Perceptions of dengue risk and acceptability of a dengue vaccine in residents of Puerto Rico.

Dengvaxia is the first dengue vaccine recommended in the United States (U.S.). It is recommended for children aged 9-16 y with laboratory-confirmed previous dengue infection and living in areas where dengue is endemic. We conducted focus groups with parents and in-depth interviews with key informants (i.e. practicing pediatricians, physicians from immunization clinics, university researchers, and school officials) in Puerto Rico (P.R.) to examine acceptability, barriers, and motivators to vaccinate with Dengvaxia. We also carried out informal meetings and semi-structured interviews to evaluate key messages and educational materials with pediatricians and parents. Barriers to vaccination included lack of information, distrust toward new vaccines, vaccine side effects and risks, and high cost of/lack of insurance coverage for laboratory tests and vaccines. Motivators included clear information about the vaccine, a desire to prevent future dengue infections, the experience of a previous dengue infection or awareness of dengue fatality, vaccine and laboratory tests covered by health insurance, availability of rapid test results and vaccine appointments. School officials and parents agreed parents would pay a deductible of $5-20 for Dengvaxia. For vaccine information dissemination, parents preferred an educational campaign through traditional media and social media, and one-on-one counseling of parents by healthcare providers. Education about this vaccine to healthcare providers will help them answer parents' questions. Dengvaxia acceptability in P.R. will increase by addressing motivators and barriers to vaccination and by disseminating vaccine information in plain language through spokespersons from health institutions in P.R.

Implications of information heard about Dengvaxia on Filipinos' perception on vaccination.

Issues that arose from the Dengvaxia vaccination program in the Philippines in 2017 were followed by a remarkable decline in immunization coverage in the country. This study intended to describe the Filipinos' perceptions about vaccination after hearing about the Dengvaxia vaccine and the vaccination program and determine its potential relationship with selected demographic factors and other variables such as: health literacy, sources of information on Dengvaxia, information heard about the vaccine, healthcare visits, and perceived health status. The study utilized secondary data derived from a national health literacy survey in the Philippines. A total of 1992 respondents were included in the analysis. Majority were females, had reached college, residing in urban areas, and were unemployed. Most obtained information about Dengvaxia from media, particularly the television and heard that it caused death and prevents dengue. Seventy-one per cent had negative vaccination perception upon obtaining information about Dengvaxia. Sex, residence type, and income were found to be associated with vaccination perception. Females and those living in rural areas were more likely to have a negative vaccination perception while those with the highest income were less likely to have negative vaccination perception. Respondents who heard that Dengvaxia prevents dengue, those who obtained Dengvaxia information from health professionals, and those who visited both public and private health facilities in the last 12 months were less likely to have negative vaccination perception. On the other hand, those with inadequate functional health literacy were more likely to have negative vaccination perception. The study presents the implications of information heard about Dengvaxia on Filipinos' perception on vaccination through selected variables and other factors. The findings are important in designing strategies in communicating health information, building public trust, and in reinforcing policies to improve vaccination uptake.

A Novel, Comprehensive A129 Mouse Model for Investigating Dengue Vaccines and Evaluating Pathogenesis.

In search of a mouse model for use in evaluating dengue vaccines, we assessed A129 mice that lacked IFN-α/ß receptors, rendering them susceptible to dengue virus (DENV) infection. To our knowledge, no reports have evaluated dengue vaccine efficiency using A129 mice. A129 mice were given a single intraperitoneal (IP) or subcutaneous (SC) injection of the vaccine, Dengvaxia. After 14 days of immunization via the IP or SC injection of Dengvaxia, the A129 mice exhibited notably elevated levels of anti-DENV immunoglobulin G and neutralizing antibodies (NAb) targeting all four DENV serotypes, with DENV-4 displaying the highest NAb levels. After challenge with DENV-2, Dengvaxia and mock-immunized mice survived, while only the mock group exhibited signs of morbidity. Viral genome levels in the serum and tissues (excluding the brain) were considerably lower in the immunized mice compared to those in the mock group. The SC administration of Dengvaxia resulted in lower viremia levels than IP administration did. Therefore, given that A129 mice manifest dengue-related morbidity, including viremia in the serum and other tissues, these mice represent a valuable model for investigating novel dengue vaccines and antiviral drugs and for exploring dengue pathogenesis.

Dengue Vaccination: Towards a New Dawn of Curbing Dengue Infection.

