The arbovirus disease dengue has spread around the world and is now an important threat to public health. From symptomatic dengue fever (DF), a small percentage of individuals may develop dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Dengue is a single positive-stranded RNA virus from the Flaviviridae family (Genus Flavivirus) 3734. Aedes aegypti and Aedes albopictus mosquitoes are the most common carriers of the dengue virus. It is the second most common mosquito-borne illness, after malaria. The clinical manifestations of hemorrhagic fever range from mild to severe.

It consists of up of a 5' untranslated region, a large open reading frame (ORF) that encodes a polypeptide chain, and a 3' UTR. The virus's translation produces ten different viral proteins, both structural and nonstructural. Dengue's four serotypes (DENV1, DENV2, DENV3 and DENV4) are further classified into distinct genotypes. DENV1 has five genotypes (I-V), DENV2 has six (Southeast Asian/American), DENV3 has four (I-IV), and DENV4 has four (Southeast Asia, America, Thailand, and Sylvatic) Sankoju et al., 2023. The dengue epidemic is complicated by immunological interactions among the four circulating serotypes and the constant turnover of viral lineages.

The DENV genomic RNA encodes three structural proteins (C, PrM, and E) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) 4. Untranslated sections (5′-UTR and 3′-UTR) surround the DENV open reading frame at both its 5′ and 3′ ends. The DENV genome contains a significant amount of variation 26.

The infection confers lifelong protective immunity to the same subtype but no immunity to the other three serotypes 27. Furthermore, previous infection with a different subtype raises the risk of developing dengue hemorrhagic fever 27. This is due to a phenomenon known as antibody-dependent enhancement (ADE). In ADE, heterotypic non-neutralizing antibodies form complexes with dengue virus, infecting mononuclear phagocytes more efficiently. As a result, a greater number of host cells are infected, increasing viral replication and worsening clinical symptoms.

The first confirmed outbreak of dengue virus occurred simultaneously in Asia, North America, and Africa in 1779 11. Dengue, which is already present in over a hundred countries, is spreading from tropical and subtropical regions due to climate change 23. In October, Bangladesh had 359 fatalities and 67,769 cases, while India had 94,198 cases and 91 deaths. African countries with documented cases include Angola, Burkina Faso, Chad, Côte d'Ivoire, Egypt, Ethiopia, Guinea, Mali, Mauritius, Sao Tome and Principe, Senegal, and Sudan. In Americas are home to the majority of dengue infections, with approximately 3.7 million confirmed cases and 1700 deaths expected by 2023.

There are four serotypes of dengue fever (DENV), ranging from DENV1 to DENV4, but neurological symptoms are frequently associated with DENV2 and DENV3 19, with DENV 2 being the most common serotype with the highest severity at our hospital 9. In fact, DENV2 and DENV3 were identified in cases of encephalitis, meningitis, and myelitis 5. DENV-4 was also detected in brain cells by immunohistochemistry and in cerebrospinal fluid (CSF) of a patient with encephalitis, whereas neurological symptoms have frequently been linked to DENV2 and DENV3 19.

It is critical to remember that dengue-related neurological problems are a complex issue caused by both the virus and the host 32. There are three potential mechanisms: the virus's direct invasion of the central nervous system, immune responses, and metabolic changes. Direct viral neurotropism is indicated by neurological involvement, the presence of CSF viral particles, and blood-brain barrier disruption. Recent studies suggest that neuroinflammation plays a role in dengue. Non-structural 1 antigen (NS1Ag) is linked to neurological symptoms and has been shown to induce cytokine release 33. Natural killer cells activate T-helper (Th) cells, which differentiate into Th17 and Th9 cells.

The production of pro-inflammatory cytokines by these cells damages the blood-brain barrier and allows other immune mediators to enter the brain, resulting in neuroinflammation 33. Prior DENV infection-related neurological consequences were classified into three types: immunological responses, viral invasion, and metabolic abnormalities. DENV encephalopathy and encephalitis, especially in dengue-endemic areas, should be considered when making a differential diagnosis of various acute febrile encephalopathies, autoimmune encephalitides, and SARS-CoV2 infections.

Dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) were originally associated with it. According to recent research, dengue virus infection-related cytokine overproduction harms immune-mediated endothelial cells, increasing vascular permeability and fluid leakage, which may eventually result in global cerebral edema 17. Without supportive therapy, death rates could be significant, and treatment results can vary.

