Dengue Virus: Infection, Immunological Response, and Vaccine Development

In the tropics and subtropics climates worldwide, the dengue virus (DENV) is the most common of arboviruses and a significant public health threat. The severe disease usually occurs during the primary infection, but more serious cases begin after the second instance of infection with a different serotype. Humans' innate immune system is composed of monocytes, macrophages, and dendritic cells, and they are capable of mounting rapid inflammatory responses. These cells are also called primary antigen-presenting cells, and they are essential for the formation of the immune system's long-term memory mechanisms. Through scientific advances, valuable knowledge into the pathogenesis of more serious diseases, and new methods to the production of dengue vaccines and antiviral drugs have been provided. We summarized details in the current literature review, including references, abstracts, and full text of journal articles. So that, we tried to review all available studies that projected existing awareness about the immune response to the dengue virus and the current status of the vaccine. Such information was selected and extracted from the PubMed, Web of Science, and Google Scholar databases for published data from 2000 to 2020 using relevant keywords containing a combination of terms, including dengue fever, epidemiology, clinical manifestation, immune response, and vaccine.


INTRODUCTION
Dengue virus (DENV) is a single-stranded RNA virus in the genus Flavivirus. It consists of four serotypes strongly linked but antigenically different. In more than 125 tropical and subtropical countries worldwide, the virus is widespread [1,2].
The most prevalent DENV transmission method is through the Aedes mosquitoes. The predominant vector of DENV is Aedes aegypti, a highly domesticated mosquito, but DENV Transmission may also be maintained by Aedes albopictus [3]. Few studies of other transmission routes, such as blood or bone marrow transfusion and solid organ transplantation [4].
Even though dengue is a well-known illness, there are variations in its clinical manifestations. In most cases, the DENV-associated condition varies from asymptomatic to acute febrile selflimiting disease. Case definitions for DENV infection are Dengue fever (DF), Dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS), which were provided by the World Health Organization (WHO) [5]. Increased dengue infection shows damage to organs such as the brain, liver, heart, or kidneys, a relevant and significant feature that has been reported in some cases, but that has been very hard to connect to the virus given the variable severity of these complications. As a result of these complications, the WHO has included organ injury in the recommendations for severe dengue cases [6]. For example, neurological effects may appear during or after acute infection, may be intermittent or permanent [7], and may involve both the central [8] and peripheral nervous systems [9].
For DENV infection, the three main immune cells are monocytes, macrophages, and dendritic cells (DCs). These cells are the significant phagocytic cells responsible for identifying and eliminating invasive pathogens in the innate immune system. They are antigen-presenting cells (APCs) that are important for adaptive cellular immunity to be initiated, expanded, and polarized. DENV targeting these cells can have a profound effect on immune modulation [10].
Dengue also takes a heavy economic burden on impacted nations' health care services. For the past sixty years, the battle for a good vaccine for dengue has been underway, but any successful cure or vaccine remains uncertain. Vaccination must be safe and less cost-effective. Several approaches were used to create the goal vaccines [11,12].
In this article, we tried to review all available studies that projected existing awareness about the immune response to the dengue virus and the vaccine's current status.

Study Design
The revised details on the Dengue virus immune response and vaccines were summarized in this literature review. Such information was selected and extracted from the PubMed, Web of Science, and Google Scholar databases for published data from 2000 to 2020 using relevant keywords including dengue fever, epidemiology, clinical manifestation, immune response, and vaccine.