Dengue is an infectious disease caused by dengue virus (DENV) and is a serious global burden. Antibody-dependent enhancement and the ability of DENV to infect immune cells, along with other factors, lead to fatal Dengue Haemorrhagic Fever and Dengue Shock Syndrome. This necessitates the development of a robust and efficient vaccine but vaccine development faces a number of hurdles. In this review, we look at the epidemiology, genome structure and cellular targets of DENV and elaborate upon the immune responses generated by human immune system against DENV infection. The review further sheds light on various challenges in development of a potent vaccine against DENV which is followed by presenting a current account of different vaccines which are being developed or have been licensed.

Philippine immunization coverage and dengvaxia: An infodemiological study.

BACKGROUND: A dengue vaccine, dengvaxia, was licensed for the first time in 2015. It was approved for use in 11 countries where dengue infection is endemic, including the Philippines. In November 2017, controversy arose in the Philippines regarding the dengvaxia vaccine. We hypothesized that the dengvaxia controversy might be correlated with immunization coverage in the Philippines. METHODS: We performed an analytical and infodemiological study on web-based interest in dengvaxia, both globally and in 18 dengue endemic countries, from 2015 to 2020 using Google Trends™. Comparisons were made with search trends for the components of the National Immunization Program (NIP) and vaccine coverage by computing the Pearson product-moment correlation coefficient (r) between each variable. RESULTS: Among the 18 countries included, the Philippines had the highest search volume index for dengvaxia, with peaks in searches coinciding with that of worldwide search trends. There was no correlation between the relative search volume for dengvaxia with that of vaccines included in the NIP in the Philippines from 2015 to 2020. There was no significant correlation between web-based interest in dengvaxia and the estimated immunization coverage from 2015 to 2019. CONCLUSION: There was no significant correlation between web-based interest in dengvaxia, the vaccines in the NIP, and national immunization coverage.

Identification of prior dengue-naïve Dengvaxia recipients with an increased risk for symptomatic dengue during fever surveillance in the Philippines.

Introduction: Dengue virus (DENV) is the leading cause of mosquito-borne viral diseases in humans. Dengvaxia, the first licensed dengue vaccine, is recommended for DENV-seropositive individuals aged 9-45 years. In the Philippines, Dengvaxia was administered to more than 830,000 children without prior serological testing in 2016-2017. Subsequently, it was revealed that DENV-seronegative children who received Dengvaxia developed severe disease following breakthrough DENV infection. As a result, thousands of children participating in the mass vaccination campaign were at higher risk of severe dengue disease. It is vital that an assay that identifies baseline DENV-naïve Dengvaxia recipients be developed and validated. This would permit more frequent and extensive assessments and timely treatment of breakthrough DENV infections. Methods: We evaluated the performance of a candidate assay, the DENV1-4 nonstructural protein 1 (NS1) IgG enzyme-linked immunosorbent assay (ELISA), developed by the University of Hawaii (UH), using well-documented serum/plasma samples including those >20 years post-DENV infection, and tested samples from 199 study participants including 100 Dengvaxia recipients from the fever surveillance programs in the Philippines. Results: The sensitivity and specificity of the assay were 96.6% and 99.4%, respectively, which are higher than those reported for pre-vaccination screening. A significantly higher rate of symptomatic breakthrough DENV infection was found among children that were DENV-naïve (10/23) than among those that were DENV-immune (7/53) when vaccinated with Dengvaxia (p=0.004, Fisher's exact test), demonstrating the feasibility of the assay and algorithms in clinical practice. Conclusion: The UH DENV1-4 NS1 IgG ELISA can determine baseline DENV serostatus among Dengvaxia recipients not only during non-acute dengue but also during breakthrough DENV infection, and has implications for assessing the long-term safety and effectiveness of Dengvaxia in the post-licensure period.

Neurological Manifestations of Perinatal Dengue.

Dengue viruses (DENVs) are single-stranded RNA viruses belonging to the family Flaviviridae. There are four distinct antigenically related serotypes, DENVs types 1, 2, 3, and 4. These are all mosquito-borne human pathogens. Congenital dengue disease occurs when there is mother-to-fetus transmission of the virus and should be suspected in endemic regions in neonates presenting with fever, maculopapular rash, and thrombocytopenia. Although most of the infected infants remain asymptomatic, some can develop clinical manifestations such as sepsis-like illness, gastric bleeding, circulatory failure, and death. Neurological manifestations include intracerebral hemorrhages, neurological malformations, and acute focal/disseminated encephalitis/encephalomyelitis. Dengue NS1Ag, a highly conserved glycoprotein, can help the detection of cases in the viremic stage. We do not have proven specific therapies yet; management is largely supportive and is focused on close monitoring and maintaining adequate intravascular volume.

