Dengue Vaccine Development Research Articles

Dengue vaccine endgame: why has the global response to exponential demand in the tropics been so slow?

IntroductionThere has been a dramatic global surge in dengue fever (DF) in recent years, with a projected 100-400 million cases annually and large outbreaks expected every 3-4 years. This concerning scenario is in sharp contrast to the very low availability of dengue vaccines to meet this spiraling demand, particularly affecting developing countries in Latin America and Africa. In our study, we aim to identify current vaccine development constraints, from a technological perspective, based on clinical trials and patent landscape data.MethodsThis study was conducted in a two-step methodology. First, candidates and launched products and methods used in the development or as part of DF vaccines were identified from the Cortellis Drug Discovery Intelligence (CDDI) platform. Second, the Derwent Innovation database was used to retrieve patent documents related to dengue vaccines. Data were collected in the period 2014-2024 (to identify the candidate and or launched vaccines) and 2018-2022 (to identify patent documents) with claims involving applications for dengue vaccine development. We presented these descriptive data in the following format: quantitative and qualitative assessments describing the vaccine development scenario and the claimed vaccine technologies.ResultsOur study indicated that 65% of dengue vaccines are still in phase 1 of development. The few current dengue vaccines that have reached phase 3 (1) and launched (2) have shown limited levels of individual protection for one or more dengue serotypes and there is an anemic pipeline of the next generation of more effective tetravalent dengue vaccines. Although the intelligent use of multiple dengue vaccine formulations in immunization campaigns can result in effective protection against all serotypes at the population level, the implementation of this is complex and challenging. The results of our study thus provide evidence of a worrisome global situation regarding the development of new dengue vaccine candidates.ConclusionTo reverse this scenario, there is an urgent need to implement new knowledge governance approaches and business models to stimulate an exponential increase in global vaccine development funding for dengue and several other vaccines.

Dengue virus: pathogenesis and potential for small molecule inhibitors.

Dengue, caused by dengue virus (DENV), is now endemic in nearly 100 countries and infection incidence is reported in another 30 countries. Yearly an estimated 400 million cases and 2200 deaths are reported. Effective vaccines against DENV are limited and there has been significant focus on the development of effective antiviral against the disease. The World Health Organization has initiated research programs to prioritize the development and optimization of antiviral agents against several viruses including Flaviviridae. A significant effort has been taken by the researchers to develop effective antivirals against DENV. Several potential small-molecule inhibitors like efavirenz, tipranavir and dasabuvir have been tested against envelope and non-structural proteins of DENV, and are in clinical trials around the world. We recently developed one small molecule, namely 7D, targeting the host PF4-CXCR3 axis. 7D inhibited all 4 serotypes of DENV in vitro and specifically DENV2 infection in two different mice models. Although the development of dengue vaccines remains a high priority, antibody cross reactivity among the serotypes and resulting antibody-dependent enhancement (ADE) of infection are major concerns that have limited the development of effective vaccine against DENV. Therefore, there has been a significant emphasis on the development of antiviral drugs against dengue. This review article describes the rescue effects of some of the small molecule inhibitors to viral/host factors associated with DENV pathogenesis.

The N and C-terminal deleted variant of the dengue virus NS1 protein is a potential candidate for dengue vaccine development

NS1 is an elusive dengue protein, involved in viral replication, assembly, pathogenesis, and immune evasion. Its levels in blood plasm are positively related to disease severity like thrombocytopenia, hemorrhage, and vascular leakage. Despite its pathogenic roles, NS1 is being used in various vaccine formulations due to its sequence conservancy, ability to produce protective antibodies and low risk for inducing antibody-dependent enhancement. In this study, we have used bioinformatics tools and reported literature to develop an NS1 variant (dNS1). Molecular docking studies were performed to evaluate the receptor-binding ability of the NS1 and dNS1 with TLR4. NS1 and dNS1 (153 to 312 amino acid region) genes were cloned, expressed and protein was purified followed by refolding. Docking studies showed the binding of NS1 and dNS1 with the TLR4 receptor which suggests that N and C-terminal sequences of NS1 are not critical for receptor binding. Antibodies against NS1 and dNS1 were raised in rabbits and binding affinity of anti-dNS1 anti-NS1 sera was evaluated against both NS1 and dNS1. Similar results were observed through western blotting which highlight that N and C-terminal deletion of NS1 does not compromise the immunogenic potential of dNS1 hence, supports its use in future vaccine formulations as a substitute for NS1.