Epidemiology
Dengue is becoming a public health concern in recent years, as the cumulative prevalence has grown dramatically in the past 20 years, and no suitable antiviral medications are easily accessible [13].
The epidemiological model assesses how about 390 million individuals living in 128 countries in endemic or epidemic regions get the most common form of arbovirus infection each year [14,15]. Around 60 million symptomatic DF cases will rise per year, leading to ten to twenty thousand deaths [16]. Last two decades, the dengue rate recorded to WHO rises from 505,430 in 2000, over 2.4 million in 2010, and 4.2 million in 2019 [17]. Reported cases of death from 960 to 4032 increased from 2000 to 2015 [18].
In 2020, dengue continued to affect several countries of Southeast Asia, with reports of increases in the numbers of cases in the Philippines, Malaysia, Vietnam,and Banglash [19], and Yemen [20], [21]. High number of cases were reported in Bangladesh (101,000), Malaysia (131,000) Philippines (420,000), Vietnam (320,000) in Asia [19]. The highest number of cases of dengue ever recorded worldwide was in 2019. All areas were affected, and dengue transmission was reported for the first time in Afghanistan [22]. About 3.1 million cases have been registered in the American region alone, with more than 25,000 identified as severe [23].
The incidence of dengue infections spread by two species of Aedes mosquitoes is affected by climate change. For their growth, survival, and feeding behavior, dengue and other arbovirus vectors, including chikungunya, Zika virus, and yellow fever, rely on temperature and precipitation [24]. Dengue transmission is highly temperature-sensitive, affecting generation time, the period from one vector-to-human transmission cycle to the beginning of a new cycle [25]. The epidemic possibility is defined by vectorial capacity. Global vector potential for the transmission of the dengue fever virus was recorded as the highest on record in the 2018 Lancet climate Countdown survey, rising to 9·1 percent for Aedes Aegypti and 11.1 percent for Aedes Albopictus, more than the baseline of the 1950s [26]. The most up-to-date maps reveal that these Aedes species are present on all continents, including North America and Europe [27]. Latest studies suggest Aedes Albopictus is widespread in Europe due to its rapid growth in the last few years [28]. Eggs of different mosquito types. The albopictus mosquito has been observed both north and south of the European continent [29], and the mosquito vector is expected to spread ever farther across Europe [30], as well as into uncolonized regions of China [31].

Clinical disease
The Dengue virus achieves entrance through the skin into the host organism after an infected bite of the mosquito. The disease's development includes humoral, cellular, and innate host immune responses and the more serious clinical signs arise after the rapid clearance of the virus from the host organism. Therefore, the most serious clinical appearance during the infection is not associated with a high viral load [32]. The WHO framework categorizes infections with the symptomatic dengue virus into an undifferentiated fever, DF syndrome, and DHF ( Fig. 1) [33].