'I was terrified for my child': understanding the link between the Dengvaxia® controversy and the measles vaccine hesitancy in Pasay City, Philippines.

BACKGROUND: The Dengvaxia® (dengue vaccine) controversy has been identified as one of the main reasons for the measles vaccine hesitancy in the Philippines. Our study aimed to identify various issues related to the Dengvaxia® controversy and to link these issues with the social perspective of measles vaccine refusal. METHODS: Semi-structured interviews and a focus group discussion using ethnography research were conducted with 41 parents and healthcare workers in Pasay City. Using Victor Turner's Social Drama Theory, our study identified existing social issues relating to the different angles of the Dengvaxia® controversy and the measles vaccine hesitancy. RESULTS: Misinformation on the failed Dengvaxia® rollout implementation has challenged the fundamental understanding of the importance of immunization programs. Our findings on vaccine hesitancy in the community showed a complex problem with compounded factors, including medical populism, moral panics and other social views. We described how Pasay City's clinic waiting room became a significantly important scenario where individuals often discuss information, concerns and experiences on vaccines and vaccine hesitancy. CONCLUSION: Our study suggests that the Dengvaxia® controversy may reduce the measles vaccination confidence in the Philippines. Lack of transparency played a crucial role in this dilemma, producing a cascading effect on the other vaccines' safety.

'Mix and Match' vaccination: Is dengue next?

The severity of the COVID-19 pandemic and the development of multiple SARS-CoV-2 vaccines expedited vaccine 'mix and match' trials in humans and demonstrated the benefits of mixing vaccines that vary in formulation, strength, and immunogenicity. Heterologous sequential vaccination may be an effective approach for protecting against dengue, as this strategy would mimic the natural route to broad dengue protection and may overcome the imbalances in efficacy of the individual leading live attenuated dengue vaccines. Here we review 'mix and match' vaccination trials against SARS-CoV-2, HIV, and dengue virus and discuss the possible advantages and concerns of future heterologous immunization with the leading dengue vaccines. COVID-19 trials suggest that priming with a vaccine that induces strong cellular responses, such as an adenoviral vectored product, followed by heterologous boost may optimize T cell immunity. Moreover, heterologous vaccination may induce superior humoral immunity compared to homologous vaccination when the priming vaccine induces a narrower response than the boost. The HIV trials reported that heterologous vaccination was associated with broadened antigen responses and that the sequence of the vaccines significantly impacts the regimen's immunogenicity and efficacy. In heterologous dengue immunization trials, where at least one dose was with a live attenuated vaccine, all reported equivalent or increased immunogenicity compared to homologous boost, although one study reported increased reactogenicity. The three leading dengue vaccines have been evaluated for safety and efficacy in thousands of study participants but not in combination in heterologous dengue vaccine trials. Various heterologous regimens including different combinations and sequences should be trialed to optimize cellular and humoral immunity and the breadth of the response while limiting reactogenicity. A blossoming field dedicated to more accurate correlates of protection and enhancement will help confirm the safety and efficacy of these strategies.

Efficacy of Dengue Vaccines in the Prevention of Severe Dengue in Children: A Systematic Review.

Dengue is a vector-borne disease caused by the dengue virus (DENV) and is a major health concern worldwide, particularly in regions of endemic disease. Dengue usually presents as a self-limited febrile illness. In some cases, more severe forms with hemorrhage and shock can occur, and children are especially prone to develop it. These forms can be lethal without appropriate management, and no antiviral treatment exists today. In the absence of a curative treatment for dengue, its clinical prevention remains essential. One vaccine - the chimeric yellow fever-dengue-tetravalent dengue vaccine (CYD-TDV) - has been approved for use in some populations, and several others are currently in development, including Takeda's tetravalent dengue vaccine candidate (TAK-003). This study is a systematic review of the current literature realized to evaluate the efficacy of the dengue vaccines in preventing severe dengue in children. This review focuses on the vaccines CYD-TDV and TAK-003. This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, PubMed Central (PMC), Medical Literature Analysis and Retrieval System Online (MEDLINE), Cochrane Library, and Google Scholar were the databases used to find the relevant data. The articles were selected using specific inclusion and exclusion criteria, and quality appraisal was realized with standardized quality assessment tools. Overall, our study shows that the dengue vaccines CYD-TDV and TAK-003 confer protection against severe dengue in children. Some distinctions exist depending on the vaccine type, the age, and the dengue serostatus of patients. While demonstrating encouraging results, this review also emphasizes the need for more in-depth studies about the safety and efficacy of dengue vaccines.

