Severe Dengue Hemorrhagic Fever Research Articles

Pericardial Effusion in Dengue Haemorrhagic Fever

Acute shock in severe dengue haemorrhagic fever (DHF) may occur concurrently with accumulation of fluid in serous body spaces such as pleural, peritoneal and pericardial cavities. Echocardiography is a non-invasive diagnostic procedure which is sensitive to detect even a small quantity of pericardial effusion. The chest radiogram in two reported cases of DHF associated with severe shock revealed that almost half of the pleural cavity was filled with fluid. Although no signs of pericardial effusion could be determined on physical examination, ECG and radiological procedures, a small amount of fluid was clearly seen on echocardiogram.

Unraveling within-host signatures of dengue infection at the population level

Dengue virus causes worldwide concern with nearly 100 million infected cases reported annually. The within-host dynamics differ between primary and secondary infections, where secondary infections with a different virus serotype typically last longer, produce higher viral loads, and induce more severe disease. We build upon the variable within-host virus dynamics during infections resulting in mild dengue fever and severe dengue hemorrhagic fever. We couple these within-host virus dynamics to a population-level model through a system of partial differential equations creating an immuno-epidemiological model. The resulting multiscale model examines the dynamics of between-host infections in the presence of two circulating virus strains that involves feedback from the within-host and between-hosts interactions, encompassing multiple scales. We analytically determine the relationship between the model parameters and the characteristics of the model’s solutions, and find an analytical threshold under which infections persist in the population. Furthermore, we develop and implement a full numerical scheme for our immuno-epidemiological model, allowing the simulation of population dynamics under variable parameter conditions.

SURVEI JENTIK NYAMUK Aedes aegypti DI PERUMAHAN WILAYAH KERJA PUSKESMAS MENTENG KOTA PALANGKA RAYA

Severe dengue or Dengue Hemorrhagic Fever (DHF) occurrence in Palangka Raya frequently becomes epidemic. The morbidity rate (incidence rate) of DHF cases in Central Kalimantan in 2016 reached 69.1 per 100,000 population with the mortality rate (fatality rate) of 1.4%. The morbidity rate reached 278.4 per 100,000 population in Palangka Raya, the second place after North Barito regency. Based on the Ministry of Health Republic of Indonesia�s Strategic Planning (Renstra), targets for dengue fever in 2016 should be <49 per 100,000 population, Central Kalimantan Province has not achieved the target yet. The Central Kalimantan Provincial Health Office reported the epidemy of DHF in 2017 occurred in the working area of Menteng Community Health Center. The report found a case that all family members of a household suffered from DHF. This community service aimed to educate the community to survey of dengue larvae independently, to develop the community�s knowledge and awareness about the importance of support from larvae monitoring speculator Juru Pemantau Jentik (also briefly known as Jumantik) and to increase community participation in DHF prevention movement in Palangka Raya. The method of this community service used site survey, observation, interview, larva examination and reporting of results. The survey activity of larvae showed that Aedes aegypti mosquito larvae were identified in 13.3% of the houses, mostly found in bathtubs, water shelters and water container of water dispensers.

Vivo-morpholino oligomers strongly inhibit dengue virus replication and production.

Dengue virus (DENV) infection is a worldwide public health problem, which can cause severe dengue hemorrhagic fever (DHF) and life-threatening dengue shock syndrome (DSS). There are currently no anti-DENV drugs available, and there has been an intensive search for effective anti-DENV agents that can inhibit all four DENV serotypes. In this study, we tested whether vivo-morpholino oligomers (vivo-MOs), whose effect on DENV infection has not previously been studied, can inhibit DENV infection. Vivo-MOs were designed to target the top of 3' stem-loop (3' SL) in the 3' UTR of the DENV genome and tested for inhibition of DENV infection in monkey kidney epithelial (Vero) cells and human lung epithelial carcinoma (A549) cells. The results showed that vivo-MOs could bind to a DENV RNA sequence and markedly reduce DENV-RNA, protein, and virus production in infected Vero and A549 cells. Vivo-MOs at a concentration of 4 µM could inhibit DENV production by more than 104-fold when compared to that of an untreated control. In addition, vivo-MOs also inhibited DENV production in U937 cells and primary human monocytes. Therefore, vivo-MOs targeting to the 3' SL in the 3' UTR of DENV genomes are effective and have the potential to be developed as anti-DENV agents.