Classic dengue fever
DF is a severe flu-like illness affecting people of all age groups (infants, children, adolescents, and adults) [34]. Fever, headache, retro-orbital pain, generalized skin rash, myalgia, and arthralgia are the classical manifestation of moderate DF type. The first symptom of DF may be skin lesions, which can be effective in creating the diagnosis. The rash is common in DF, with an occurrence recorded in some> 80% studies and maybe evanescent and polymorphic in appearance in some studies [35]. It is possible to predict a full recovery from dengue fever, while certain dengue infections lead to atypical severe disease without DHF or DSS symptoms [ Human NK cells, representing 10-15% of all circulating lymphocytes, are bone marrowderived lymphocytes that share a common progenitor with T-cells. The primary lymphoid population involved in innate immunity constitutes NK cells. Virally infected cells and activated resident macrophages are quickly recruited into infected organs and tissues through chemoattractant stimuli [69]. To restrict viral replication during the early stages of DENV infection and thus reduce corresponding pathogenesis, early activation of NK cells and type-I INF-dependent immunity may be necessary. Cytokines that reduce inflammation and tissue injury are also produced by NK cells [70,71]. In a DENV-infected mouse model, early activation of NK cells and B-lymphocytes could be significant for primary DENV infection clearance [70].
Moreover, viral antigens were observed in DENV-infected cells such as Kupffer cells, alveolar macrophages, endothelial cells, lymphocytes, and monocytes [73]. This viral load constitutes a significant risk factor for serious disease progression. The infection of these cells essentially impairs hemostatic and immune responses to DENV. Infected cells die primarily via apoptosis and, to a lesser degree, via necrosis. Necrosis tends to trigger toxic agents that cause the mechanisms of fibrinolysis and coagulation. Depending on the degree of inflammation of bone marrow stromal cells and interleukin levels such as IL-6, IL-8, IL-10, and IL-18, hemopoiesis is inhibited, resulting in decreased blood thrombogenicity. Platelets are closely aligned with endothelial cells and retain vascular integrity, requiring an average number of functioning platelets. High blood virus load and probable viral tropism of endothelial cells, severe thrombocytopenia, and platelet dysfunction may contribute to serious capillary fragility, clinically described as petechiae, simple bruising, and gastrointestinal mucosal bleeding identified by DHF [74].
Many innate immune response cells are granulocytes that retain mediators, including particular inflammatory proteins and cytokines [75]. The most abundant leukocytes in the blood are neutrophils, which are an essential element of innate immunity. Chemotaxis is induced by epithelial cells, and resident macrophages, which secreted chemokines like IL-8 and other cytokines such as TNF-alpha and IFN-β. These neutrophils generate TNF-alpha that can act against viral infections and create cationic peptides cysteine, defined as defensins. [76]. Little information is available regarding the role of these cells during viral infection. The circulating levels of neutrophilic elastase and lactoferrin in children with DENV infection were evaluated in early work described by Juffrie et al. They found a significant rise in IL-8, which is significantly related to neutrophil degranulation [77]. Blood examination of patients suffered from DHF also revealed a slightly earlier rise (5-6 days) in the number of immature neutrophils but a later increase (10-12 days) in the number of mature neutrophils. These data indicated that neutrophils could promote the stimulation of complement, coagulation, and fibrinolytic system, creating an aberrant immune activation [78]. Recent research revealed that DENV could form neutrophil extracellular traps (NETs) In Vitro [79]. A study conducted found that the amount of neutrophil elastase is higher in people afflicted with DENV. Patients with DHF had slightly higher elastase activity levels compared to patients without DHF, which meant that inflammation could be related to the more severe form [80]. Opasawatchai et al. have recently studied the genotype and functional reactions of neutrophils in DENV patients. The findings exhibited that neutrophils upregulate CD66b expression during acute DENV infection and generate a more vigorous respiratory reaction. In cells isolated from DENV-infected patients during the acute process of infection, drastic decondensation of nuclei, an early event in NET growth, has also been markedly increased. The in vitro incubation of the DENV-2 virus within the NETs significantly decreased infectivity. In the serum of patients with DHF, but not uncomplicated DF, elevated amounts of NET components were found. Also, the levels of pro-inflammatory cytokines were elevated relative to those in DF patients. They indicated that during DENV infection, NETs may perform a dual function and neutrophils are participated in immunological responses [81].

The Complement system
The complement system is also one of the immune response to the infection. It is composed of over 30 different soluble and cell surface proteins, and the complement system is an essential component of innate immune responses to different pathogens. It is triggered by classical, lectin, and alternative pathways and controlling viral infections by different mechanisms, including virion or infected cell lysis, anaphylatoxin production, and T and B cell response [82]. Recent research by Avirutnan et al. is starting to focus attention on the dual function of the complement system in DENV infection defense and pathogenesis [83]. Anti-DENV antibodies could cause supplementation on the surface of infected endothelial cells in an in vitro study [84]. In a prospective study, NS1 could activate complement proteins correlated with disease severity [85]. In another prospective study, complement factors were high in DHF patients than in DF patients [86]. The association between NS1 activity and complement activation or altered complement activation regulation in dengue pathogenesis was recorded in these studies [85,86].

