Dengue virus belongs to the Flavivirus family characterized by single stranded, positive sense RNA genome. Mutation rates in RNA viruses are exponentially greater than agents with DNA genomes due to the lack of proof reading mechanisms in the RNA dependant RNA polymerases of the former. This leads to the development of antigenic diversity because of varying levels of inter-virus genetic recombination. Although no licensed vaccine is currently available to combat dengue, a substantial amount of research has been undertaken over many years and in several countries. As a result, a number of conventional and novel vaccines are being developed and several are undergoing clinical trials.
In theory, an effective vaccine against dengue is possible because it causes an acute infection and the viral levels are effectively controlled in a span of 3 to 7 days. Further, an individual exposed to a particular type of dengue is immune against re-infection with that subtype, thus leading to experiments in animal models, which have shown that passive transfer of virus specific antibodies are protective against subsequent challenge with that specific viral subtype. The major obstacles relating to the development of an effective dengue vaccine include a lack of complete understanding regarding the pathogenesis of dengue hemorrhagic fever and the absence of a representative animal model. Pre-existing heterotypic dengue antibody is a risk factor for DHF; therefore, an effective vaccine will have to be tetravalent and needs to prevent infection with all four DV serotypes.
Recent advances in molecular biology and recombinant DNA technology have made it possible to create new strains that have the non-structural proteins of a certain subtype flanked by envelope antigens from a combination of different strains. This has lead to the emergence of the chimeric dengue vaccine. Recent studies have shown that by means of DNA shuffling and screening techniques, an envelope antigen capable of inducing neutralizing antibodies against all 4 types of dengue virus has been developed. Another approach has been the introduction of antibody inducing plasmid into DNA vaccines. This has also shown to produce significant antibody response in animal trials. Some other areas of interest include recombinant envelope vaccine, whole cell inactivated dengue vaccine and the development of a tetravalent live attenuated vaccine. Studies have shown that non-structural proteins in comparison to envelope antigens do not elicit efficient immune response on exposure. Novel approaches to find attenuated strains that selectively identify infected dendritic cells are underway. This increases the effectiveness and the safety of the vaccine.
The importance of understanding the correlation between protection and mechanisms of pathogenesis cannot be neglected. However, there is an escalating need to provide a solution to the global threat of dengue infection and the complications associated with the same. Better disease management, vector control and improved public health measures will help reduce the current disease burden, but a safe and effective vaccine is probably the only long-term solution to this problem.
Deepu Alex, Carlene Gong, Chelsea Johnson, Cheryl King, Anthony Ho, Katarro Rountree, and Lisa Sani
Graduate Students, Master of Science Program in Biohazardous Threat Agents and Emerging Infectious Diseases. Georgetown University School of Medicine Department of Microbiology and Immunology. Washington, DC
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