Epidemic Dengue Fever in Southeast Asia

1. What is Dengue Fever?

Dengue fever (DF) used to be called "broken bone fever" because it often causes severe joint and muscle pain. Dengue fever is an acute infectious disease caused by the dengue virus, but it does not spread between humans. It is mainly transmitted by mosquito bites, mainly Aedes aegypti and Aedes albopictus. The incubation period is 3 to 15 days, most of which is 5 to 8 days.

In most cases, dengue fever is mild, patients have slight fever and body pain, the rash is rare, there is no bleeding tendency, superficial lymph nodes are often swollen. And its clinical manifestations are similar to influenza, easy to be ignored, cured within 1 to 4 days.

A small number of patients are not fortunate, they suddenly aggravated on the 3rd to 5th, and there was meningitis such as severe headache, nausea, vomiting, disturbance of consciousness, and neck stiffness. Some people even developed major gastrointestinal bleeding and hemorrhagic shock, which could be life-threatening. It is known as dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS).

2. Dengue Virus

Dengue virus, short for DENV, is a roughly spherical structure composed of the viral genome and the capsid protein. DENV is made up of four different serotypes: DENV1, DENV2, DENV3, and DENV4. And each serotype can be again divided into several genotypes based on envelope genes, thereby giving partial cross-protective immunity to other serotypes.

The DENV genome is an approximately 11,000 base sense single-stranded RNA (ssRNA) encoding three structural proteins (capsid protein C, membrane precursor M, envelope protein E) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5).

Figure 1: Dengue virus genome

The DENV E protein is a dimer present on the surface of mature virus particles and plays an important role in the initial attachment of the particles to the host cells. It contains specific epitopes that neutralize antigens and viruses, which can induce the production of neutralizing antibodies and hemagglutination inhibitory antibodies.

DENV M proteins resume a crucial role in the formation and maturation of viral particles. DENV NS3 is a serine protease, as well as an RNA helicase and an NTP enzyme. DENV NS4A is a non-structural protein involved in altering cell membrane curvature and inducing autophagy.

NS4B is a small hydrophobin that binds to the endoplasmic reticulum. After induction of IFNA1 (interferon type I alpha)and IFNB1 (interferon type I beta), it may block phosphorylation of STAT1. In fact, the activity of Tyk2 kinase decreases with dengue virus, so STAT1 phosphorylation is also decreased. Therefore, the innate immune system response may be prevented.

When NS5 is expressed alone, it leads to inactivation of STAT2 (signal transduction by a response to interferon). When NS5 is cleaved by NS4B with a protease (NS2B3), it can degrade STAT2. In fact, after cleavage of NS5 by the protease, there is binding to the E3 ligase of STAT2, and the E3 ligase targets STAT2 for degradation.

DENV can only replicate in the host organism. After infecting the host cell, DENV hijacks the host cell's machinery to replicate the viral RNA genome and proteins. Upon maturity, the newly synthesized dengue viruses are released and continue to infect other host cells.

Figure 2: Dengue virus replication process

(sourcing: https://www.nature.com/articles/nrmicro1067)

3. The causes of frequent outbreaks of dengue fever in southeast Asian countries

Dengue fever is generally prevalent from May to November, with peaks in July to September.

The temperature in Southeast Asia is even, the humidity is high, and the rainfall is large. The average annual temperature is around 27 ℃. Studies have shown that temperature and humidity are positively correlated with the spread of the dengue virus.

Because dengue virus is a mosquito-borne virus, the temperature, and humidity in these areas are suitable for mosquito growth and reproduction in summer and autumn. Any factors that contribute to the increase in mosquito density may increase the chance of dengue virus infection and outbreak. And studies have also demonstrated that the temperature is above 20 ℃, as the temperature rises, the external latency of the virus in the mosquito body will be shortened, which means that the cycle of the virus between humans and mosquitoes is shortened.

In addition, precipitation is also one of the most important climatic factors affecting the transmission of dengue, because mosquitoes survive in the water from eggs, larvae, pupas to hatching, and mosquitoes are easily found in humid and rainy places.

4. Prevention

4.1 engue Vaccine

Because four different dengue virus serotypes can cause disease, the vaccine must be immune to all four types. It is, therefore, challenging to develop a vaccine against this disease.

Dengue vaccine research and development has gone through decades and tried a variety of technologies. In 2014, the world's first Dengue vaccine, CYD-TDV, developed by Sanofi Pasteur Vaccine, was successfully tested in Indian adults. And this vaccine was approved for market in many countries at high risk of Dengue epidemics in 2015.

However, the vaccine was exposed to only effectively protect people who had the disease before but worsen conditions in those who do not infect the disease in 2017. It caused a panic at that time, so the world health organization suspended the first vaccine in 2018. But the research on Dengue vaccine is never stopped, many companies have been working on Dengue vaccine.

Since there is no vaccine, the elimination of vector mosquitoes and the early detection of outbreaks are the top priorities in dengue control to prevent the spread of the virus.