Damian Sendler: The flavivirus dengue virus is the cause of dengue fever, a mosquito-borne viral disease (DENV). Dengue is responsible for an estimated 400 million cases and 22,000 deaths around the world each year. Tropical and subtropical regions have reported cases of the disease. This virus (DENV) is transmitted by Aedes mosquitoes in large numbers. Three structural proteins and seven non-structural proteins are found in the four antigenically distinct serotypes DENV-1 to DENV-4, each of which has a distinct genotype. Severe cases of dengue hemorrhagic fever or dengue shock syndrome (DSS) can manifest as thrombocytopenia, leucopenia, and increased permeability of the blood vessels. Immune responses against DENV serotypes are triggered by primary infection, but heterotypic infection with different serotypes and antibody-dependent enhancement increase disease severity (ADE). Some countries have not approved tetravalent CYD Denvaxia, which is the first licensed DENV vaccine. Obstacles to vaccine development include: a lack of an appropriate animal model, insufficient pathogen pathogenesis mechanistic studies, and antibody-dependent epitope exchange (ADE).
Damian Jacob Sendler: It has been a major public health concern for the last few decades that dengue fever is caused by the dengue virus (DENV) (Bhatt et al. 2013). As a result, it has been labeled a “neglected tropical disease” (Hotez et al. 2009). Approximately 400 million cases of dengue fever and 22,000 deaths occur each year around the world (Bhatt et al. 2013; Shepard et al. 2016). Patients with dengue infection may go undiagnosed for months or even years, but the disease has spread throughout the world through endemic and epidemic transmission cycles (Bhatt et al. 2013).
Dr. Sendler: One of the most common viruses in the family Flaviviridae, DENV is positive (+) stranded RNA-containing flavivirus in the species Dengue virus. Others in this family include the viruses that cause Japanese encephalitis, West Nile virus, and the disease that causes yellow fever (YFV). DENV has four distinct serotypes (serotypes 1, 2, 3, and 4) that differ antigenically from one another. DENV-5, a newly discovered fifth serotype, was found in the blood of a Malaysian patient in 2007 (Mustafa et al. 2015). Numerous mutations in the viral genome give rise to different serotype subtypes and genotypes. Supplementary Table S11 summarizes the genotypes and the endemic regions for each of them. Dengue fever has been found in all of India’s serotypes. Dengue infection causes a wide range of symptoms, from mild fever to severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). A single dengue serotype provides lifelong immunity to the disease, but only partial immunity to other dengue serotypes (Wahala and de Silva 2011). Dengue pathogenesis is complicated by the presence of an immune response known as antibody-dependent enhancement (Rothman and Ennis 1999).
Dengue virus infects humans in more than 100 countries each year, with roughly 3.6 billion people at risk (Diamond and Pierson 2015). (Diamond and Pierson 2015). Dengue fever has increased by 30 times in the last 50 years (CDC 2014). Travelers from endemic regions can contract DENV while on vacation in areas where the disease is prevalent. In addition to their impact on public health, these epidemics have a significant economic impact on the countries they affect, including India.
In Jakarta, Indonesia, and Cairo, Egypt, dengue fever was first documented in 1779. (Wu et al. 2011). A confirmed outbreak of the disease in North America occurred in Philadelphia in 1780, however (Rush 1951). In the years 2010–2016, the WHO (see WHO 1997) received an average number of suspected or confirmed dengue cases from around the world (Fig. 1). More than 1.6 million cases of dengue fever were reported in North and South America in 2010; 49 000 of these were severe cases.. More than 2.38 million cases of dengue fever were reported in the United States in 2016. Brazil accounted for the majority of the outbreak’s 1.5 million cases. More than 3 million cases of dengue fever have been reported in the United States so far this year (PAHO 2019).
Beginning in the early nineteenth century, outbreaks of dengue fever were documented in Africa’s eastern, western, and southern regions (Amarasinghe et al. 2011; Were 2012). Dengue virus serotypes 1, 2, and 3 were responsible for a number of outbreaks in East and West Africa between 1980 and 2000. (Sang 2007). Seychelles (1977-1979), Réunion Island (1977-1978), Djibouti (1992-1993), Comoros (1992-1993), and Cape Verde (2009) have all had large epidemics of dengue fever (Cornet 1993; Sang 2007).