In Silico Analysis of Active Compounds from Allium tuberosum as Drug Candidate for Inhibitor DENV-3 Envelope Protein

Dengue fever has become a global health issue, the development of dengue vaccine has not yet been established. Medicinal plants are an ideal alternative for DENV infection drugs. The purpose of this study was to determine in silico the potential of active compounds from Allium tuberosum as envelope protein inhibitors of DENV-3. The method of this research is to do docking analysis of compounds with DENV-3 envelope protein and analysis of amino acid residues using MVD, pharmacokinetic analysis using SwissADME, toxicity analysis using ProTox-II. The best docking value for the potential activity to inhibit the receptor DENV-3 is the thymidine compound (RS: -81.1245 kcal/mol). The highest activity of thymidine is the most promising as a drug candidate, as evidenced by the toxicity analysis which is predicted to have non-carcinogenic, non-mutagenic, inactive properties against hepatotoxicity, cytotoxicity and immunotoxicity parameters, as well as pharmacokinetic analysis that fulfills 6 parameters of lipopolicity, molecular weight, polarity. , insolubility, insaturation, and flexibility which indicate the drug candidate of thymidine is safe for its bioavailability. The conclusion from the results of this study is that one compound has the ability as an antiviral, binding score with DENV-3 is good, and is safe in terms of pharmacokinetics and toxicity, namely thymidine compound.

LITERATURE REVIEW: KAJIAN EFEKTIVITAS PERKEMBANGAN VAKSIN VIRUS DENGUE MASA KINI

Dengue fever is a disease caused by the dengue virus (DENV) which often becomes a problem for public health in the world with approximately 390 million cases of infection. The lack of specific antiviral therapy for DENV is a driving force for the development of a dengue vaccine as a strategy to fight the DENV virus. This review discusses the development of dengue vaccines and makes effectivity comparisons with dengue vaccines that have been developed such as Dengvaxia, TV003/TV005, and DENVax to know the current status of the development of these vaccines. Keywords : Dengue fever, Dengue Virus, vaccines, development, effectivity

Dengue Vaccines: Current Status and Future Perspectives

Dengue fever (DF), caused by the dengue virus (DENV), is a major public health problem worldwide, with approximately 390 million reported annual infections. The lack of specific antiviral therapies and limited means of vector control has led to the development of a dengue vaccine as a promising strategy to combat this disease. The purpose of this review is to provide a comprehensive analysis of the current status and prospects of dengue vaccines. This review describes different approaches used in dengue vaccine development, including live-attenuated, inactivated, subunit, and viral vector vaccines. Each approach is evaluated for immunogenicity, safety, and efficacy based on preclinical and clinical studies, highlighting the strengths and limitations of each vaccine candidate. Future directions and research priorities in dengue vaccine development are highlighted. In conclusion, dengue vaccines have great potential to reduce the burden of DF worldwide. However, some challenges remain regarding vaccine safety, efficacy, delivery, and availability. By addressing these challenges and leveraging advances in vaccine technology, there can be more effective control and prevention of DF and protection of public health, leading to improvement in the quality of life.

Fully automated high-throughput immuno-µPlaque assay for live-attenuated tetravalent dengue vaccine development.

Dengue fever has remained a continuing global medical threat that impacts half of the world's population. Developing a highly effective dengue vaccine, with live-attenuated tetravalent vaccines as leading candidates, remains essential in preventing this disease. For the development of live virus vaccines (LVVs), potency measurements play a vital role in quantifying the active components of vaccine drug substance as well as drug product during various stages of research, development, and post-licensure evaluations. Traditional plaque-based assays are one of the most common potency test methods, but they generally take up to weeks to complete. Less labor and time-intensive potency assays are thus called for to aid in the acceleration of vaccine development, especially for multivalent LVVs. Here, we introduce a fully automated, 96-well format µPlaque assay that has been optimized as a high-throughput tool to evaluate process and formulation development of a live-attenuated tetravalent dengue vaccine. To the best of our knowledge, this is the first report of a miniaturized viral plaque method for dengue with full automation via an integrated robotic system. Compared to the traditional manual plaque assay, this newly developed method substantially reduces testing time by approximately half and allows for the evaluation of over ten times more samples per run. The fully automated workflow, from cell culture to plaque counting, significantly minimizes analyst hands-on time and improves assay repeatability. The study presents a pioneering solution for the rapid measurement of LVV viral titers, offering promising prospects for advancing vaccine development through high-throughput analytics.

