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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