After World War II, dengue outbreaks became a major problem in Southeast Asian countries, mainly because of urbanization (Ooi and Gubler 2009). Dengue hemorrhagic fever was first reported in the Philippines in 1953 and 1956, respectively, the first two outbreaks (Gubler 1998). There have been annual dengue epidemics in Southeast Asian countries since 1950. These outbreaks have affected countries like the Philippines and Bangkok in Thailand (Ooi and Gubler 2009). Indonesia had the second-highest number of dengue cases between 2004 and 2010, behind only Brazil. In 2009–2010, the majority of dengue cases in Indonesia were caused by serotype-4 (Taslim et al. 2018). However, severe dengue infection with serotype 3 was reported in 2013 (Lardo et al. 2016). Dengue virus serotype-1 was the most common in Indonesia between 2007 and 2010. (Sasmono et al. 2015).
Inoculating suckling mice with the serum of a dengue patient infected was how the dengue virus was first discovered in 1943 in Japan (Kimura 1944). Three dengue strains were isolated from dengue patients’ blood injected into the brains of white mice in successive generations between 1942 and 1945 using mice-brain passage experiments (Hotta 1952).
Dengue outbreaks involving all serotypes except DENV-5 have been reported on several occasions in the Indian subcontinent because of the region’s favorable climatic conditions (Dar et al. 2006; Mustafa et al. 2015). In India, there were approximately 16 000 cases and 545 deaths as a result of the 1996 epidemic (Mutheneni et al. 2017). Dengue’s incidence has risen steadily since 2010 to about 15 per million people in various states. In India, more than 100,000 infections result in death each year, and 200–400 people die as a result (NVBDCP 2021). In 2017, there was a dengue epidemic that resulted in 188,401 infections and 325 deaths (NVBDCP). In 1780, the first case of a clinical dengue-like illness was reported in Madras (today’s Chennai) (Gupta et al. 2012). It wasn’t until 1946 that a “virus” was found to be the cause of dengue fever (Gupta and Ballani 2014). There was no major dengue epidemic until 1963. All DENV serotypes were detected in the northern part of West Bengal, especially in the Siliguri, Darjeeling, Jalpaiguri, and Alipurduar regions in 2019–2020.
Spiral-shaped dengue virions have a diameter of approximately 50 nm, an outer protein layer on the surface of the lipid bilayer, and an inner nucleocapsid core, according to electron micrographs (Kuhn et al. 2002) This is shown in (Fig. 2B). Capsid (C), membrane (M), envelope (E), and seven other non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5) make up DENV’s three structural proteins (Perera and Kuhn 2008). Detailed information about DENV’s structural and nonstructural proteins can be found in Table 1. E protein dimers were found to be arranged in a herringbone-like pattern in virion envelope reconstructions from cryo-electron micrographs (Fig. 2B). Glycoproteins in an icosahedral shape are found on the outer surface of the spherical immature and mature particles, which are derived from the ER membrane. Lipid bilayer contains an inner-most nucleus made up of a ssRNA genome and capsid proteins (C). This nucleus is an RNA–protein complex. Mature and immature DENV are infectious and non-infectious depending on the conformational changes in the M and E proteins at different pH levels in the environment (Perera and Kuhn 2008). An immature (spiky) to an adult (smooth) morphology structural transition happens as a result of E protein conformational changes in the trans-Golgi network (TGN) (Modis et al. 2004). In the TGN (low pH), E proteins bound to membrane proteins undergo conformational changes prior to DENV maturation (Yu et al. 2008). Peptides that are released from E protein after maturation have infectious properties (pH 7.0) in the extracellular space (Figs 3A–3D). The molecular structures of the nonstructural proteins NS1, NS2A, NS4A, and NS44B are largely unknown at the present time for various reasons. NS1 aids viral RNA replication as well as viral defense by inhibiting complement activation (Lindenbach and Rice, 1999). (Chung et al. 2006). One part of the replication complex is made up of the NS2A protein and the NS4B protein (Chambers et al. 1989). One strand of the DENV genome is approximately 11 kilobases long (Miller et al. 2006). Untranslated regions (UTRs), open reading frames (ORFs), and the 3′ UTR region are all parts of the RNA genome (Fig. 4). The genome lacks a poly (A) tail at the 3′ end and has a type I cap (m7GpppAmp) at the 5′ end with a single ORF that encodes a polyprotein.