Innate immune pathways for dengue virus detection
Immune cells are the first to respond to infection by a pattern recognition receptor (PRR) [87,88]. When DENV is internalized in cells, dsRNA intermediates are produced throughout viral genome replication [89]. Crucially, PRRs generated by different susceptible cell types in the skin can detect this crucial step of the DENV replication cycle [90]. PRR recognition may enable the development of cytokines and chemokines that cause an antiviral condition to occur. Type 1 interferon (IFN) responses are caused by activating these PRR [91,92]. Activation of TLR-3 contributes to the activation of transcriptional interferon regulatory factors IRF-3and IRF-7. This results in transcriptional upregulation of type I (alpha and β) INF [93][94][95]. However, the IFN plays a key role in complex innate and adaptive immune processes, including tolerance to viral entry, promotion of T-cell immune response, and successful antibody class-switching responses [96].

Adaptive Immune Response
Infection clearance is linked to humoral and cellular adaptive immune responses to DENV infection and plays a significant role in protecting against re-infection. It is also considered to play a key role in decreasing the severity of the disease seen in patients with DHF or DSS [48].
A series of events targeted at healing and pathogen removal is provoked by stimulation of macrophages and mast cells at pathogen entrance areas. These lead to inflammatory mediators release, alteration of tight endothelial junctions, and adhesion molecules. Allow the recruiting of other innate immune cells to the site and the activation of neighboring resident tissue cells to respond to the threat (Fig. 5) [97][98][99].

B cells and antibody responses
During infection with DENV, B cells have been seen to play a significant role, demonstrated by the latest findings of a substantially high number of plasmablast/plasma cells that occur during the acute phase [101]. In order to cause B cell proliferation and differentiation into effector plasma cells or long-lived memory B cells, activation of B cells by dengue-specific B cell receptor (BCR) has been clarified [102].
In the adaptive immune system, B cells play an important role in the secretion of antigen-specific antibodies that shield and react to invading pathogens. Activated B cells contribute to the development of immunoglobulins (IgM, IgG, and IgA) unique to viruses, most of which attach to the viral envelope protein and neutralize virions, thereby blocking them from reaching target cells. IgE will stimulate innate immune cells via the high-affinity crystallizable fragment (Fc) epsilon receptor, which is displayed at significant concentrations on mast cells and elevated on activated DCs [103].
The main DENV infection has a reasonably normal immune response, via an initial IgM followed by an IgG response to dengue antigens. An increased IgG with a reduced IgM is observed during secondary infection. [104]. Plasma cells and titers of DENV-specific antibodies rise in the blood within days after infection. Using human serum-deprived from IgM, it was shown that the IgG reaction already accounted for ~50 % of the neutralizing potential of DENV-specific immune serum at 4-7 days after the onset of fever. In comparison to other viral infections, such as HIV, which may cause hypergammaglobulinemia, only a small rise in the activation of polyclonal B cells was found [105]. In addition, the DENV-specific B cells in primary infection are extremely serotypespecific [106].
The main targets of antibodies produced during primary and secondary DENV infections are the E, prM, and NS1 proteins. Antibodies to E and prM have been shown by antibody-dependent enhancement (ADE) to improve infection of Fc receptor-bearing cells in vitro, and this has been hypothesized to lead to in vivo pathogenesis [107].
Numerous mechanisms can deter infection, including preventing binding, inhibiting the virus fusion with the endosomal vacuole, which prevents the release of viral RNA, and complementary lysis of the antibody-coated virus [108,109]. In animal studies, the antibodymediated defense has been successfully confirmed by the active transmission of antibodies to envelop proteins [110,111].