Associations of DC-SIGN (CD209) promoter -336G/A polymorphism (rs4804803) with dengue infection: A systematic review and meta-analysis

Background and aimDengue virus entry into a host is associated with a cell surface protein, DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin). A common CD209-336G/A (rs4804803) polymorphism in DC-SIGN may affect severity of dengue virus infection (DEN) and incidence of dengue fever (DF) or the more severe dengue hemorrhagic fever (DHF). However, the reported associations of these two outcomes and CD-209 have been inconsistent, which prompted a meta-analysis to obtain more precise estimates. MethodsA literature search yielded seven case-control studies. We calculated pooled odds ratios (OR) and 95% confidence intervals using standard genetic models. Outlier treatment examined sources of potential heterogeneity. Subgroup analysis was performed for ethnicity and age. ResultsAll significant outcomes for association indicating reduced risk were pegged at P=0.007–0.05. In the homozygous and recessive models, these were observed in the overall analysis (OR 0.52–0.55), and subgroups of South/Central Americans (OR 0.30–0.32) and school-age children (OR 0.44) in the DHF analysis as well as the codominant model among Asians in DF (OR 0.59). These significant outcomes are strengthened by their non-heterogeneity (P>0.10) and robustness of the effects. Most pooled effects in DF and DEN were variable. ConclusionsThe DC-SIGN -336G/A polymorphism significantly affects DHF and DF incidence with the effect more pronounced in certain analyzed patient subgroups.

Dengue Virus Nonstructural Protein 1 Induces Vascular Leakage through Macrophage Migration Inhibitory Factor and Autophagy.

Dengue virus (DENV) is the most common mosquito-borne flavivirus; it can either cause mild dengue fever or the more severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). One of the characteristic features of DHF/DSS is vascular leakage; although DENV nonstructural protein 1 (NS1) has been proved to induce vascular leakage after binding to Toll-like receptor 4, the down-stream mechanism has not yet been fully understood. In the sera of DENV-infected patients, the concentrations of DENV NS1 and inflammatory cytokine macrophage migration inhibitory factor (MIF) are positively correlated with disease severity, but whether DENV NS1 induces vascular leakage through MIF secretion remains unknown. We demonstrated that recombinant NS1 induced vascular leakage and MIF secretion both in human endothelial cell line HMEC-1 and in mice. Furthermore, these phenomena were inhibited in the presence of anti-NS1 antibodies both in vitro and in vivo. DENV NS1 also induced LC3-I to LC3-II conversion and p62 degradation in endothelial cell line, which indicated the formation of autophagy. To clarify whether MIF or autophagy mediated DENV NS1-induced vascular leakage, various inhibitors were applied. The results showed that DENV NS1-induced vascular leakage and VE-cadherin disarray were blocked in the presence of MIF inhibitors, anti-MIF-antibodies or autophagy inhibitors. An Atg5 knockdown clone further confirmed that autophagy formation of endothelial cells was required in NS1-induced vascular leakage. Furthermore, DENV NS1-induced LC3 puncta were also decreased in the presence of MIF inhibitors, indicating that MIF mediated DENV NS1-induced autophagy. Taken together, the results suggest a potential mechanism of DENV-induced vascular leakage and provide possible therapeutic targets against DHF/DSS.

Human antibody response to dengue virus: implications for dengue vaccine design.

Dengue, a global health threat, is a leading cause of morbidity and mortality in most tropical and subtropical countries. Dengue can range from asymptomatic, relatively mild dengue fever to severe and life-threatening dengue hemorrhagic fever. Disease severity and outcome is largely associated with the host immune response. Several candidate vaccines in clinical trials appear promising as effective measures for dengue disease control. Vaccine development has been hampered by safety and efficacy issues, driven by a lack of understanding of the host immune response. This review focuses on recent research findings on the dengue host immune response, particularly in humans, and the relevance of these findings to challenges in vaccine development.