In the event of a successful infection, DENV primarily attacks and replicates in dendritic cells and infects macrophages, monocytes, and lymphocytes, as well (Wan et al. 2018). Cell surface molecules like Fc receptors, glycosaminoglycans (GAG), lipopolysaccharide-binding CD14 associated molecules, heparan sulfate, and DC-SIGN receptors are used for receptor-mediated endocytosis (dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin). Cellular clathrin-coated vesicles allow DENV entry into cells (Seema and Jain 2005). Acidification of late endosomes results in structural changes to the E protein, which results in the fusion of viral and host cell membranes and the subsequent release of the nucleocapsid into the cytoplasm (Fig. 5). The acidic pH of the endosome helps the virus bind to the endosome membrane. Nucleocapsid (NC) release occurs after the RNA genome is uncoated and viral materials are transported to the ER by the cytoskeletal transport machinery. Cap-dependent translation of the DENV positive-stranded RNA into a polyprotein is the first step in the process. At the ER membrane, positive-sense RNA serves as a template for the replication of the RNA genome. To produce both negative and positive strand viral RNA, DENV’s NS5 protein, which is involved in RNA cap methylation and RdRp activity, is required (El Sahili and Lescar 2017). Translation of viral capsid proteins takes place in the cytoplasm, while viral E and M proteins are inserted into the ER membrane while translation is taking place. As soon as enough positive-sense anti-genome RNA copies have been transcribed from negative anti-genome RNA, capsid proteins in the cytoplasm wrap the genomic RNA and it enters the ER lumen where it picks up the M (produced by the furin-mediated proteolysis of the host protease PrM) and E-containing envelope from the ER (Fischl and Bartenschlager 2011). During virion assembly and release, pH affects the conformation and organization of the E protein on the mature virion surface (see Fig. 3). After passing through the ER and the trans-Golgi network, the virions that were previously enveloped are left in the lumen. ER-derived outer membranes are added to enveloped virions in the final step of the process, as they enter the cytoplasm (Fig. 5). To release the mature progeny virions from their envelopes, the ER membrane and plasma membrane fuse, allowing them to enter the extracellular space (Diamond and Pierson 2015).
Aedes aegypti and Aedes albopictus are the primary and secondary vectors of DENV, respectively (Carrington and Simmons 2014). Aedes aegypti is an endophilic (i.e., water-breeding in containers) and day-biting (i.e., blood-feeding) mosquito that lives primarily in tropical and subtropical regions and can be found on nearly every continent except Antarctica (Carrington and Simmons 2014). (Thavara et al. 2001). This species of mosquito is a more aggressive day-time biter, which is exophilic in natural field conditions, but it still feeds almost exclusively on humans. Aedes albopictus (Ponlawat and Harrington 2005; Delatte et al. 2010). Four DENV serotypes are transmitted in two cycles: sylvatic (wild animal transmission) and human (human infection) (Chen and Vasilakis 2011). The sylvatic cycle is distinct from the human transmission cycle in both ecology and evolution. Sylvatic environments of Southeast Asia and West Africa, peninsular Malaysia and eastern Senegal are maintained by non-human primates or by a monkey-Aedes-monkey cycle (Rudnick 1986).
Damian Sendler
Both laboratory diagnosis using a culture or blood sample and the detection of anti-dengue antibodies in serum/plasma are methods for detecting dengue infection. Serum, plasma, or circulating blood cells or tissue can contain DENV for the first 1 to 7 days after infection, which is when the fever is at its peak. As long as the appropriate primers are used, RT-PCR or conventional PCR (using appropriate oligonucleotides) can be used to isolate the virus or viral RNA for detection within that time period. Body fluid viral loads can be quantified using quantitative PCR (Q-PCR). Serum/plasma samples of patients are tested for anti-dengue immunoglobulin M (IgM) antibodies and/or non-structural protein 1 (NS-1) antigens using either enzyme-linked immunosorbent assays (ELISA) or immunochromatographic-based rapid card tests (Fig. 6). Hemagglutination-inhibition (HI), complement fixation (CF), neutralization (NT), IgM capture enzyme-linked immunosorbent assay (MAC-ELISA), and indirect IgG ELISA are the five most accurate serological tests for diagnosing dengue infection. Cross-reactivity with other flaviviruses (e.g. Zika virus) compromises the accuracy of the NS1 and IgM diagnostics (Wellekens et al. 2020).
A wide range of symptoms, ranging from a mild fever to more serious physiological conditions, are associated with dengue virus infection. Dengue fever (DF) is the most common symptom of a primary infection with a specific dengue serotype, which can be asymptomatic or cause mild disease symptoms (Mathew and Rothman 2008).
