By Hannah Johnson

Dengue fever is a severe viral disease that affects nearly 100 million people worldwide each year. Currently, the only treatment available for this disease is in symptom management; however, recently advances to treat disease etiology have been made^2,5. In the last few years a vaccine has been approved for the prevention of dengue in multiple areas of the world^2,4.

Dengue spreads to humans through the bite of infected female Aedes aegypti or Aedes albopictus mosquitos, which act as vectors for the virus. Once a mosquito has bitten a dengue infected human, the virus will multiply in the mosquito’s midgut before spreading to secondary tissues which includes the salivary glands. After 8-12 days, newly infected mosquitos are capable of infecting a new viral host. Some of the common symptoms seen with dengue are fever followed by headache, vomiting, and more, depending on the form of dengue contracted (Table 1).

Dengue	Severe Dengue
Severe headache	Severe abdominal pain
Pain behind the eyes	Persistent vomiting
Muscle and joint pain	Rapid breathing
Nausea	Bleeding gums
Vomiting	Fatigue
Swollen glands	Restlessness
Rash	Blood in vomit

According to the World Health Organization (WHO), dengue is one of the most prevalent mosquito borne infections with a rate of 96 million symptomatic infections and 40,000 deaths every year; however, some estimate the inclusion of asymptomatic infections increases the actual infection rate up to 390 million per year².  Dengue is an endemic in over 100 countries in Africa, the Americas, and Western Pacific, with Asia accounting for approximately 70% of the disease burden² (Figure 1). For a virus without any established treatments, the increasing prevalence of this disease creates a push for further development of preventions and treatments for this virus.

Dengue virus has 4 serotypes, which are groups within a species separated by different surface antigens⁸. The different antigens trigger an immune response specific to that serotype, allowing the same person to be infected multiple times. For people who are seronegative (meaning they have never been infected with dengue) the infection is typically mild; however, seropositive people (people who have been infected with a serotype of dengue before) tend to have a more severe form of dengue when infected by another serotype. This phenomenon is known as antibody-dependent enhancement (ADE)⁹. ADE occurs in some cases when the antibody concentration gets too low (which in dengue can happen after a period), the antibodies will actually help bring the virus into the cells⁹. This allows for more infection to occur than would happen without the antibody assistance. This tendency of severe dengue in seropositive people has led to the need for any vaccines or therapeutics to be capable of inhibiting all serotypes of dengue^2,3,4,5.

While the need for a vaccine to prevent all four types of dengue virus has been a challenging task for researchers, in 2015, the first dengue vaccine, coined Dengvaxia, was distributed for public use in Mexico³. Currently, Dengvaxia has been put into use in 20 endemic countries and was recently approved by the FDA in 2019^3,4. Dengvaxia is a tetravalent vaccine capable of suppressing infection by all four serotypes; however, there was limited activity against the serotype most associated with severe dengue⁴. Clinical trial findings of Dengvaxia revealed that since the vaccine acts as a primary infection, seronegative people would be more at risk of developing a severe secondary infection⁴. Thus, a previous dengue infection is required to be given the vaccine. This requirement limits the public use of Dengvaxia to people living within endemic regions and is not for travelers or residents of non-endemic regions who are unlikely to have contracted the disease previously. The approval of Dengvaxia has opened the way for more dengue vaccines to be produced. Presently, there are 3 vaccines showing promising results in Phase II and Phase III clinical trials⁴. While these additional vaccines vary in how they trigger an immune response to the vaccine, clinical data suggest they are just as or more effective than Dengvaxia, demonstrating that soon Dengvaxia may not be the only or best vaccine for the prevention of dengue⁴.

Furthermore, new research in both treating and preventing dengue has emerged with the discovery of a viral inhibitor, JNJ-A07⁵. This discovery may provide the jump start needed in establishing an actual treatment for dengue rather than the current symptomatic treatments in place. JNJ-A07 prevents the formation of the NS3-NS4B protein interaction, which is essential to the viral replication machinery⁵. Normally, non-structural protein 4B (NS4B) causes NS3, a helicase, to detach from the virus’s single stranded RNA, increasing NS3’s activity and allowing it to be more effective in separating genomic strands^5,7. In vivo studies show significant reduction in viral infection both before and after dengue infection⁵ meaning it can potentially be used as both a treatment and a preventative measure. Moreover, dengue virus is less likely to develop drug resistance to JNJ-A07 as the mutations required for high drug resistance in the virus cannot be replicated in mosquitos and so cannot infect humans⁵. All of these findings have enabled JNJ-A07 to enter clinical trials⁶.

Dengue is becoming more prevalent in the world resulting in a need for increased development towards establishing better treatments and vaccines². In addition to Dengvaxia, Mosquirix, a vaccine for the mosquito-borne malaria, was recently approved¹⁰. There has even been a promising small clinical trial for a vaccine that targets the saliva of mosquitos to prevent all mosquito-borne diseases¹¹. These findings together reveal the leaps we are making towards treating these very prevalent mosquito-borne diseases.

TL:DR

• Dengue fever is a mosquito-borne disease rapidly becoming prevalent in the world today, where secondary infection is raised in severity by antibodies from the first infection. 
• The first vaccine for dengue was recently approved by the FDA and 3 promising vaccines are currently in clinical trials.
• A new antiviral, JNJ-A07, was discovered as a potential treatment for dengue that has recently entered clinical trials.

---

References

1. Simmons, C. P., et al. “New England J.” Med 366 (2012): 1423-1432.
2. https://www.who.int/news-room/fact-sheets/detail/dengue-and-severe-dengue
3. https://www.cdc.gov/dengue/about/index.html
4. Redoni, Marianna, et al. “Dengue: Status of current and under‐development vaccines.” Reviews in medical virology 30.4 (2020): e2101.
5. Kaptein, Suzanne JF, et al. “A pan-serotype dengue virus inhibitor targeting the NS3–NS4B interaction.” Nature 598.7881 (2021): 504-509.
6. https://www.science.org/content/article/first-drug-dengue-excruciating-disease-may-be-horizon
7. Frick, D N, and A M I Lam. “Understanding helicases as a means of virus control.” Current pharmaceutical design vol. 12,11 (2006): 1315-38. doi:10.2174/138161206776361147
8. https://www.microscopemaster.com/serotype.html
9. https://www.chop.edu/centers-programs/vaccine-education-center/vaccine-safety/antibody-dependent-enhancement-and-vaccines
10. https://www.cdc.gov/malaria/malaria_worldwide/reduction/vaccine.html
11. https://www.niaid.nih.gov/news-events/mosquito-borne-disease-vaccine-safe