Adaptive T cell responses
The cell-mediated adaptive immune response consists of CD4+ and CD8+ T cells to enable B cells to activate and destroy virally infected host cells [112]. While T cells play an important role in the battle against viral infections, both harmful and defensive actions of T cells in the sense of DENV infection have been recorded [65, [113][114][115].
Dendritic cells link innate and adaptive immune responses. In vitro, infected DCs stimulate T cell IFN-γ production [116][117][118]. Others revealed that DENV-infected DCs mediated the immediate propagation of naive CD4+T cells but stayed nonpolarized in the role of the effector. Down regulation of the production of IFN-alpha/βstimulated genes [119]. Both types of T cells play a defensive role in murine models towards DENV infection, avoiding serious illness and promoting viral clearing [120][121][122][123].
Another subset of CD4 T cells is called follicular T helper cells (Tfh), which allows T cells to support and activate B cells [124]. Protective functions in human infectious diseases and vaccines have been identified with Tfh cells [125][126][127]. They supply B cells with many types of T cell assistance, like stimuli encouraging survival, chemoattraction, proliferation, division of plasma cells, hypermutation, and recombination of class switches. They are important and have an evident responsibility to protective immunity against pathogens [128].
For infected APCs, tissue-resident CD8+ T cells roam the skin and can produce instant adaptive immunity. Cytotoxic cells CD8 and CD4 + T produce cytotoxic molecules including granzymes and perforins that can destroy virusinfected cells through pathways based on MHC I and MHC II. By generating inflammatory cytokines such as IFN-γ and TNF-alpha, T helper (Th1) cells mediate and encourage antiviral immune responses, while regulatory CD4+T cells inhibit inflammation induced by immune response by generating cytokines like IL-10 and transforming growth factor (TGF)-β. DENVspecific germinal center B cells are aided by Tfh cells and are important for efficient germinal center reactions, facilitating high-affinity antibodies, memory B cells, and long-lived plasma cells [112].
Studies in both the murine and humans established defensive HLA alleles associated with strong T cell responses [129].

Dengue Virus Vaccine
With many dengue cases worldwide, vaccine production has a promising prospect to control the disease, especially to protect children from infection. Dengue has four distinct serotypes; the affected person has long-term immunity against a subsequent infection with a related DENV serotype following regeneration of one serotype. However, subsequent DENV infection with a different serotype is associated with ADE, a mechanism that leads to the manifestation of DHF [107,130]. Therefore, vaccine production should promote long-lasting immunity and simultaneously defend against all four DENV serotypes. A list of vaccine candidates is summarized in Table 1.
Multiple candidates for tetravalent vaccines are being created. That includes live-attenuated vaccines, inactivated whole-virus vaccines, protein-based vaccines, chimeric vaccines, and synthetic particle-like mRNA virus vaccines [131].
Four serotypes form the dengue serocomplex, each of which consists of multiple genotypes [132]. The four serotypes share genetic homology of 65-75 % with one another and are antigenically different. This high level of pathogen sequence heterogeneity, characteristically correlated with RNA viruses, presents special vaccine production obstacles [113].

Live attenuated vaccines (LAV)
Live attenuated (LAV) vaccinations appear to replicate natural infection by inducing humoral and cellular responses that elicit long-lasting immunity. LAVs comprise a weaker version of a live virus [133].
Serial dilutions have been used to attenuate DENV by culturing with primary dog kidney (PDK) cells, accompanied by a final passage with fetal rhesus lung cells. The monkeys are used to test applicants for vaccines and screen them. The DENV-2, -3, and -4 vaccines showed a mild reaction. DENV-1 attenuated, leading to fever and rash in 40 % of trial patients [134].
Just 30 percent overall effectiveness was demonstrated by a live-attenuated tetravalent chimeric yellow fever dengue vaccine (CYD23), showing partial (60-80 percent) defense against three out of four DENV serotypes. Despite three subsequent immunizations and high neutralization titers, no defense against DENV2 infection against all four serotypes was observed [135].
The optimal dengue vaccine should be given in single doses, give protection against all serotypes, provide long-term protection with no side effects [136]. Actually, in around 20 dengueendemic countries in Asia, Latin America, Oceania and Europe, there is only one vaccine approved for the protection against dengue. This LVA recombinant tetravalent vaccine is the Dengvaxia (CYD-TDV) established by Sanofi Pasteur [41]. Phase III experiments revealed the vaccine's effectiveness that relied on age, serostatus, and serotype and revealed a benefit at the population level. This vaccine is only approved for individuals between the ages of 9 and 45 years of age who live in an infected area. This vaccine is also not available to the people most at risk of developing severe dengue-related symptoms. Unfortunately, the vaccine has less protection against serotypes 1 and 2 than serotypes 3 and 4 [137,138].