In DHF, hemostasis malfunction, increased vascular permeability, and severe increased vascular leakage can lead to DSS with shock, which is a severe febrile disease with these symptoms. Reduced peripheral perfusion from DSS, a hypovolemic shock, can cause tissue damage and multi-organ failure. The DHF goes through various stages, including critical and convalescent. Thrombocytopenia (less than 100 000 cells/cu. mm) and high hemoconcentration (up to 20% increase in hematocrit from baseline in patients of the same age) are required by the WHO to diagnose DHF.
Infected cells’ first line of defense is thought to be the production of interferons (IFNs) (Rodenhuis-Zybert et al. 2010). Interstitial dendritic cells (DCs) are first infected by DENV, which then activates the production of both Type I and Type II IFNs within hours (Shresta et al. 2004). Natural killer (NK) cells produce IFNs as part of the virus clearance process in the host (Azeredo et al. 2006). Infected cells have DENV sensors that are Toll-like receptors (TLRs). RNA from the dengue virus is primarily recognized by intracellular TLRs like TLR3, TLR7, and TLR8, all of which belong to the TLR family (Sariol et al. 2011). Following acidification of the endosome, TLR3 recognizes DENV RNA and induces strong IL-8 and IFN-/ responses (Green et al. 2014). It is believed that when TLR3 recognizes DENV-RNA, it activates the TIR domain-containing adaptor interferon (TRIF), which phosphorylates and engages in interactions with TRAF3 and TRAF6 (Fig. 7A). To activate NF-B, TRAF6 works with TAK1 to dephosphorylate IKB and activate AP1. Other than that, TRAF3 interacts with TNK-1 and IKK-1, leading to the phosphorylation of the IRF3 protein. Once activated, activated IRF3, AP-1, and NF-B translocate to the nucleus, where they induce transcription of IFN-, ISGs, and other cytokines (both interferons and chemokines), including IFN- and IFN-/. (Lee et al. 2012). MyD88, an adaptor molecule involved in the MAPK and NF-B pathways, is also involved in the induction of IFN-/ via TLR7/8/9 (Kao et al. 2018).
Virus-infected cells undergo an extensive reorganization of their membranes (e.g., unfolded protein response causes ER membrane expansion). As a result, DENV is able to maintain host metabolism and protein production without being degraded by host lysosomes. Cellular pathways are activated to promote ER expansion and increase fat metabolism, but the delicate balance between these two processes must be maintained to avoid the risk of ER stress-induced death being compromised. Autophagy is utilized by DENV to aid in viral replication. As a final point, DENV non-structural proteins directly affect the innate immune response signaling cascade, preventing the RNAi pathway and IFN-/ induction/signaling from taking effect. Non-structural protein 4B (NS4B) and subgenomic flavivirus RNA are both involved in DENV’s interference with RNAi pathways (sfRNA). To prevent RNAi, NS4B interferes with Dicer’s ability to function. DENV sfRNAs interfere with Dicer’s ability to cleave dsRNA by binding to RNase NS4B. Different mechanisms are used by DENV non-structural proteins to thwart the antiviral responses of the host. In order to avoid the innate immune system’s detection, the viral NS5 protein forms 2′-O-methylation on the 5′-cap structure of the viral RNA (Tremblay et al. 2019). Denial-of-service attacks (DENV) can also disrupt IFN induction by mimicking the function of melanoma differentiation-associated gene 5 (MDA5) (Dong et al. 2012). RIG-I/MAVS interaction is disrupted by DENV NS4A’s ability to bind to MAVS CARD domains and prevent host immune responses (He et al. 2016). By recruiting the viral NS2B-NS3 protease, DENV directly suppresses the host’s antiviral IFN (type I) pathway (Aguirre et al. 2012). The innate immune response is regulated by DENV NS2A and NS4B, which inhibit TBK1/IKK-directed downstream signaling (Dalrymple et al. 2015). Staining of STAT1 and nuclear translocation of ISGs are prevented by viral NS2A, NS4A and NS4B proteins (Fig. 7B). The DENV NS5 protein connects UBR-4 and STAT2 by binding to the STAT protein. ubiquitination and proteasome-mediated degradation of STAT2 are directed by this bridge (Ashour et al. 2009). Finally, DENV’s ability to disrupt the host’s innate immune response may influence the adaptive immune response and influence disease outcomes.