It is interesting to note that "expanded dengue syndrome" (EDS) refers to dengue fever symptoms affecting multiple organ systems Aris et al., 2022. This condition is more common in high-risk groups, including the elderly, pregnant women, children, hemoglobinopathies, patients with coronary artery disease, and those with compromised immune systems. EDS can cause complications in the hematology, renal, gastrointestinal, respiratory, and cardiovascular systems. Pregnant women, young children, the elderly, those with hemoglobinopathies, and people with weakened immune systems are all at high risk Aris et al., 2022.

and how does the dengue vaccination appear?

The first is the live and attenuated tetravalent vaccination Qdenga® (also known as TAK-003), developed by the Japanese laboratory Takeda 22. After a year of use, the vaccine was found to be 80% effective when administered in two doses at three-month intervals. Indonesia approved its use in October 2022, and the European Union approved it in December 2022 22. The United Kingdom arrived in January 2023, followed by Brazil in the middle of the year.

Intramuscular inoculation is required for individuals who have previously experienced dengue or to prevent it in those who have not contracted the virus. Qdenga®’s primary mechanism of action is local replication and the induction of neutralizing antibodies, which provide protection against dengue fever caused by any of the four dengue virus serotypes 22.

Qdenga® activates a variety of immune system defense mechanisms, including complement-based inhibitors, complement-based fusion inhibitors, functional inhibitors against dengue 1's nonstructural protein (NS1), and cell-mediated immune responses (CD4+, CD8+, and natural killer cells). A 0.5 ml dose of the Qdenga vaccine contains live and attenuated fragments of all serotipos DENV1, DENV2, DENV3, and DENV4, with 3.3, 2.7, 4.0, and 4.5 >= log10 UFP/dosis, respectively. 

On the other hand, the Advisory Committee on Immunization Practices recommends Dengvaxia®, the only dengue vaccine that is routinely used and approved by the US Food and Drug Administration 24. Sanofi Pasteur is the manufacturer. The vaccine protects against illness caused by any of the four dengue virus serotypes. A dose contains the quimeric dengue-fiebre amarilla virus (live and attenuated), and the DICC50/dosis for all serotypes ranges from 4.5 to 6.0 log10 DICC50 24.

Sanofi Pasteur licensed the first dengue vaccine (Dengvaxia®) in Mexico in 2015, and more than 20 countries followed, based on the safety and efficacy of two phase III trials and a single season of disease surveillance 31. Unfortunately, the optimism that a dengue vaccine would finally be available was quickly dashed when a safety signal was detected in vaccine recipients who were dengue non-immune at the time of vaccination 30. In the third year of the phase III clinical trial, the youngest, non-immune vaccine recipients had higher rates of hospitalization and severe dengue than their unvaccinated counterparts 10.

The Butantan-Dengue Vaccine, also called Butantan-DV, is similar to the NIH's previously tested TV003 formulation and was developed with ingredients licensed from the US NIH Hou et al., 2022. When they signed a co-development and licensing agreement in 2018, MSD joined the partnership. Participants in the phase III experiment, who ranged in age from 2 to 59 years old and received a single dose of vaccine, were monitored for any case of dengue, regardless of severity, caused by any strain of DENV 31. The trial began in 2016. The trial included both immune and non-immune individuals to dengue 31.

The United States National Institutes of Health (NIH) has created two live-attenuated single-dose vaccine candidates, TV003 and TV005, using deletions and structural gene chimerization 14. These vaccines include DENV-1, DENV-3, and DENV-4 strains that have 30 nucleotide deletions for attenuation. In phase 1 trials, there was no difference in adverse events (AEs) between vaccine and placebo groups. Phase 2 and 3 trials are currently underway in Taiwan and Brazil 14.

The complex relationship between dengue fever and its neurological aftereffects has been shown by the current investigation. New avenues for understanding and potentially mitigating the neurological impact of dengue virus (DENV) infection have been opened up by the discovery of genetic markers, including genome-wide association studies (GWAS), and the exploration of the underlying mechanisms of dengue virus neural invasion. Finally, new insights for the development of miRNA-based therapeutics will come from an understanding of the production and function of miRNAs during DENV infection and the associated signal molecules in the miRNA-mediated regulatory network.