Dengue Vaccine Research Articles

Mathematical analysis of a three-strain model for dengue with vaccination

Abstract Dengue has emerged as the most widespread mosquito-borne ailment in humans, causing an estimated 390 million infections within the endemic regions of the world annually. In this paper, a novel mathematical model is proposed for three strains of dengue virus with vaccination measures. Some of the important qualitative analysis carried out are as follows: The dengue serotypes 1, 2 and 3 sub-models are qualitatively analyzed, using well constructed candidates of Lyapunov function. The sub-models’ infection-free equilibria are proven to be locally asymptotically stable. The infection-free and endemic equilibria of the sub-models are established to be globally asymptotically stable. The complete model’s infection-free equilibrium is proven to be locally and globally asymptotically stable. Also, simulations are also presented to validate the theoretical analysis in the paper. The solution profiles of all epidemiological compartments when the reproduction numbers are both below one and greater than one are graphically presented. It was observed that, for the scenarios when the dengue reproduction number R 0 is below and above one, the solution trajectories converge to the infection-free and dengue-endemic steady states, respectively. Sensitivity analyses using the Latin Hypercube Sampling (LHS), and also using contour plots and surface plots are performed on the dengue serotypes associated reproduction numbers. The impact of influential parameters are graphically presented. Worthy of mention, is the significant impact of dengue transmission rates (positively correlated) and dengue vaccination rates and vaccine effectiveness levels (negatively correlated). Different scenario analyses to investigate the impact of dengue vaccination measures are presented. It was observed that enhanced dengue vaccination programme under the administration of safe and highly effective vaccine could curtail the spread and co-circulation of different dengue serotypes within the population.

Knowledge, attitude, and practice regarding dengue vaccine: a baseline study of community members and health providers in Indonesia.

Despite recent behavioral interventions aimed at reducing the burden of dengue, persistent unfavorable related behaviors in the Indonesian community suggest that vaccination could be effective. However, before this is implemented nationally, public perception and acceptance of the vaccine should be assessed in addition to health providers' points of view. This study aimed to assess the knowledge, attitudes, and practices (KAP) of community members and health providers in Indonesia. A cross-sectional survey was conducted in six districts of three Indonesian provinces. Respondents included both community members and health providers living within the territory of the selected primary health care centers. Pretested questionnaires were used to gather information on the sociodemographic characteristics and KAPs regarding dengue vaccines. An independent t-test was performed to compare the mean KAP scores between community members and health providers, while a logistic regression analysis was used to identify the predictors in each domain. Only 18.5% of health providers possessed high knowledge of the dengue vaccine versus only 12.5% of community members. Approximately one-third of the health providers versus one-fourth of community members displayed a high to moderate score for attitudes about dengue vaccines. Dengue vaccination practices demonstrated a more favorable score for both health providers and community members at 59.1% and 41.1%, respectively. No individual sociodemographic characteristics were associated with KAPs; rather, only education was correlated with better dengue vaccination practices. We also found that good knowledge of dengue was the only factor associated with all domains. Our findings highlight the urgent need to deliver educational interventions to health providers and community members in Indonesia to improve their awareness of dengue vaccines.

Improving precision of vaccine efficacy evaluation using immune correlate data in time-to-event models

Understanding potential differences in vaccine-induced protection between demographic subgroups is key for vaccine development. Vaccine efficacy evaluation across these subgroups in phase 2b or 3 clinical trials presents challenges due to lack of precision: such trials are typically designed to demonstrate overall efficacy rather than to differentiate its value between subgroups. This study proposes a method for estimating vaccine efficacy using immunogenicity (instead of vaccination status) as a predictor in time-to-event models. The method is applied to two datasets from immunogenicity sub-studies of vaccine phase 3 clinical trials for zoster and dengue vaccines. Results show that using immunogenicity-based estimation of efficacy in subgroups using time-to-event models is more precise than the standard estimation. Incorporating immune correlate data in time-to-event models improves precision in estimating efficacy (i.e., yields narrower confidence intervals), which can assist vaccine developers and public health authorities in making informed decisions.