Damian Jacob Markiewicz Sendler: It takes approximately 6 days for an infection to trigger an adaptive immune response, during which cellular and humoral immunity are both developed. DENV antigens can be recognized by CD4+ T lymphocytes, which help to generate antibodies against DENV envelope protein (E) (domain III) and PrM glycoprotein on DENV’s surface (Gromowski and Barrett 2007; Lai et al. 2008). Evidence suggests that CD8+ T cells preferentially recognize non-structural proteins, but CD4+ T cells preferentially recognize structural proteins (Rivino et al. 2013). By activating naive CD4+ and CD8+ T cells to differentiate into virus-lysis effector T cells, or by producing cytokines, DENV infection causes an adaptive immune response (Rothman 2011). There are two ways in which activated CD4+ cells respond to viral infection with the aid of helper T cells: Th1 and Th2. Intracellular DENV infection is disrupted by the production of IL-2, IFN- and TNF- by Th1 cells, which in turn increases inflammatory responses and tissue damage. There are several cytokines secreted by Th2 cells that aid in T-cell activation and proliferation specific to these cell types, such as interleukin 4, 5, 6, 10, and 13. (Sun and Kochel 2013). B-cells produce the anti-NS1 antibody because the NS1 protein is so critical to DENV biology and is found in high concentrations in the sera of infected individuals. The complement system is activated by these NS1 soluble antibodies, which lyse DENV-infected cells. By binding to TLR4, the DENV NS1 protein activates macrophages and PBMCs, disrupting blood vessel endothelial cell monolayer integrity (Modhiran et al. 2015). DENV-infected cells’ NS1 proteins interact with TLR4 on platelets’ plasma membranes. P-selectin (e.g. CD62P or platelet activation dependent granule membrane protein) is upregulated, leading to an increase in apoptotic pathways and the destruction of platelets (Chao et al. 2019). Anti-DENV NS1 antibodies can activate the NF-B pathway, resulting in the release of multiple inflammatory factors (Lin et al. 2005). DHF’s pathogenesis is thought to be largely influenced by the imbalanced release of various cytokines. As a result of the interaction between viral epitopes on infected cells and memory T cells, pro-inflammatory cytokines are produced, which damage the vascular endothelium and cause plasma leakage. Disease severity in DHF and DSS is associated with elevated levels of IL-2R, soluble CD4, and soluble CD8 (Kurane et al. 1991).
Damian Jacob Sendler
Antipyretics and tepid sponging are the most common methods of treating a fever or pain from a dengue virus infection. However, several seaweed sulfated polysaccharides have been studied and found to have high antiviral activity against DENV, despite the lack of a specific antiviral drug for dengue (Damonte et al. 2004). G3d and C2S-3, two seaweed polysaccharide compounds, showed antiviral activity against all DENV serotypes by interfering with virus internalization inside the host cell by blocking host cell receptors (heparan sulfate) that allow the virus to enter the cell (Talarico et al. 2005). By interfering directly with the viral E protein and altering the structure of that protein, sulfated polysaccharide Curdlan also showed an inhibitory effect on DENV (Ichiyama et al. 2013). Caulerpa cupressoides, a coenocytic green seaweed, has also been shown to inhibit DENV-1 infection pathogenicity in vitro (Rodrigues et al. 2017). Nucleoside biosynthesis is inhibited in the host cell by the combination of ribavirin (a guanosine analog) and other nucleotide analogs (brequinar, INX-08189) (Patkar and Kuhn 2006; Yeo et al. 2015). Interferons against DENV are secreted in response to Glycyrrhizin and its derivatives or modified products, which inhibit DENV protein transport and post-translational modifications (Baltina et al. 2019). When taken up by cells, 6-azauridine, a uridine analogue, inhibits de novo pyrimidine synthesis and DNA synthesis and is converted intracellularly into mono-, di-, and triphosphate derivatives, which are then incorporated into RNA and inhibit protein synthesis (NCBI PubChem Database 2021). In vitro and in vivo studies have shown that NITD008 (a nucleoside adenosine analog) has antiviral effects against DENV and all other flaviviruses (Yin et al. 2009). Curcumin (from turmeric), an experimental antiviral drug, was recently tested for its anti-dengue activity. Inhibiting DENV replication, curcumin and its analogs, such as bis-demethoxy curcumin (CC2), acyclic curcumin (CC3), and cyclohexanone curcumin (CC5), showed efficacy in preventing severe infection (Balasubramanian et al. 2019). Other experimental antiviral treatments using CP26, CDDO-me, UV-4B, ivermectin, and ketotifen are also in trial and face great difficulties in controlling dengue fever (Wellekens et al. 2020).