A cross-sectional survey to evaluate prescribers' knowledge and understanding of safety messages following Dengvaxia® product information update.

PURPOSE: We evaluated the effectiveness of additional risk minimisation measures (aRMMs; i.e., educational materials) distributed to prescribers to ensure that only individuals with evidence of prior dengue infection (PDI, i.e., dengue seropositive) would be vaccinated with the tetravalent dengue vaccine (CYD-TDV; Dengvaxia®). METHODS: A survey was conducted in 2020 among 300 CYD-TDV prescribers in Brazil and Thailand to ascertain three success criteria: prescribers' awareness of the materials (receiving and reading them); knowledge of the key messages; and whether their self-reported behaviour regarding practice-related scenarios was aligned with the updated guidance. RESULTS: The aRMMs were not generally effective as <80% of prescribers in both countries met two of the three predefined success criteria. In Brazil, 98.7% were aware of the aRMMs whereas in Thailand this criterion was fulfilled by 74.0%. Almost all prescribers knew that CYD-TDV was recommended only in individuals with PDI (98.7% and 96.7% in Brazil and Thailand, respectively). In Brazil, where vaccination was restricted to those with a documented history of PDI, 11.3% considered that confirmation should be done through a blood test. More than 75% in both countries considered additional signs of dengue, as early warning signs, and not only those regarded as such by the 2009 WHO guidelines. CONCLUSIONS: These results do not support that the aRMMs were effective as the predefined success criteria were not met. The use of reliable rapid diagnosis tests together with the revised prescribing information and educational materials will facilitate the implementation and compliance with pre-vaccination screening for CYD-TDV eligibility.

Current Development and Challenges of Tetravalent Live-Attenuated Dengue Vaccines.

Dengue is the most common arboviral disease caused by one of four distinct but closely related dengue viruses (DENV) and places significant economic and public health burdens in the endemic areas. A dengue vaccine will be important in advancing disease control. However, the effort has been challenged by the requirement to induce effective protection against all four DENV serotypes and the potential adverse effect due to the phenomenon that partial immunity to DENV may worsen the symptoms upon subsequent heterotypic infection. Currently, the most advanced dengue vaccines are all tetravalent and based on recombinant live attenuated viruses. CYD-TDV, developed by Sanofi Pasteur, has been approved but is limited for use in individuals with prior dengue infection. Two other tetravalent live attenuated vaccine candidates: TAK-003 by Takeda and TV003 by National Institute of Allergy and Infectious Diseases, have completed phase 3 and phase 2 clinical trials, respectively. This review focuses on the designs and evaluation of TAK-003 and TV003 vaccine candidates in humans in comparison to the licensed CYD-TDV vaccine. We highlight specific lessons from existing studies and challenges that must be overcome in order to develop a dengue vaccine that confers effective and balanced protection against all four DENV serotypes but with minimal adverse effects.

Public trust and the COVID-19 vaccination campaign: lessons from the Philippines as it emerges from the Dengvaxia controversy.

While the entire world prepares and begins to roll out COVID-19 vaccines, the Philippines is still reeling from the consequences of the Dengvaxia controversy in 2016. Those highly political events led to the erosion of public trust in leaders and a significant damage to vaccine confidence in the country, now potentially impacting the uptake of COVID-19 vaccines. We discuss how public trust and confidence can be rehabilitated through accountability, transparency, and proper communication from the most trusted sources of the population. We also highlight key lessons for policymakers and leaders on allowing science to take the front seat, and politics behind, for the safety and well-being of the people during this public health crisis.

Implementation strategies for the first licensed dengue vaccine: A meeting report.

