New research improves understanding on dengue, but vaccine search continues

As COVID-19 cases rapidly rise in India (more than 4.4 million cases now), the annual scourge of dengue fever is also slowly raising its head.

India is labelled as ‘hyper-endemic’, by the World Health Organisation (WHO) for dengue. Which means, the virus is active in almost the entire country and throughout the year. The worst period being monsoon to winter.

The dengue virus is prevalent in at least 150 countries. Most of them are endemic and suffer the impact with varying degree of occurrence. About 40% of the world’s population is at the risk of dengue virus infections with 400 million cases reported annually.

Lack of complete understanding of the (pathogenesis) is one of the main hurdles for developing effective anti-virals for dengue, which is caused by the females of Aedis aegypti and Aedes albopictus mosquitoes. There is no specific drug and an effective vaccine is far off, say experts.

However, it’s all not ‘gloom and doom’. Recent research from the University of Hyderabad (UoH), has broken new ground with three important findings in one year. These include, identifying all the four strains (serotypes) of the virus in the country, developing a simple, diagnostic test and finding the reason for the huge drop in blood platelet count in patients with severe dengue, which potentially leads to death in some severe cases.

The link between dengue and COVID-19

The latest UoH study, published in the Journal of Virology, has established that the virus coded protein, labelled as (NS3) protease enters the mitochondrial matrix and causes degradation in cells and thereby drop in blood platelets.

Naresh Sepuri and M. Venkatramana, the lead researchers explained, “For the first time we have shown that the NS3 protein enters into the innermost mitochondrial compartment called matrix. It cleaves to the protein named GrpEL1 and causes a drop in platelets termed thrombocytopenia, a condition manifested in severe dengue patients.”

Mitochondria, the powerhouse of cells consist of an extensive membrane network and matrix fluid, besides their own genome. So far only the interactions between viral proteins and the mitochondrial membrane proteins are known. The viral proteins interfere with the functions of the mitochondrial membrane proteins.

The scientists say that the SARS-CoV-2 virus-encoded proteins also have mitochondrial target sequence and have the potential to interfere with its key functions. Therefore, the identification of the first mitochondrial matrix protein being targeted by a human virus in dengue infection, may strengthen capabilities to deal with human viruses, including COVID-19, they explain.

Both the dengue and COVID-19 viruses are enveloped in protein structure and are RNA based. In the last 20-30 years, the viruses causing Ebola, HIV/AIDS, Zika and H1N1 are RNA based. While the dengue virus has 10 proteins the coronavirus has 30 in its form.

“We checked whether any of these coronavirus proteins can enter into the mitochondria and found that three of them can. These could cause the sudden breathlessness or hypoxia being reported in COVID-19 cases”, Venkatramana explained.

The UoH team is expanding its work further to gain more insight into this phenomenon. Meanwhile, the prospect of dengue-coronavirus combination cases affecting people in the next few months is a cause of worry. Therefore, it’s better to be vigilant and be prepared, they said.

Typically, with the onset of monsoon in India, viral diseases like Malaria, dengue, chikungunya rear its head. 2020, looks like a ‘double whammy’ with the huge challenge posed by COVID19 spreading rapidly in the country.

All four virus strains

The university research team led by Venkatramana identified all four strains of the virus causing dengue fever in Hyderabad for the first time. In 2019, Telangana saw a big spike with around 6000 dengue cases, with a peak between August-September.

Dengue is caused by four types of viruses (DENV-1, DENV-2, DENV-3, DENV-4) belonging to the Flaviviridae family. They can cause mild to severe fever or potentially lethal complications such as hemorrhagic fever.

The viruses are transmitted through the bite of infected female mosquitoes during daytime which thrive in fresh water, including puddles, water coolers, buckets, etc., that are stored in indoor environments. Although the country is considered hyper-endemic with all four strains, there is limited data available regarding the strains circulating, especially from south India.

According to the National Vector Borne Disease Control Programme (NVBDCP), in 2019 a total of 157,315 cases were reported with 166 deaths in the country. Gujarat was the leader with the highest of 18,219 cases, followed by Karnataka (16,986), Maharastra (14,907), Rajasthan (13,706) and Telangana (13,331).

Cheaper diagnosis

The existing, commercially available antigen-based test gives a positive or negative result to the existence of the virus in a patient and is also expensive. Often, the costs of diagnostics, hospitalisation and treatment  are higher than what some can afford. The UoH researchers have recently developed an Elisa-based, antibody test that can detect the virus presence more accurately up to a week in the patient. It has been tested on over 300 patients, claimed Venkatramana.

The treatment regimen can be more effective and costs brought down if the particular strain can be identified at an early stage. “Our focus will be on coming up with alternative, cost-effective, diagnostic tests for dengue, Zika and chikungunya, whose viruses belong to the same family,” Venkataramana says.

Dengue and the environment 

Dengue, Zika, West Nile, chikungunya, malaria are all caused by mosquitoes, which are ubiquitous in their presence. Currently, control of these diseases/mosquitoes is mostly limited to the use of broad-spectrum insecticide sprays, which can harm humans, animals and insects due to their negative impact on the environment.

In recent years, scientists developed genetically modified mosquitoes to prevent diseases. They are being used to combat mosquito-borne pathogens – including viruses such as dengue and Zika – in many locations around the globe, including the United States. Efforts have been made to control malaria, the most common mosquito-borne disease using GM versions.

Dengue vaccine

An effective vaccine against dengue has been elusive for over two decades now. There have been failed attempts and some with limited success. Sanofi, the French multinational company, developed a vaccine named Dengvaxia, which had mixed results. Its use is now limited to a very few countries. Experts say that the problem with developing a vaccine against dengue virus is its tough task of encoding protection from all four serotypes.

In recent years, Takeda Pharmaceuticals, the Japanese major has claimed progress in its vaccine efficacy upto 80 percent in a clinical trial carried out among 20,000 children aged between 4 to 16 years in the 12-month period after the second dose, which was administered three months after the first dose.

In the statement last November, Rajeeva Venkayya, President of the Global Vaccine Business Unit at Takeda has been quoted as, the data “is evaluating the performance of our dengue vaccine candidate in a diverse set of countries across Asia and Latin America, and in a study population that intentionally includes a large proportion of children who had never been exposed to dengue.”

Till the development of an effective anti-viral drug or an efficacious vaccine, the best hope to contain the serious effects of dengue is early detection of its severity and right treatment.

Read more: Higher average temperatures linked to chikungunya risk in India

Banner image: Garbage in stagnant water during the monsoons becomes the place for breeding dengue mosquitoes. Photo by S. Gopikrishna Warrier/Mongabay.