Role of pre-existing immunity in driving the dengue virus serotype 2 genotype shift in the Philippines: A retrospective analysis of serological data

ObjectiveThe invasion of dengue virus (DENV)-2 Cosmopolitan genotype into the Philippines, where the Asian II genotype previously circulated challenges the principle of dengue serotype-specific immunity. Assessment of antibodies in this population may provide a mechanistic basis for how new genotypes emerge in dengue-endemic areas. MethodsWe evaluated the neutralizing antibody (nAb) and antibody-dependent enhancement (ADE) responses against the two genotypes using archived serum samples collected from 333 patients with confirmed dengue in Metro Manila, Philippines, before, during, and after the introduction of the Cosmopolitan genotype. We quantified nAb titers in baby hamster kidney (BHK-21) cells with or without the Fcγ receptor IIA (FcγRIIA) to detect the capacity of virus-antibody complexes to neutralize or enhance DENV. ResultsThe nAb potency of the archived serum samples against the two genotypes was greatly affected by the presence of FcγRIIA. We found significant differences in nAb titers between the two genotypes in BHK-21 cells with FcγRIIA (P <0.0001). The archived serum samples were incapable of fully neutralizing the Cosmopolitan genotype, but instead strongly promoted its ADE compared to the Asian II genotype (P <0.0001). ConclusionThese results reinforce the role of pre-existing immunity in driving genotype shifts. Our finding that specific genotypes exhibit differing susceptibilities to ADE by cross-reactive antibodies may have implications for dengue vaccine development.

Insights into dengue immunity from vaccine trials.

The quest for an effective dengue vaccine has culminated in two approved vaccines and another that has completed phase 3 clinical trials. However, shortcomings exist in each, suggesting that the knowledge on dengue immunity used to develop these vaccines was incomplete. Vaccine trial findings could refine our understanding of dengue immunity, because these are experimentally derived, placebo-controlled data. Results from these trials suggest that neutralizing antibody titers alone are insufficient to inform protection against symptomatic infection, implicating a role for cellular immunity in protection. These findings have relevance for both future dengue vaccine development and application of current vaccines for maximal public health benefit.

Development of MVA-d34 Tetravalent Dengue Vaccine: Design and Immunogenicity.

Dengue fever, an infectious disease that affects more than 100 million people every year, is a global health problem. Vaccination may be the most effective prevention strategy for the disease. However, the development of vaccines against dengue fever is complicated by the high risk of developing an antibody-dependent increase in infection. This article describes the development of an MVA-d34 vaccine against the dengue virus based on a safe and effective MVA viral vector. The DIII domains of the envelope protein (E) of the dengue virus are used as vaccine antigens, as antibodies against these domains do not cause an enhancement of infection. The use of the DIII domains of each of the four dengue virus serotypes made it possible to generate a humoral response against all four dengue virus serotypes in immunized mice. We also showed that the sera of vaccinated mice present virus-neutralizing activity against dengue serotype 2. Thus, the developed MVA-d34 vaccine is a promising candidate vaccine against dengue fever.

A live dengue virus vaccine carrying a chimeric envelope glycoprotein elicits dual DENV2-DENV4 serotype-specific immunity

The four dengue virus serotypes co-circulate globally and cause significant human disease. Dengue vaccine development is challenging because some virus-specific antibodies are protective, while others are implicated in enhanced viral replication and more severe disease. Current dengue tetravalent vaccines contain four live attenuated serotypes formulated to theoretically induce balanced protective immunity. Among the number of vaccine candidates in clinical trials, only Dengvaxia is licensed for use in DENV seropositive individuals. To simplify live-virus vaccine design, we identify co-evolutionary constraints inherent in flavivirus virion assembly and design chimeric viruses to replace domain II (EDII) of the DENV2 envelope (E) glycoprotein with EDII from DENV4. The chimeric DENV2/4EDII virus replicates efficiently in vitro and in vivo. In male macaques, a single inoculation of DENV2/4EDII induces type-specific neutralizing antibodies to both DENV2 and DENV4, thereby providing a strategy to simplify DENV vaccine design by utilizing a single bivalent E glycoprotein immunogen for two DENV serotypes.

Dengue determinants: Necessities and challenges for universal dengue vaccine development.

Dengue illness can range from mild illness to life-threatening haemorrhage. It is an Aedes-borne infectious disease caused by the dengue virus, which has four serotypes. Each serotype acts as an independent infectious agent. The antibodies against one serotype confer homotypic immunity but temporary protection against heterotypic infection. Dengue has become a growing health concern for up to one third of the world's population. Currently, there is no potent anti-dengue medicine, and treatment for severe dengue relies on intravenous fluid management and pain medications. The burden of dengue dramatically increases despite advances in vector control measures. These factors underscore the need for a vaccine. Various dengue vaccine strategies have been demonstrated, that is, live attenuated vaccine, inactivated vaccine, DNA vaccine, subunit vaccine, and viral-vector vaccines, some of which are at the stage of clinical testing. Unfortunately, the forefront candidate vaccine is less than satisfactory, and its performance depends on serostatus and age factors. The lessons from clinical studies depicted ambiguity concerning the efficacy of dengue vaccine. Our study highlighted that viral structural heterogeneity, epitope accessibility, autoimmune complications, genetic variants, genetic diversities, antigen competition, virulence variation, host-pathogen specific interaction, antibody-dependent enhancement, cross-reactive immunity among Flaviviruses, and host-susceptibility determinants not only influence infection outcomes but also hampered successful vaccine development. This review integrates dengue determinants allocated necessities and challenges, which would provide insight for universal dengue vaccine development.