Comparative Study of Envelope Proteins of Dengue Virus of All Four Serotypes Isolated In India

Dengue virus infections spread mainly by the Aedes mosquitoes, affect 50 to 100 million people annually, of which a small percentage can suffer severe dengue hemorrhagic fever that can be fatal, and dengue fever in epidemic form has been affecting mainly the tropical countries. The tragedy is compounded by the fact that there are as yet no drugs or vaccines to treat the disease or act as preventives. Also, dengue virus belongs to the Flavivirus family, which also includes the latest Zika virus that is also spread by the same vector. The impact of such viruses makes it important to understand and characterize them, especially their surface proteins which continue to remain the first point of attack for drug and prophylaxis design. In this paper we consider the dengue surface situated envelope protein for all dengue serotypes from India to characterize the sequences and determine their similarities and dissimilarities with a view to assist in monitoring viral changes and in design of drugs and vaccines. We found the nucleotide sequences of the envelope genes of all four dengue serotypes to be very similar at the 3´-end, while there are slightly more differences near the 5´-end where the presence of the glycosilation site is known to be accompanied by large variability in the amino acid sequences. Phylogenetic analysis showed that the dengue type 4 (DENV4) is cladistically slightly removed compared to the other three dengue serotypes (DENV1, DENV3 and DENV2). The codon usage profiles show differences in codon usage biases between various serotypes. All four serotypes exhibit similar transition-transversion ratios and amino acid usage patterns; hydropathy indexes show small differences between DENV1, 4 and DENV2, 3. Our analyses identified three surface exposed regions in the protein sequences that are common to all four serotypes, which may be of interest in vaccine design.

Biomarkers of severe dengue disease - a review.

Dengue virus infection presents a wide spectrum of manifestations including asymptomatic condition, dengue fever (DF), or severe forms, such as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) in affected individuals. The early prediction of severe dengue in patients without any warning signs who may later develop severe DHF is very important to choose appropriate intensive supportive therapy since available vaccines for immunization are yet to be approved. Severe dengue responses include T and B cell activation and apoptosis, cytokine storm, hematologic disorders and complement activation. Cytokines, complement and other unidentified factors may transiently act on the endothelium and alter normal fluid barrier function of the endothelial cells and cause plasma leakage. In this review, the host factors such as activated immune and endothelial cells and their products which can be utilized as biomarkers for severe dengue disease are discussed.

Common variants of chemokine receptor gene CXCR3 and its ligands CXCL10 and CXCL11 associated with vascular permeability of dengue infection in peninsular Malaysia

Dengue causes significantly more human disease than any other arboviruses. It causes a spectrum of illness, ranging from mild self-limited fever, to severe and fatal dengue hemorrhagic fever, as evidenced by vascular leakage and multifactorial hemostatic abnormalities. There is no specific treatment available till date. Evidence shows that chemokines CXCL10, CXCL11 and their receptor CXCR3 are involved in severity of dengue, but their genetic association with the susceptibility of vascular leakage during dengue infection has not been reported. We genotyped 14 common variants of these candidate genes in 176 patients infected with dengue. rs4859584 and rs8878 (CXCL10) were significantly associated with vascular permeability of dengue infection (P<0.05); while variants of CXCL11 showed moderate significance of association (P=0.0527). Haplotype blocks were constructed for genes CXCL10 and CXCL11 (5 and 7 common variants respectively). Haplotype association tests performed revealed that, “CCCCA” of gene CXCL10 and “AGTTTAC” of CXCL11 were found to be significantly associated with vascular leakage (P=0.0154 and 0.0366 respectively). In summary, our association study further strengthens the evidence of the involvement of CXCL10 and CXCL11 in the pathogenesis of dengue infection.

Assessing Host Immune Response to Dengue Virus Infection at Single‐Cell Resolution

Dengue virus (DENV) is a mosquito‐borne pathogen, commonly found in tropical and subtropical climates, that results in a broad range of disease pathologies ranging from asymptomatic to dengue fever (DF) to the more severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Despite reports characterizing elevated levels of inflammatory cytokines in serum and correlating the manifestation of the severe disease symptoms to increased immune responses, attempts to delineate the signaling profile have been hindered by the low‐efficiency, dose‐dependent DENV infection of cultured cells. Understanding the signaling profile may reveal the hallmarks of disease progression and dictate the manifested severity of the infection. In this study, we eliminate the complexity of interpreting averaged signaling profile from heterogeneous population by isolating infected cells in a single‐cell barcode chip (SCBC), a device that enable simultaneous detection of multiple secreted cytokines at the single‐cell level. This strategy will allow us to effectively differentiate DENV‐infected from non‐infected cells, profile the types and levels of cytokines and chemokines secreted by these infected cells, and examine how various immune cells response to DENV infection. This single‐cell signaling profile will provide insight into how DENV infection may perturb the host immune system signaling networks and aid in the identification of therapeutic targets that can modulate DENV infection and suppress progression into DHF/DSS.Supported by NIH grant U19‐AI089992

