a repertoire of as many as 1060 potential drug molecules exist in nature.
By focusing on antiviral molecules representing major constituents of easily available/cultivable plants, it may be possible to ensure sustainable supply of the drug. In the absence of drugs and vaccines, vector control assumes high importance.
Countries afflicted by dengue, with the exception of Cuba and Singapore, have by and large failed to implement effective mosquito eradication strategies. Cubans have successfully used the bacterium, Bacillus thuringiensis that feeds on Aedes larvae, to achieve vector control. In Vietnam, similar results have been achieved using a shrimp-like organism called mesocyclops. The applicability of these biopesticides must be evaluated in India. Efforts must be made to tap into the Rs 1,600 crore mosquito-repellant market, which is growing at an annual rate of 15%, to fund innovative vector control measures. Effective vector control would not only address dengue, but a host of other mosquito-borne diseases such as malaria and chikungunya as well.
Finally, India must undertake field site development and epidemiological characterization of its population before it can hope to test new drugs and vaccines. It is critical for India to quantify its epidemiologic and economic burden of dengue so that it can formulate key policy decisions on research priorities, prevention programmes and clinical training for disease management.
Time to act
Umesh Chaturvedi, a dengue research pioneer in India, believes that dengue is a curse that is here to stay unless we choose to act against it10. In this era of global commerce and international travel, dengue does not respect geographical boundaries. Failure of India to contain dengue will contribute to failure at the global level. Each dengue-endemic country has to actively combat dengue and the chain of defense against dengue will only be as strong as its weakest link and India must not be the weak link in this fight.
India needs to develop a focused dengue research initiative that would complement and integrate with the efforts that are being initiated globally. There has been an influx of researchers from varied disciplines converging on dengue and contributing to rapid strides in our understanding of dengue virus biology in recent years11.
The WHO, particularly its departments on the Special Programme for Research and Training in Tropical Diseases and the Initiative for Vaccine Research, along with several international consortia, such as the PDVI, the Innovative Vector Control Consortium (a consortium of five academic institutions from the UK, USA and South Africa), Dengue Control (DENCO) and DENFRAME (a consortium with partners from Europe, Asia and Latin America) and several dengue-endemic countries are addressing dengue-specific issues pertaining to the development of vaccines and diagnostics, disease management, drug discovery and vector control.
The Indian Department of Biotechnology (DBT) began funding small research projects in dengue since 2005 to explore the possibility of developing dengue vaccines and drugs. However, a comprehensive and dedicated dengue initiative is yet to take off in this country. The number of scientists working on dengue in India is woefully inadequate. The country needs to motivate more scientists to channelize their efforts and expertise into addressing dengue.
To mount the multi-pronged initiative against dengue, we propose that India must create a dedicated national dengue institute whose primary long term objective would be to control and ultimately eliminate dengue. A major thrust area for this institute would be to explore ways and means of implementing existing knowledge into tangible prevention/intervention tools. It will also promote clinical research to evolve better case management and basic research to aid in the evaluation of diagnostics, drugs and vaccines. In harnessing the technology and expertise to achieve its objective, this institute would set up collaboration with industry, research centers, hospitals and government entities. Fostering good synergy among research, prevention and control, and policy would be critical to the success of this institute's objective.
This seems to be the most opportune time to set up such a focused Indian dengue initiative with the government tripling its healthcare budget to $34.5 billion in the 11th Five Year Plan (2007-12) and a proactive secretary at the helm of the DBT. A concerted and dedicated effort is bound to result in tangible progress in the battle against dengue in the coming years.
References
Trend of dengue case and CFR in India National Vector Borne Disease Control Programme, Govt. of India World Health Assembly. Revision of the International Health Regulations (WHA 58.3) Bharaj, P. et al. Concurrent infections by all four dengue virus serotypes during an outbreak of 2006 in Delhi, India. Virol. J. 5, 1 (2008) Farrar, J. et al. Editorial:Towards a global dengue research agenda. Trop. Med. Int. Health 12, 695-699 (2007) Centers for Disease Control & Prevention Etemad, B. et al. An envelope domain III-based chimeric antigen produced in Pichia pastoris elicits neutralizing antibodies against all four dengue virus serotypes. Amer. J. Trop. Med. Hyg. (2008) (in press) Halstead, S. (personal communication) Dobson, C.M. Chemical space and biology. Nature 432, 824-828 (2004) Chaturvedi, U.C. Editorial: The curse of dengue. Indian J. Med. Res. 124, 467-470 (2006) Swaminathan, S. et al. Dengue: Recent advances in biology and current status of translational research. Curr. Mol. Med. (2008) (in press)