Chimeric live attenuated vaccines
The most developed vaccine is the chimeric vaccine for dengue/yellow fever since its genetic backbone incorporates one of the DENV serotypes with the yellow fever E and prM genes. It was shown that this vaccine was attenuated, reliable, healthy and significantly improbable to be transmitted by arthropod vectors [139]. Chimer Ivax-Dengue (Sanofi Pasteur) produces dengue-only antibodies [140].
Another chimeric live vaccine was the PDK-53 DEN-2 vaccine. In primary PDK, this virus has been amplified by passage. The DENV-2 genes are replaced by those of DENV-1, 3, and 4. In the United States and Colombia, step 1 safety trials are ongoing. The three attenuating mutations are found outside the structural protein genes and tend to be very stable. If delivered to mice and monkeys, the tetravalent vaccine is developed by merging four chimeric dengue viruses [141,142].
Phase III trials are currently in progress on two live-attenuated dengue vaccines. Takeda is developing one such live-attenuated dengue vaccine. The DENVax vaccine formed of attenuated DENV-2 (DEN2-PDK-53), whereas three chimeric DENV-1, DENV-3 and DENV-4 are incorporated into the backbone of DEN2-PDK-53. Therefore, the distinction from Dengvaxia is the presence of NS proteins attributable to the backbone of DENV2. In phase one and two clinical trials, this vaccine performed well with high neutralizing antibody titers in nonhuman primates and humans [143].
The National Institutes of Health (NIH) developed the other tetravalent live-attenuated dengue vaccine. It is undergoing trials in Brazil, but even other pharmaceutical manufacturers have produced vaccines based on the same principle. The vaccine comprises three full-length DENV serotypes amplified by one or multiple NS3 deletions, while the fourth is a chimeric virus wherein the DENV 2 prM and E replaces NS3 in the DENV-4 [144]. This vaccine behaved well during the phase I and II trials and was effective [145].

Inactivated vaccines
The method of purified formalin-inactivated whole virus vaccine is a promising vehicle for the production of a vaccine for tetravalent dengue, but findings have been less than satisfactory. It has been shown that formaldehyde treatment induces intermolecular cross-links between proteins that contribute to altered conformation changes and antigenic epitopes [145,146]. WRAIR has manufactured a purified, inactivated DENV-2 vaccine [147].

DNA vaccines
Vector-based vaccines using DNA technology have been exposed to animal research recently. A DNA vaccine is a plasmid that contains one or more unique antigens encoding genes that can be inserted in vivo to express antigens and activate immune responses. BALB/c mice were vaccinated intradermally with a DNA vaccine expressing prM and E protein of DENV2 [148]. The effectiveness of three non-replicating DENV2 vaccines in rhesus monkeys alone or conjunction has been tested by scientists [149]. DNA vaccines are safe, simple to prepare, low-cost and ideal for commercial production, lacking increased immunogenicity. The approaches to address this problem can also be plasmid alteration with highly effective promoters, alternate distribution mechanisms, multiple doses, and co-immunization with adjuvants [150].