Spatial and temporal predictions of mosquito potential breeding sites and densities: integration of satellite imagery, in-situ data, and process-based modeling

Abstract. Dengue fever, primarily transmitted worldwide by the mosquito Aedes aegypti, poses significant public health challenges in tropical and subtropical regions. While effective vector control is crucial in the absence of reliable dengue vaccines, traditional control methods face obstacles like mosquito resistance to insecticides and a very high cost. By combining geospatial data, including satellite imagery, as descriptors, and entomological surveys as target variables in a Random Forest model, we predicted the number of potential mosquito breeding sites, derived the associated environmental carrying capacity for larvae, and used the Arbocarto process-based model to predict Ae.aegypti population densities in an urban region of French Guiana, South America. Our findings highlight that remote sensing data may help predict the number of potential breeding sites over urban areas. Our simulations indicate higher mosquito densities in urban residential areas and a strong spatial and temporal heterogeneity. These densities fluctuate according to intra-annual variations in temperature and precipitation, with higher densities associated with intermediate housing. A comparison with the conventional estimation of environmental carrying capacity for larvae in the current Arbocarto procedure highlights the advantages of our approach. Our study demonstrates the utility of integrating remote sensing with predictive modeling to enhance vector surveillance and control strategies, and provides a replicable approach for monitoring a dengue vector mosquito population in dynamic urban landscapes.

The role of antibody-dependent enhancement in dengue vaccination

Dengue is the most rapidly spreading vector-borne disease worldwide, with over half the global population at risk for an infection. Antibody-dependent enhancement (ADE) is associated with increased disease severity and may also be attributable to the deterioration of disease in vaccinated people. Two dengue vaccines are approved momentarily, with more in development. The increasing use of vaccines against dengue, combined with the development of more, makes a thorough understanding of the processes behind ADE more important than ever. Above that, due to the lack of treatment options, this method of prevention is of great importance. This review aims to explore the impact of ADE in dengue vaccinations, with the goal of enhancing potential vaccination strategies in the fight against dengue.

Long term T cell response and safety of a tetravalent dengue vaccine in healthy children

As robust cellular responses are important for protection against dengue, this phase 2 study evaluated the kinetics and phenotype of T cell responses induced by TAK-003, a live-attenuated tetravalent dengue vaccine, in 4–16-year-old living in dengue-endemic countries (NCT02948829). Two hundred participants received TAK-003 on Days 1 and 90. Interferon-gamma (IFN-γ) enzyme-linked immunospot assay [ELISPOT] and intracellular cytokine staining were used to analyze T cell response and functionality, using peptide pools representing non-structural (NS) proteins NS3 and NS5 matching DENV-1, -2, -3, and -4 and DENV-2 NS1. One month after the second TAK-003 dose (Day 120), IFN-γ ELISPOT T cell response rates against any peptide pool were 97.1% (95% CI: 93.4% to 99.1%), and similar for baseline dengue seropositive (96.0%) and seronegative (98.6%) participants. IFN-γ ELISPOT T cell response rates at Day 120 were 79.8%, 90.2%, 77.3%, and 74.0%, against DENV-1, -2, -3, and -4, respectively, and remained elevated through 3 years post-vaccination. Multifunctional CD4 and CD8 T cell responses against DENV-2 NS peptides were observed, independent of baseline serostatus: CD8 T cells typically secreted IFN-γ and TNF-α whereas CD4 T cells secreted ≥ 2 of IFN-γ, IL-2 and TNF-α cytokines. NAb titers and seropositivity rates remained substantially elevated through 3 years post-vaccination. Overall, TAK-003 was well tolerated and elicited durable T cell responses against all four DENV serotypes irrespective of baseline serostatus in children and adolescents aged 4–16 years living in dengue-endemic countries. TAK-003-elicited CD4 and CD8 T cells were multifunctional and persisted up to 3 years post-vaccination.

Comparison of the sensitivity and specificity of commercial anti-dengue virus IgG tests to identify persons eligible for dengue vaccination.

The Advisory Committee on Immunization Practices (ACIP) has set forth recommendations that dengue pre-vaccination screening tests must exhibit at least 98% specificity and 75% sensitivity. Our research rigorously assesses the performance of various commercial tests against these benchmarks using well-characterized specimens from Puerto Rico. The findings from our study are particularly relevant given FDA approval and ACIP recommendation of Sanofi Pasteur's Dengvaxia vaccine, highlighting the need for accurate pre-vaccination screening tools.