English

Dengue viral infection can result in range of clinical manifestations from asymptomatic infection to dengue fever and the severe dengue hemorrhagic fever/ dengue shock syndrome which can result in death if it is not managed appropriately. So efficient and accurate diagnosis of dengue is of primary importance for clinical care surveillance activities and outbreak control. The present study was conducted between July 2014 to November 2014 which was an outbreak in anantapuram dist, Andhra Pradesh. A total number of 2410 serum samples were collected from acute suspected cases of dengue fever and were subjected to IgM anti-body captured ELISA supplied by NIV PUNE and J. Mitra in the dept. of microbiology, Govt. medical college, anantapuram, out of which 234 samples were positive. IgM anti-body detection by IgM captured ELISA has been an important tool for routine diagnosis of dengue with 90% sensitivity and 98% specificity when used from the 3 rd to 5 th day of

Nordihydroguaiaretic acid (NDGA) inhibits replication and viral morphogenesis of dengue virus

Dengue is the most common mosquito borne viral disease in humans. The infection with any of the 4 dengue virus serotypes (DENV) can either be asymptomatic or manifest in two clinical forms, the mild dengue fever or the more severe dengue hemorrhagic fever that may progress into dengue shock syndrome. A DENV replicative cycle relies on host lipid metabolism; specifically, DENV infection modulates cholesterol and fatty acid synthesis, generating a lipid-enriched cellular environment necessary for viral replication. Thus, the aim of this work was to evaluate the anti-DENV effect of the Nordihydroguaiaretic acid (NDGA), a hypolipidemic agent with antioxidant and anti-inflammatory properties. A dose-dependent inhibition in viral yield and NS1 secretion was observed in supernatants of infected cells treated for 24 and 48h with different concentrations of NDGA. To evaluate the effect of NDGA in DENV replication, a DENV4 replicon transfected Vero cells were treated with different concentrations of NDGA. NDGA treatment significantly reduced DENV replication, reiterating the importance of lipids in viral replication. NDGA treatment also led to reduction in number of lipid droplets (LDs), the neutral lipid storage organelles involved in DENV morphogenesis that are known to increase in number during DENV infection. Furthermore, NDGA treatment resulted in dissociation of the C protein from LDs. Overall our results suggest that NDGA inhibits DENV infection by targeting genome replication and viral assembly.

Invariant NKT cell response to dengue virus infection in human.

BackgroundDengue viral infection is a global health threat without vaccine or specific treatment. The clinical outcome varies from asymptomatic, mild dengue fever (DF) to severe dengue hemorrhagic fever (DHF). While adaptive immune responses were found to be detrimental in the dengue pathogenesis, the roles of earlier innate events remain largely uninvestigated. Invariant natural killer T (iNKT) cells represent innate-like T cells that could dictate subsequent adaptive response but their role in human dengue virus infection is not known. We hypothesized that iNKT cells play a role in human dengue infection.MethodsBlood samples from a well-characterized cohort of children with DF, DHF, in comparison to non-dengue febrile illness (OFI) and healthy controls at various time points were studied. iNKT cells activation were analyzed by the expression of CD69 by flow cytometry. Their cytokine production was then analyzed after α-GalCer stimulation. Further, the CD1d expression on monocytes, and CD69 expression on conventional T cells were measured.ResultsiNKT cells were activated during acute dengue infection. The level of iNKT cell activation associates with the disease severity. Furthermore, these iNKT cells had altered functional response to subsequent ex vivo stimulation with α-GalCer. Moreover, during acute dengue infection, monocytic CD1d expression was also upregulated and conventional T cells also became activated.ConclusioniNKT cells might play an early and critical role in the pathogenesis of severe dengue viral infection in human. Targeting iNKT cells and CD1d serve as a potential therapeutic strategy for severe dengue infection in the future.