Efficacy of the Dengue Vaccine
CYD-TDV has been approved in many countries. The approvement is based on a vaccine effectiveness of 56 to 61 percent against virologically verified dengue among children in Asia and Latin America [151,152]. In a phase 3 large-scale randomized clinical trial of TAK-003 vaccine involving children from 4 to 16 years living in Latin America and Asia, Biswal et al. recently tested the efficacy, safety, and immunogenicity of two doses of TAK-003. They confirmed that TAK-003 was successful towards symptomatic [153].
In a massive, multicounty trial, an experimental dengue vaccine has shown positive early results, but crucial concerns remain about its efficacy and safety. For example, it is also uncertain if the vaccine that had an 80.2 percent effectiveness in the study could increase the seriousness of the disease in some patients, as occurred with a dengue vaccine given to 1 million children in the Philippines before the issue became apparent in 2017 [154].
In selected highly endemic areas, the Philippines were the first country to implement Dengvaxia on a wide scale, targeting around 1 million children aged 9-10 years. An excess risk of hospitalization for dengue and extreme dengue was identified in November 2017 in vaccine subjects who did not have a prior dengue infection at the time of vaccination. Sanofi revealed a recent discovery that when given to people not previously exposed to dengue, their new dengue vaccine presents a risk 2012-2015, dengue reports were very high, overflowing hospital emergency rooms and resembling a' war zone'. There was a 65% growth in the number of dengue cases Philippines between 2014 and 2015. At the end of 2015, there were 200,415 confirmed dengue cases and 598 deaths, compared with 121,000 cases recorded in 2014 [156]. The news on the safety issues of dengue vaccines led to substantial public outrage, with lack of faith in vaccines spreading to standard childhood vaccines [157].
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread steadily across the world since December 2019. The strength and rate of transmission of SARS has contributed to major incidence and death, placing tremendous strain on public health services around the world and on the global economy. The development of SARS vaccines and therapeutics is therefore a top priority and a very active area [158] points should be learned from the long and years. An excess risk of hospitalization for dengue and extreme dengue was identified in November 2017 in vaccine subjects who did not have a prior dengue infection at the time of vaccination. Sanofi revealed a recent discovery that when given to people not previously exposed to dengue, their new dengue vaccine presents a risk [155]. From 2015, dengue reports were very high, overflowing hospital emergency rooms and resembling a' war zone'. There was a 65% growth in the number of dengue cases in the Philippines between 2014 and 2015. At the end of 2015, there were 200,415 confirmed dengue cases and 598 deaths, compared with 121,000 The news on the safety issues of dengue vaccines led to with lack of faith in vaccines spreading to standard childhood The severe acute respiratory syndrome 2) has spread steadily across the world since December 2019. The strength and rate of transmission of SARS-CoV-2 has contributed to major incidence and death, placing tremendous strain on public health services around the world and on the global economy. The development of SARS-CoV-2 vaccines and therapeutics is therefore a top 158]. Important points should be learned from the long and complex process of producing a vaccine against dengue. First, apart from neutralizing action, we know that it is important to thoroughly analyze the titers of antibodies caused by any vaccine. Like observed in both DENV infection SARS-CoV-2 infection [160], low neutralizing antibodies titers induced infection not protection. Secondly, population genetic analysis of 103 corona virus -2 genomes found that corona virus-2 developed into two main for form on the basis of gene mutations human populations, over six human coronaviruses are prevalent, and even more are prevalent in wild animal species. To date, it is unknown if the ongoing mutation and recombination of SARS-CoV-2 coul other SARS-CoV-2 serotypes, or even to another novel coronavirus. Vaccine candidates that can offer protection against divergent coronaviruses would also be desirable. Last, clinical evidence found that the efficiency and effectiveness of dengue vaccines could be impaired by serotype, baseline serostatus, and age [152, findings advised that applicants for SARS vaccines should be carefully tested in a number of animal models in order to validate their protection and effectiveness and that participants in the human sample should represent different communities. This is further emphasized by the varying seriousness of SARS-CoV age and sex at greater risk of serious illness during primary infection [163].