Dengue vaccine development: challenges and prospects.

Dengue vaccine development is a high public health priority. To date, no dengue vaccine is in widespread use. Here we review the challenges in dengue development and the latest results for the second-generation dengue vaccines. The biggest hurdle is the immunological interaction between the four antigenically distinct dengue serotypes. The advantages of second-generation dengue vaccines are the inclusion of nonstructural proteins of the dengue backbone and a more convenient dosing with reduced numbers of doses needed. Although dengue-primed individuals can already benefit from vaccination with the first licensed dengue vaccine CYD-TDV, the public health need for the dengue-naive population has not yet been met. The urgent need remains to identify correlates of both protection and enhancement; until such correlates have been identified, all second-generation dengue vaccines still need to go through full phase 3 trials. The 5-year efficacy and safety data for both second-generation dengue vaccines are imminent.

The practicality of Malaysia dengue outbreak forecasting model as an early warning system.

Dengue is a harmful tropical disease that causes death to many people. Currently, the dengue vaccine development is still at an early stage, and only intervention methods exist after dengue cases increase. Thus, previously, two scientific experimental field studies were conducted in producing a dengue outbreak forecasting model as an early warning system. Successfully, an Autoregressive Distributed Lag (ADL) Model was developed using three factors: the epidemiological, entomological, and environmental with an accuracy of 85%; but a higher percentage is required in minimizing the error for the model to be useful. Hence, this study aimed to develop a practical and cost-effective dengue outbreak forecasting model with at least 90% accuracy to be embedded in an early warning computer system using the Internet of Things (IoT) approach. Eighty-one weeks of time series data of the three factors were used in six forecasting models, which were Autoregressive Distributed Lag (ADL), Hierarchical Forecasting (Bottom-up and Optimal combination) and three Machine Learning methods: (Artificial Neural Network (ANN), Support Vector Machine (SVM) and Random Forest). Five error measures were used to evaluate the consistency performance of the models in order to ensure model performance. The findings indicated Random Forest outperformed the other models with an accuracy of 95% when including all three factors. But practically, collecting mosquito related data (the entomological factor) was very costly and time consuming. Thus, it was removed from the model, and the accuracy dropped to 92% but still high enough to be of practical use, i.e., beyond 90%. However, the practical ground operationalization of the early warning system also requires several rain gauges to be located at the dengue hot spots due to localized rainfall. Hence, further analysis was conducted in determining the location of the rain gauges. This has led to the recommendation that the rain gauges should be located about 3–4 km apart at the dengue hot spots to ensure the accuracy of the rainfall data to be included in the dengue outbreak forecasting model so that it can be embedded in the early warning system. Therefore, this early warning system can save lives, and prevention is better than cure.

Mice immunized with trimethyl chitosan nanoparticles containing DENV-2 envelope domain III elicit neutralizing antibodies with undetectable antibody-dependent enhancement activity.

Dengue is a disease that poses a significant global public health concern. Although a tetravalent live-attenuated dengue vaccine has been licensed, its efficacy is still debated due to evidence of vaccine breakthrough infection. To avoid this issue, dengue vaccines should stimulate a high degree of serotype-specific response. Thus, envelope domain III (EDIII), which contains serotype-specific neutralizing epitopes, is an attractive target for dengue vaccine development. In this study, we investigated how EDIII encapsidated in N, N, N-trimethyl chitosan chloride nanoparticles (TMC NPs) stimulates a serotype-specific response and whether this response exerts a potential in vitro breakthrough infection. The immune response to DENV-2 elicited by EDIII TMC NP-immunized mice was monitored. We demonstrated that immunization with EDIII TMC NPs resulted in a high level of anti-EDIII antibody production. These antibodies included IgG, IgG1, and IgG2a subtypes. Importantly, antibodies from the immunized mice exerted efficient neutralizing activity with undetectable antibody dependent enhancement (ADE) activity. We also found that EDIII TMC NPs activated functional EDIII-specific CD4+ and CD8+ T cell responses. In conclusion, EDIII TMC NPs stimulated humoral immunity with a strong neutralizing antibody response, as well as a cellular immune response against DENV-2.