In the absence of effective and long-term vector control, the development of a DENV vaccine has become a top priority. The main obstacles to the development of a DENV vaccine are the virus’s complicated pathogenesis and ADE effect, as well as the virus’s evolving genome. With an average mutation rate of 10–3 substitutions/nucleotide/replication round, DENV could evolve into a new lineage of viruses over time (Dolan et al. 2021). For example, in 2006–2008, a new lineage of DENV-3 emerged in India, and in 2011, a cosmopolitan genotype of DENV-2 emerged in India (Harapan et al. 2020). Dengue outbreaks are caused by the emergence and replacement of new genotypes of DENV, and developing a vaccine to combat this could be a difficult task.
Damien Sendler: The use of animal models is the most efficient and reliable method of evaluating the fundamental immunology for the development of vaccines against DENV infections (Shresta et al. 2006). Before testing in non-human primates, mice are the most commonly used animal model. Asian rhesus macaques of Indian origin may serve as an animal model for dengue hemorrhagic fever, according to recent research (Onlamoon et al. 2010). Researchers have created a dengue-infected mouse model (AG129) that shows both mild and severe signs and symptoms, as well as clinical features, that can be used for vaccine trials and antiviral drug discovery. C57BL/6J hTNF+++, IFN-/R / Tg, Tg HLA-A*02:01, and B10.Tg HLA-DR3 have also been established as genetically engineered or transgenic mouse dengue models for research purposes (reviewed in Coronel-Ruiz et al. 2020). Several studies have found that DENV can infect and replicate in the fibroblasts of the northern treeshrew, Tupaia belangeri (Bustos-Arriaga et al. 2011).
It is the most developed attenuated vaccine candidate that has undergone numerous phase I trials in the United States. Inactivated whole-virion vaccines, synthetic peptides, subunit vaccines, vector expression, recombinant live vector systems, infectious cDNA clone-derived vaccines, and naked DNA are just a few of the molecular technologies currently being used to develop an alternative DENV vaccine (Gubler 1998; Blaney et al. 2004). Sanofi Pasteur CYD-TDV (Dengvaxia), DENVax, and TV005 vaccines are currently being tested in large clinical trials for tetravalent DENV vaccines (Diamond and Pierson 2015). Phase III trials are currently underway for the latter two (Prompetchara et al. 2019).
The first licensed dengue vaccine, the tetravalent chimeric yellow fever virus-DENV (CYD), has just been approved for clinical use in Mexico, Thailand, Brazil, El Salvador, and Costa Rica, among other countries (Aguiar et al. 2016; Prompetchara et al. 2019). It was developed by Sanofi Pasteur (Mexico) based on a yellow fever (YF) 17D vaccine virus backbone, chimerized with prM and E proteins from DENV1-4 replacing the YF prM and E (Guy et al. 2015), and is currently registered in the European Union, the United States, and 20 other dengue-endemic countries (Guy et al. 2015) (Thomas and Yoon 2019). However, only Brazil and the Philippines have dengue vaccination programs in place (Thomas and Yoon 2019). Initially, it was only approved for use in dengue-endemic areas in specific doses for people aged 9–45 or 9–60. Children aged 9–16 in Latin America who received CYD-TDV had a favorable safety profile and developed antibodies against all four dengue serotypes (Villar et al. 2013). This recommendation was made in 2016, but only for patients aged 9 and over, and not for those who were not vaccinated against Dengvaxia. US Food and Drug Administration (FDA) approved Dengvaxia in the territories of Guam, Puerto Rico, and the US Virgin Islands as the first vaccine approved for the prevention of dengue disease caused by dengue virus serotypes 1, 2, 3, and 4 only for people between the ages of 9 and 16 who live in dengue-endemic areas and have confirmed dengue infections (Thomas and Yoon 2019).
