Dengue virus; coming soon to a mosquito near you!

Dengue is endemic today in over 100 countries in Asia, the Pacific, the Americas and Africa, affecting mostly urban and sub-urban tropical and sub-tropical areas. DengueIt typically causes a flu-like illness known as dengue fever; the “dengue triad” of symptoms is a fever, a headache, and a rash. It also causes severe joint and muscle pain – thus it has also been called “bonebreak fever”. The more severe version is known as dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS), where patients experience blood loss and shock. There are four fivea serotypes of the dengue virus in humans – DENV-1, DENV-2, DENV-3, and DENV-4; each of them with different viral protein antigens on the surface of the virus.

The transmission of the dengue virus involves both its human host and the Aedes aegypti mosquito vector; when a female mosquito sucks blood from a dengue-infected person, the virus goes along. The virus then infects the mosquito, eventually reaching its salivary glands. Then just before the infected mosquito sucks blood from another person, it injects its anesthetic saliva into the person, thus passing the virus to the second person. And the cycle repeats.

Although A. aegypti is primarily found in tropical and sub-tropical areas, secondary Aedes vectors are able to survive in colder climates like those of the United States and Europe. As a consequence, the dengue virus is quickly gaining a foothold in these regions. 

Dengue virus schematic

Dengue virus; Illustration by David S. Goodsell and the RCSB PDB.

The dengue virus is a single-stranded RNA flavivirus.The dengue virus envelope protein, found on the surface of the virus, attaches to the surface of our cells, and causes our cells to take in the virus. It would be useful to block this action in treating dengue; unfortunately, the precise way the envelope protein is binding to the surface of our cells is still not known, so we are unable to develop any drugs in this direction.

Flaviviruses like dengue are also able to block our immune system from responding during infection by inhibiting signaling within the response of our innate immune system, leading to a slower clearance of the virus from our bodies.


Because there is currently no drug or vaccine available for dengue, doctors can only offer symptomatic relief to patients. One of the main problems with developing a vaccine for dengue is because of its four five serotypes. Our immune system fights off viral infections by producing antibodies in response to viral antigens; because the immune system retains these antibodies, there is long-term protection against the serotype we were originally infected with. However, cross-protection between serotypes is only transient, depending on antibody levels, which decrease with time. When antibody levels are high, antibodies against one serotype can cross-protect against other serotypes; when antibody levels are low, the effects of the antibodies are negligible. However, when antibody levels are in the mid-range, antibody-dependent enhancement kicks in, and then people who have initially been infected with one dengue virus serotype have a higher chance of developing DHF or DSS if infected with another serotype. Thus any vaccine developed has to protect against all fourb serotypes simultaneously so as to minimize the chance of DHF or DSS developing in people who have been given a vaccine protecting against one serotype but not another. These types of vaccines are known as tetravalent vaccines, because they counter all four serotypes at the same time. At this point in time, the most promising vaccine is being developed by Sanofi Pasteur, which is currently in Phase III of clinical trials.

Vaccines against dengue virus currently under development

Developer Status
Sanofi Pasteur Live attenuated chimeric tetravalent vaccine, phase 3 clinical trials
Inviragen Live attentuated tetravalent vaccine, phase 2 clinical trials
Butantan Live attenuated tetravalent vaccine, phase 2 clinical trials
Merck Subunit protein tetravalent vaccine, phase 1 clinical trials
Glaxosmithkline Purified inactivated tetravalent vaccine, phase 1 clinical trials
Naval Medical Research Center Plasmid DNA vaccine, phase 1 clinical trials

The best way to prevent infection by the dengue virus is to stop its vectors – namely, the Aedes mosquitos; the easiest way to do this is by reducing the number of places where it can lay its eggs, by clearing any standing water.

 

 

References:

WHO | Dengue Control

R. Perera and R. J. Kuhn. Structural Proteomics of Dengue Virus Curr Opin Microbiol. 2008 August; 11(4): 369–377. doi:  10.1016/j.mib.2008.06.004

Michael S.Diamond. Mechanisms of Evasion of the Type I Interferon Antiviral Response by Flaviviruses Journal of Interferon & Cytokine Research. September 2009, 29(9): 521-530. doi:10.1089/jir.2009.0069.

B. Adams, E. C. Holmes, C. Zhang, M. P. Mammen, Jr, S. Nimmannitya, S. Kalayanarooj, and M. Boots.Cross-protective immunity can account for the alternating epidemic pattern of dengue virus serotypes circulating in Bangkok Proc Natl Acad Sci U S A. 2006 September 19; 103(38): 14234–14239. doi:  10.1073/pnas.0602768103

 

Edit:

Footnote a: In October 2013, scientists announced the discovery of a fifth dengue serotype, found in the blood of a dengue patient from Malaysia.

Footnote b: As there has only been one case of the fifth serotype being found in humans, it is likely that primates other than humans still remain as the hosts for the fifth serotype – meaning that the infection of the patient in Malaysia with the fifth serotype was accidental. However, if more cases are found, we will have to factor this fifth serotype into our vaccines.

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