WHO classification of symptomatic dengue infection [33]
; Article no.JPRI.65418 complex process of producing a vaccine against dengue. First, apart from neutralizing action, we know that it is important to thoroughly analyze the titers of antibodies caused by any vaccine.
ved in both DENV infection [159] and , low neutralizing antibodies titers induced infection not protection. Secondly, population genetic analysis of 103 2 genomes found that corona 2 developed into two main forms L and S form on the basis of gene mutations [161]. In human populations, over six human viruses are prevalent, and even more are prevalent in wild animal species. To date, it is unknown if the ongoing mutation and 2 could give rise to 2 serotypes, or even to another novel coronavirus. Vaccine candidates that can offer protection against divergent coronaviruses would also be desirable. Last, clinical evidence found that the efficiency and effectiveness of ngue vaccines could be impaired by serotype, 152,162]. These findings advised that applicants for SARS-CoV-2 vaccines should be carefully tested in a number of animal models in order to validate their protection and effectiveness and that participants in the human sample should represent different s. This is further emphasized by the CoV-2 based on age and sex at greater risk of serious illness

FUTURE PROSPECTS
In the future, DENV research will most probably remain a challenging and exciting area. Future directions for the prevention and treatment of dengue infection are mosquito (vector) spread, dengue vaccine production, and antiviral drugs.
The need to develop a dengue vaccine has highly acquired significance due to the progressive transmission and rising incidence of dengue infection. There is a need for a safe, reliable, and economical tetravalent dengue vaccine for global public health. One approved vaccine is Dengvaxia by Sanofiadministration of the vaccine has been widely debated by various parties [41].
The current antiviral study has focused on discovering novel compounds targeting the replication and innate immune evasion proteins responsible for DENV. The NS4b targeting compound inhibits all four serotypes synthesis. There are several possible targets of NS2B/NS3 protease that decrease infectivity. Also, complement-mediated lysis was induced by a monoclonal antibody against NS1 had defensive effects in vivo. Scrupulous efforts aim to produce antiviral medications that can be used to stabilize DF and prevent life events [164].
Mosquito (vector) spread management achieved by holding in standing water guppies ( reticulata) or copepods (doridicola agilis

Innate and adaptive immune responses to dengue virus [100]
In the future, DENV research will most probably remain a challenging and exciting area. Future directions for the prevention and treatment of dengue infection are mosquito (vector) spread, dengue vaccine production, and antiviral drugs.
op a dengue vaccine has highly acquired significance due to the progressive transmission and rising incidence of dengue infection. There is a need for a safe, reliable, and economical tetravalent dengue vaccine for global public health. One approved -Pasteur. The administration of the vaccine has been widely The current antiviral study has focused on discovering novel compounds targeting the replication and innate immune evasion proteins nsible for DENV. The NS4b targeting compound inhibits all four serotypes in vitro RNA synthesis. There are several possible targets of NS2B/NS3 protease that decrease infectivity.

CONCLUSION
Dengue has grown as a major public health issue that affects survival, affecting about 2.5 billion people in more than 100 countries. The doctor should be aware of this disease's different clinical symptoms and ensure that the treatment procedure is timely and sufficient. The doctor should also be aware of the immune repose to the dengue virus infection mechanism and involved cells. Greater knowledge of this immune response may help to solve the dengue prevention and eradication puzzle. Future directions to fight this awful disease are directed at mosquito surveillance, vaccine production, and antiviral drug regimen techniques.

LIMITATION OF THE STUDY
This literature review did not involve projects for university study and theses from students regarding this research's limitations. Also, not all cells of the immune system involved in the immune response have not been covered.

CONSENT AND ETHICAL APPROVAL
As per international standard or university standard guideline participant consent and ethical approval has been collected and preserved by the authors.

100]
infecting the mosquito population with bacteria of Dengue has grown as a major public health issue that affects survival, affecting about 2.5 billion people in more than 100 countries. The doctor should be aware of this disease's different clinical symptoms and ensure that the treatment and sufficient. The doctor should also be aware of the immune repose to the dengue virus infection mechanism and involved cells. Greater knowledge of this immune response may help to solve the dengue prevention and eradication puzzle. Future ht this awful disease are directed at mosquito surveillance, vaccine production, and

LIMITATION OF THE STUDY
This literature review did not involve projects for university study and theses from students g this research's limitations. Also, not all cells of the immune system involved in the immune response have not been covered.

CONSENT AND ETHICAL APPROVAL
As per international standard or university standard guideline participant consent and approval has been collected and