Dengue vaccine DENVax, developed by the Centers for Disease Control and Prevention (CDC, USA) in collaboration with Inviragen and now licensed to Takeda, is another promising tetravalent recombinant live-attenuated vaccine (Osaka, Japan). For 48 months after vaccination, TAK-003 showed antibody responses against all four serotypes, with no risk of severity in the case of seropositive or seronegative baseline seropositive individuals (Tricou et al. 2020). TAK-003 demonstrated high efficacy in children aged 4–16 years in a phase III clinical trial involving both seropositive and seronegative patients (Biswal et al. 2020). DENV serotypes differed in terms of immunogenicity, but why this is the case is still a mystery to researchers. For DENV-1, DENV-2 (the most effective), and DENV-3, TAK-003 was effective (80.6 percent of the time) in both previously seropositive and previously seronegative participants (Biswal et al. 2019). Its effectiveness against DENV-4 infections, on the other hand, remains in question.
Another tetravalent vaccine candidate (TV005) (NIAID, USA) contains a mixture of modified full-length and chimeric DENV strains and is based on directed mutagenesis, resulting in attenuation without sacrificing immunogenicity. (Prompetchara et al. 2019). DENV-1, DENV-3, and DENV-4 strains were mutated at the 3′ end, and a DENV-2/4 chimera was constructed using the DENV-4 backbone and the DENV-2 prM and E, in place of the DENV-4 prM and E. (Whitehead 2016). There were four vaccine candidates used to make TV003 before it: rDEN1D30, rDEN2/4D30, rDEN3D30 and rDEN4D30. 90% of those who received TV005 developed neutralizing antibodies against all four DENV serotypes after just one dose (Kirkpatrick et al. 2015). V180 vaccine (DEN1-80, Hawaii Biotech) and D1ME100 DNA vaccine are two other vaccines currently being studied (Wellekens et al. 2020).
Three well-known Indian vaccine manufacturers, Panacea Biotec, Serum Institute, and Biological E, have received clinical development and commercialization licenses for the live-attenuated tetravalent vaccine TV003/TV005 (Swaminathan and Khanna 2019). The Indian National Regulatory Authority has given Pancea Biotech permission to conduct human trials on monovalent vaccines. First and second trials will be conducted in northern and southern India to evaluate the safety, reactogenicity, immunogenicity, and efficacy of TetraVax-DV (TV-003/TV-005) (Swaminathan and Khanna 2019). Panacea Biotech has tentatively scheduled its commercial launch for 2020 following the vaccine’s trial. Preclinical toxicity studies for TetraVax-DV are currently being conducted at the Serum Institute of India. Department of Biotechnology (DBT) under Indian Ministry of Science and Technology, Department of Health Research/ Indian Council of Medical Research (DHR/ICMR) under Indian Ministry of Health and Family Welfare and the National Institute of Allergy and Infectious Diseases (NIAID) of the United States National Institutes of Health, Department of Health and Human Services, have recently decided to prioritize collaborative research on promising dengs..
Due to the lack of an effective vaccine to control the severity of dengue by all serotypes, dengue has grown into a serious health problem for humans. An individual’s defense against the dengue virus has not yet been determined. Complex and multi-factored pathogenesis of DHF and DSS can be found in both viral and host factors. It is imperative that dengue virus vaccines be affordable because most countries affected by outbreaks are economically disadvantaged. Although some live-attenuated tetravalent vaccines are licensed for dengue and some are in the trial stage, the unique complexity of DENV pathogenesis and its relationship to immune enhancement are the main obstacles to the development of an efficient dengue vaccine. To better understand how the host’s genetics and soluble proteins, like cytokines and chemokines, affect the body’s resistance to dengue virus infection, more research is needed. PDVI and WHO have worked together to characterize antibody responses in order to distinguish between neutralizing and virally-enhancing features that may be present. Tetravalent vaccines based on live-attenuated DNA viral vectors are the subject of current research. The creation of an appropriate animal model for dengue infection should also be an important part of the research. Because the number of effective dengue drugs and vaccines is so small, we must also pay attention to vector control strategies. Additionally, human activities such as water retention in plastic, metal containers, and cement tanks increase the breeding of dengue-infectious mosquitoes, which in turn spreads the disease. The management of dengue vector mosquitoes should include environmental, chemical, and biological methods. In order to reduce the spread of the dengue virus, these strategies should concentrate on high-human–vector contact areas. Dengue virus infections could be reduced with insecticide-treated curtains and new mosquito traps. Surveillance is an important part of dengue prevention because it provides the necessary data for risk assessment and program implementation. We need data on DENV serotypes or genetic sequences infected people in epidemic areas, along with a correlation of mild/severe illness caused by primary or secondary infection, with the circulating serotype.