Rab18 Facilitates Dengue Virus Infection by Targeting Fatty Acid Synthase to Sites of Viral Replication

Positive-sense RNA viruses, such as dengue virus (DENV), hijack the intracellular membrane machinery for their own replication. The Rab18 protein, a member of the Rab GTPase family, key regulators of membrane trafficking, is located on the organelles involved in DENV infection, such as the endoplasmic reticulum (ER) and lipid droplets (LDs). In this study, we addressed the potential involvement of Rab18 in DENV infection by using cells overexpressing the wild-type, GTP-bound active form, or GDP-bound inactive form of Rab18 and cells with Rab18 knockdown. DENV replication, measured by viral protein, viral RNA, and viral progeny production, as well as LD induction, was reduced in cells with inactive Rab18 and in cells deprived of Rab18 expression, suggesting a positive role of Rab18 in the DENV life cycle. Interestingly, the interaction of fatty acid synthase (FASN), a key lipogenic enzyme in lipid biosynthesis, with DENV NS3 protein relied on the conversion of the GDP-bound to the GTP-bound form of Rab18. Furthermore, the targeting of FASN to sites participating in DENV infection, such as the ER and LDs, depends on functional Rab18. Thus, Rab18-mediated membrane trafficking of FASN and NS3 facilitates DENV replication, probably by ensuring a sufficient and coordinated lipid supply for membrane proliferation and arrangement. Infection by dengue virus (DENV), an important mosquito-borne virus threatening ∼40% of the world's population, can cause mild dengue fever or severe dengue hemorrhagic fever and dengue shock syndrome. The pathogenesis mechanisms of DENV-related diseases are not clear, but high viral replication is believed to be a risk factor for the severe form of DENV infection. Thus, understanding the detailed mechanism of DENV replication might help address this devastating virus. Here, we found that Rab18, a small GTPase involved in vesicle trafficking and located in the endoplasmic reticulum network and on the surfaces of lipid droplets, positively regulates DENV replication. The functional machinery of Rab18 is required to recruit the enzyme fatty acid synthase to sites of DENV replication and to interact with DENV NS3 protein to promote fatty acid biosynthesis. Thus, DENV usurps Rab18 to facilitate its own replication.

Low Levels of Antibody-Dependent Enhancement in Vitro Using Viruses and Plasma from Dengue Patients

BackgroundThe majority of dengue patients infected with any serotype of dengue virus (DENV) are asymptomatic, but the remainder may develop a wide spectrum of clinical symptoms, ranging from mild dengue fever (DF) to severe dengue hemorrhagic fever (DHF). Severe cases occur more often in patients who experience a secondary infection with a different virus serotype. A phenomenon called antibody-dependent enhancement (ADE) has been proposed to explain the onset of these severe cases, but the exact mechanism of ADE remains unclear.Methodology/Principal FindingVirus neutralization and ADE assays were performed using ultracentrifugation supernatants of acute-phase sera from patients with secondary infections or human monoclonal antibodies (HuMAbs) as anti-DENV antibodies. Virus sources included infectious serum-derived viruses from the ultracentrifugation precipitates, laboratory-culture adapted DENV, or recombinant DENVs derived from patient sera. In contrast to the high levels of ADE observed with laboratory virus strains, low ADE was observed with autologous patient-derived viruses, when patient sera were used to provide the antibody component in the ADE assays. Similar results were obtained using samples from DF and DHF patients. Recombinant-viruses derived from DHF patients showed only minor differences in neutralization and ADE activity in the presence of HuMAbs or plasma derived from the same DHF patient.Conclusion/SignificanceSerum or plasma taken from patients during the acute phase of a secondary infection showed high levels of ADE, but no neutralization activity, when assayed in the presence of laboratory-adapted virus strains. By contrast, serum or plasma from the same patient showed high levels of neutralization activity but failed to induce significant ADE when the assays were performed with autologous virus. These results demonstrate the significance of the virus source when measuring ADE. They also suggest that repeated passage of DENV in cell culture has endowed it with the capacity to induce high levels of ADE.

Dengue virus infection: current concepts in immune mechanisms and lessons from murine models

Dengue viruses (DENV), a group of four serologically distinct but related flaviviruses, are responsible for one of the most important emerging viral diseases. This mosquito-borne disease has a great impact in tropical and subtropical areas of the world in terms of illness, mortality and economic costs, mainly due to the lack of approved vaccine or antiviral drugs. Infections with one of the four serotypes of DENV (DENV-1-4) result in symptoms ranging from an acute, self-limiting febrile illness, dengue fever, to severe dengue haemorrhagic fever or dengue shock syndrome. We reviewed the existing mouse models of infection, including the DENV-2-adapted strain P23085. The role of CC chemokines, interleukin-17 (IL-17), IL-22 and invariant natural killer T cells in mediating the exacerbation of disease in immune-competent mice is highlighted. Investigations in both immune-deficient and immune-competent mouse models of DENV infection may help to identify key host–pathogen factors and devise novel therapies to restrain the systemic and local inflammatory responses associated with severe DENV infection.