Dengue vaccination would enhance the control of dengue, one of the most frequent vector-borne viral diseases globally. CYD-TDV is the first dengue vaccine to be licensed, but global uptake has been hampered due to its use being limited to seropositive persons aged 9 years and above, and the need for a 3-dose schedule. The Partnership for Dengue Control (PDC) organized a meeting with key opinion leaders and stakeholders to deliberate on implementation strategies for the use of CYD-TDV. New data have emerged that support the shortening of the primary schedule from a 3 to 2 dose schedule, extending the age range below 9 to 6 years of age, and expanding the indication from endemic populations to also include travelers to endemic areas. Cost-effectiveness may improve with the modified 2-dose regimen and with multiple testing. Strategies to implement a dengue vaccination program have been developed, in particular school-based strategies. A range of delivery scenarios can then be considered, using various settings for each step of the intervention. However, several challenges remain, including communication about limiting the use of this vaccine to seropositive individuals only. Affordability will vary from country to country, as will government commitment and community acceptance. Well-tailored communication strategies that target key stakeholders are expected to make up a significant part of any future dengue vaccination program.

Dengvaxia: the world's first vaccine for prevention of secondary dengue.

The objective of this manuscript was to review and evaluate the efficacy and safety data of Dengvaxia for the treatment of severe secondary dengue infection. Dengvaxia is the brand name for chimeric yellow fever-dengue-tetravalent dengue vaccine (CYD-TDV). A literature search through PubMed was conducted using the keywords 'dengue vaccine', 'Dengvaxia', 'efficacy' or 'safety'. Trials were selected if they appropriately assessed vaccine efficacy or were related to the vaccine approval process for CYD-TDV. Findings from this review underline the evolution of vaccine efficacy against seroprevalence, serotypes, and various ages. There are currently no preventive measures or antiviral treatments for dengue; CYD-TDV is the first vaccine to receive US Food and Drug Administration approval. Protective responses seen with the complete administration of CYD-TDV can become a standardized tool as part of a world vaccination program.

Antibody-Dependent Enhancement: A Challenge for Developing a Safe Dengue Vaccine.

In 2019, the United States Food and Drug Administration accorded restricted approval to Sanofi Pasteur's Dengvaxia, a live attenuated vaccine (LAV) for dengue fever, a mosquito-borne viral disease, caused by four antigenically distinct dengue virus serotypes (DENV 1-4). The reason for this limited approval is the concern that this vaccine sensitized some of the dengue-naïve recipients to severe dengue fever. Recent knowledge about the nature of the immune response elicited by DENV viruses suggests that all LAVs have inherent capacity to predominantly elicit antibodies (Abs) against the pre-membrane (prM) and fusion loop epitope (FLE) of DENV. These antibodies are generally cross-reactive among DENV serotypes carrying a higher risk of promoting Antibody-Dependent Enhancement (ADE). ADE is a phenomenon in which suboptimal neutralizing or non-neutralizing cross-reactive antibodies bind to virus and facilitate Fcγ receptor mediated enhanced entry into host cells, followed by its replication, and thus increasing the cellular viral load. On the other hand, antibody responses directed against the host-cell receptor binding domain of DENV envelope domain-III (EDIII), exhibit a higher degree of type-specificity with lower potential of ADE. The challenges associated with whole DENV-based vaccine strategies necessitate re-focusing our attention toward the designed dengue vaccine candidates, capable of inducing predominantly type-specific immune responses. If the designed vaccines elicited predominantly EDIII-directed serotype specific antibodies in the absence of prM and FLE antibodies, this could avoid the ADE phenomenon largely associated with the prM and FLE antibodies. The generation of type-specific antibodies to each of the four DENV serotypes by the designed vaccines could avoid the immune evasion mechanisms of DENVs. For the enhanced vaccine safety, all dengue vaccine candidates should be assessed for the extent of type-specific (minimal ADE) vs. cross-reactive (ADE promoting) neutralizing antibodies. The type-specific EDIII antibodies may be more directly related to protection from disease in the absence of ADE promoted by the cross-reactive antibodies.

Hidden heterogeneity and its influence on dengue vaccination impact.