Dengue vaccines: where are we now and where we are going?

Dengue, the main arboviral disease worldwide,1 is a disease of high epidemiological impact caused by serotypes 1, 2, 3, or 4 of dengue virus.2 At least 60 million symptomatic infections occur annually worldwide, resulting in about 10 000 deaths. More than 4 billion people are at risk in countries that present optimal conditions for Aedes spp mosquitoes—the key vector of dengue virus.3 Thus, the development of safe and effective dengue vaccines is a priority according to WHO.2 Only one tetravalent dengue vaccine, CYD-TDV (Dengvaxia; Sanofi Pasteur), has already been licensed in endemic countries.

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.

Current status and perspectives on vaccine development against dengue virus infection.

Dengue virus (DENV) consists of four serotypes in the family Flaviviridae and is a causative agent of dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. DENV is transmitted by mosquitoes, Aedes aegypti and A. albopictus, and is mainly observed in areas where vector mosquitoes live. The number of dengue cases reported by the World Health Organization increased more than 8-fold over the last two decades from 505,430 in 2000 to over 2.4 million in 2010 to 5.2 million in 2019. Although vaccine is the most effective method against DENV, only one commercialized vaccine exists, and it cannot be administered to children under 9 years of age. Currently, many researchers are working to resolve the various problems hindering the development of effective dengue vaccines; understanding of the viral antigen configuration would provide insight into the development of effective vaccines against DENV infection. In this review, the current status and perspectives on effective vaccine development for DENV are examined. In addition, a plausible direction for effective vaccine development against DENV is suggested.

Discovery of B-cell epitopes for development of dengue vaccines and antibody therapeutics.

Dengue is one of the most frequently transmitted viral infections globally which creates a serious burden to the healthcare system in many countries in the tropical and subtropical regions. To date, no vaccine has demonstrated balanced protection against the four dengue serotypes. Dengvaxia as the only vaccine that has been licensed for use in endemic areas has shown an increased risk in dengue-naïve vaccines to develop severe dengue. A crucial element in protection from dengue infection is the neutralizing antibody responses. Therefore, the identification of protective linear B-cell epitopes can guide vaccine design and facilitate the development of monoclonal antibodies as dengue therapeutics. This review summarizes the identification of dengue B-cell epitopes within the envelope (E) protein of dengue that can be incorporated into peptide vaccine constructs. These epitopes have been identified through approaches such as bioinformatics, three-dimensional structure analysis of antibody-dengue complexes, mutagenesis/alanine scanning and escape mutant studies. Additionally, the therapeutic potential of monoclonal antibodies targeting the E protein of dengue is reviewed. This can provide a basis for the design of future dengue therapies.

Seroepidemiologic study on convalescent sera from dengue fever patients in Jinghong, Yunnan.

After dengue virus (DENV) infection, antibody-dependent enhancement (ADE) is easy to occur when the neutralizing antibody (NAb) gradually decreases to a sub-neutralizing concentration. In this cohort surveillance, we utilized sera samples collected from dengue fever patients at different convalescent phases in Jinghong City, to investigate the dynamic change rule of DENV-specific antibodies, and to analyze the risk of ADE caused by secondary infection with heterologous serotypes DENVs. For baseline serosurvey, 191 four-year and 99 six-year sera samples during convalescence were collected in 2017 and 2019, respectively. The positive rate of DENV-specific immunoglobulin G was 98.4% in 2017, which significantly decreased to 82.8% in 2019. The geometric mean titer (GMT) of NAb decreased from 1:155.35 to 1:46.66. Among 290 overall samples, 73 paired consecutive samples were used for follow-up serosurvey. In four-year sera, the GMTs of NAb against DENV-3 and cross-reactive antibodies against DENV-1, DENV-2 and DENV-4 were 1:167.70, 1:13.80, 1:18.54 and 1:45.26, respectively, which decreased to 1:53.18, 1:10.30, 1:14.60 and 1:8.17 in six-year sera. In age-stratified analysis, due to the increasing number of ADE positive samples from 2017 to 2019 in 31–40 and 51–60 years groups, the risk of ADE in DENV-4 infection was positively associated with the extension of convalescent phase, and the odd ratio was higher than other groups. With the recovery period lengthened, the risk of secondary infection with DENV-1 and DENV-2 was reduced. Our results offer essential experimental data for risk prediction of severe dengue in hyper-endemic dengue areas, and provide crucial scientific insight for the development of effective dengue vaccines.