Heart rate variability in patients being treated for dengue viral infection: new insights from mathematical correction of heart rate

Introduction: Severe dengue hemorrhagic fever (DHF) is a viral infection that acts to increase permeability of capillaries, resulting in internal hemorrhage. Linear frequency domain Fourier spectral analysis represents the most published noninvasive tool for diagnosing and assessing health status via calculated heart rate variability (HRV). As such, HRV may be useful in assessing clinical status in DHF patients, but is prone to erroneous results and conclusions due to the influence of the average HR during the time period of HRV assessment (defined as the “prevailing” HR). We tested the hypothesis that alterations in HRV calculated with linear frequency analysis would be minimal when mathematically corrected for prevailing HR following dengue viral infection.Methods: Male (N = 16) and female (N = 11) patients between the ages of 6 months and 15 years of age (10 ± 6 SD years) were tracked through the progression of the dengue viral infection with treatment following the abatement of a fever (defervescence). Electrocardiographic recordings were collected and analyzed for HRV.Results: High frequency (HF), low frequency (LF), and LF/HF ratio were unaffected by correction for prevailing HR.Conclusion: HRV corrected for changes in HR did not alter the interpretation of our data. Therefore, we conclude that cardiac parasympathetic activity (based on HF frequency) is responsible for the majority of the HR reduction following defervescence in patients with dengue viral infection.

Heterosandwich immunoswab assay for dengue virus Ns1 antigen detection

Dengue and the more severe dengue hemorrhagic fever have been a very critical public health problem globally. Millions of people especially in the tropical areas get infected with dengue. An efficient diagnostic is very important for early screening of dengue infection. In dengue-infected patients, the nonstructural protein NS1 is present on the surface of infected cells and secreted in plasma. The NS1 antigen is an important target for developing a quick diagnostic largely due to its long presence in the blood. We have developed a simple-to-use immunoswab-based diagnostic procedure employing monoclonal antibodies and the second-generation quadromas. The detection limit for NS1 has been established to be in the subnanogram range. The assay is very sensitive, has a visual end point, and also being extremely inexpensive. With this assay, screening time for a dengue-infected person would be very rapid.

Lipidated Dengue-2 Envelope Protein Domain III Independently Stimulates Long-Lasting Neutralizing Antibodies and Reduces the Risk of Antibody-Dependent Enhancement

BackgroundDengue virus is a mosquito-transmitted virus that can cause self-limiting dengue fever, severe life-threatening dengue hemorrhagic fever and dengue shock syndrome. The existence of four serotypes of dengue virus has complicated the development of an effective and safe dengue vaccine. Recently, a clinical phase 2b trial of Sanofi Pasteur's CYD tetravalent dengue vaccine revealed that the vaccine did not confer full protection against dengue-2 virus. New approaches to dengue vaccine development are urgently needed. Our approach represents a promising method of dengue vaccine development and may even complement the deficiencies of the CYD tetravalent dengue vaccine.Methodology/Principal FindingsTwo important components of a vaccine, the immunogen and immunopotentiator, were combined into a single construct to generate a new generation of vaccines. We selected dengue-2 envelope protein domain III (D2ED III) as the immunogen and expressed this protein in lipidated form in Escherichia coli, yielding an immunogen with intrinsic immunopotentiation activity. The formulation containing lipidated D2ED III (LD2ED III) in the absence of exogenous adjuvant elicited higher D2ED III-specific antibody responses than those obtained from its nonlipidated counterpart, D2ED III, and dengue-2 virus. In addition, the avidity and neutralizing capacity of the antibodies induced by LD2ED III were higher than those elicited by D2ED III and dengue-2 virus. Importantly, we showed that after lipidation, the subunit candidate LD2ED III exhibited increased immunogenicity while reducing the potential risk of antibody-dependent enhancement of infection in mice.Conclusions/SignificanceOur study suggests that the lipidated subunit vaccine approach could be applied to other serotypes of dengue virus and other pathogens.