The CYD-TDV vaccine was recently developed to combat dengue, a mosquito-borne viral disease that afflicts millions of people each year throughout the tropical and subtropical world. Its rollout has been complicated by recent findings that vaccinees with no prior exposure to dengue virus (DENV) experience an elevated risk of severe disease in response to their first DENV infection subsequent to vaccination. As a result of these findings, guidelines for use of CYD-TDV now require serological screening prior to vaccination to establish that an individual does not fall into this high-risk category. These complications mean that the public health impact of CYD-TDV vaccination is expected to be higher in areas with higher transmission. One important practical difficulty with tailoring vaccination policy to local transmission contexts is that DENV transmission is spatially heterogeneous, even at the scale of neighborhoods or blocks within a city. This raises the question of whether models based on data that average over spatial heterogeneity in transmission could fail to capture important aspects of CYD-TDV impact in spatially heterogeneous populations. We explored this question with a deterministic model of DENV transmission and CYD-TDV vaccination in a population comprised of two communities with differing transmission intensities. Compared to the full model, a version of the model based on the average of the two communities failed to capture benefits of targeting the intervention to the high-transmission community, which resulted in greater impact in both communities than we observed under even coverage. In addition, the model based on the average of the two communities substantially overestimated impact among vaccinated individuals in the low-transmission community. In the event that the specificity of serological screening is not high, this result suggests that models that ignore spatial heterogeneity could overlook the potential for harm to this segment of the population.

Dengue and Zika virus infections are enhanced by live attenuated dengue vaccine but not by recombinant DSV4 vaccine candidate in mouse models.

BACKGROUND: A tetravalent live attenuated dengue vaccine, Dengvaxia, sensitised naïve recipients to severe dengue illness upon a subsequent natural dengue infection and is suspected to be due to antibody-dependent enhancement (ADE). ADE has also been implicated in the severe neurological outcomes of Zika virus (ZIKV) infection. It has become evident that cross-reactive antibodies targeting the viral pre-membrane protein and fusion-loop epitope are ADE-competent. A pre-clinical tetravalent dengue sub-unit vaccine candidate, DSV4, eliminates these ADE-competent epitopes. METHODS: We compared protective efficacy and ADE-competence of murine polyclonal antibodies induced by DSV4, Dengvaxia and an 'in house' tetravalent mixture of all four laboratory DENV strains, TV DENV, using established mouse models. FINDINGS: DSV4-induced antibodies, known to be predominantly type-specific, provided significant protection against lethal DENV challenge, but did not promote ADE of either DENV or ZIKV infection in vivo. Antibodies elicited by Dengvaxia and TV DENV, which are predominantly cross-reactive, not only failed to offer protection against lethal DENV challenge, but also promoted ADE of both DENV and ZIKV infection in vivo. INTERPRETATION: Protective efficacy against DENV infection may be linked to the induction of neutralising antibodies which are type-specific rather than cross-reactive. Whole virus-based dengue vaccines may be associated with ADE risk, despite their potent virus-neutralising capacity. Vaccines designed to eliminate ADE-competent epitopes may help eliminate/minimise ADE risk. FUNDING: This study was supported partly by ICGEB, India, the National Biopharma Mission, DBT, Government of India, Sun Pharmaceutical Industries Limited, India, and NIAID, NIH, USA.

The importance of effective risk communication and transparency: lessons from the dengue vaccine controversy in the Philippines.

In 2016 the Philippine Department of Health (DOH) introduced a novel dengue vaccine in a mass immunization program to reduce the substantial economic and social burden of the disease on households and the government. The vaccine manufacturer's announcement regarding new findings on the small but increased risk of severe dengue for vaccinated seronegative patients caused turmoil as various people claimed that the vaccine caused deaths and that health authorities are corrupt. While health department staff split-some having to preserve its reputation and others to monitor over 800,000 children administered the vaccine-communication between the frontline health workers and parents suffered. As a result, public confidence in vaccines dramatically dropped and the repercussions challenge the public health system. We examine factors that contributed to the crisis and argue for strengthening risk communication strategies and increasing transparency on decision making to counter misinformation and protect public health.

Dengue proteins with their role in pathogenesis, and strategies for developing an effective anti-dengue treatment: A review.

Dengue virus is an arbovirus belonging to class Flaviviridae Its clinical manifestation ranges from asymptomatic to extreme conditions (dengue hemorrhagic fever/dengue shock syndrome). A lot of research has been done on this ailment, yet there is no effective treatment available for the disease. This review provides the systematic understanding of all dengue proteins, role of its structural proteins (C-protein, E-protein, prM) in virus entry, assembly, and secretion in host cell, and nonstructural proteins (NS1, NS2a, NS2b, NS3, NS4a, NS4b, and NS5) in viral assembly, replication, and immune evasion during dengue progression and pathogenesis. Furthermore, the review has highlighted the controversies related to the only commercially available dengue vaccine, that is, Dengvaxia, and the risk associated with it. Lastly, it provides an insight regarding various approaches for developing an effective anti-dengue treatment.