Unlocking Hope: Paving the Way for a Cutting-Edge Multi-Epitope Dengue Virus Vaccine.

Dengue fever is a significant health issue in Pakistan, demanding a vaccine effective against all the viral strains. This study employs reverse vaccinology to develop potential dengue vaccine candidates (DVAX I-III). The study thoroughly examinedconserved areas of dengue virus serotypes 1-4's structural and non-structural proteins. Key viral proteins were analyzed to find antigenic peptides, which were incorporated into vaccine candidates and potentiated with adjuvants. Computational methods predicted peptide structures and evaluated their binding to immune receptors TLR 2, TLR 4, HLA *A1101, and DRB*401. A molecular dynamics simulation lasting 100ns of the DVAX II-TLR4 complex at different time intervals clearly indicated that the ligand is attached to the receptor. Normal mode analysis assessed the stability and flexibility of these interactions. Encouragingly, all three vaccine candidates demonstrated favorable interactions with these immune receptors and the potential to induce a robust immune response. These findings suggest their safety and warrant further in vivo studies to evaluate their efficacy for clinical development.

Serotypic and genotypic profile of dengue virus outbreaks in India between 2011 and 2017.

The epidemiology of dengue has been demonstrating significant changes in recent years, with rising incidence of infection in countries with known endemicity and occurrence of fresh outbreaks in previously unaffected territories. India, which has been a traditional hotspot dengue virus (DENV) transmission in the endemic south-east Asian region, has also been affected by the sweeping changes in dengue epidemiology. Two remarkable developments characterize the alterations witnessed by India 2011-2017. Firstly, all parts of the country have witnessed abrupt replacement of existing DENV lineages with emerging novel strains. Secondly, co-circulation of multiple serotypes of DENV have been reported from all across the country 2011-2017; thereby hinting at the transition of the country towards hyper-endemicity. Considering the potential clinical implications of such epidemiological transformation in terms increasing involvement of pediatric patients and growing predisposition to serious complications, the present review provides an update on the serotypic and genotypic profile of dengue outbreaks that have been witnessed by different zones of India between 2011 and 2017. Dividing the country into northern, southern, eastern, western, central and north-eastern zones, we describe discrete zone-specific distribution patterns of DENV serotypes and genotypes and observe simultaneous circulation of different DENV strains in different parts of the country. Random shifts in the genetic characteristics of the circulating strains and the widespread co- circulation of all four serotypes underscore the need for undertaking continuous and representative molecular surveillance of the circulating DENV strains across the country for prompt identification of emerging strains and novel mutants; gain insights into the formulation of Dengue vaccines and develop a clearer understanding of the molecular basis of immune evasion, disease epidemiology and pathogenesis.

The dengue vaccine: a major scientific challenge and a public health issue

Almost half of the world's population is exposed to the risk of transmission of the four dengue virus serotypes (DENV 1-4), by mosquitoes of the genus Aedes. A dengue vaccine is effective if it induces prolonged protective immunity against all circulating viral strains, irrespective of the age and infection history of the vaccinated subject. An effective vaccine strategy against dengue is based on the injection of live attenuated viruses in a tetravalent formulation. In this review, we present the most promising candidate vaccines against dengue, their successes and also the questions raised by the correlates of protection that have been adopted to assess their level of effectiveness against the disease.

Dengue outbreaks in northern Nigeria: Evaluating the recommended Takeda vaccine and future prevention strategies.

Dengue fever, caused by the dengue virus (DENV), poses a significant public health challenge globally, with Nigeria experiencing sporadic outbreaks. A clear understanding of the dengue burden has not been achieved in Nigeria, just as in other African countries. Understanding the epidemiology and burden of dengue fever is essential for effective prevention and control strategies. This paper examines the recent dengue outbreaks in northern Nigeria, particularly in Sokoto state, and evaluates the recommended Takeda dengue vaccine (TDV) along with future prevention strategies. Despite limited surveillance and underreporting, dengue fever is endemic in Nigeria (with over 5 million cases and 5000 dengue-related deaths in 2023), with recent outbreaks indicating a growing concern. The TDV, a live attenuated tetravalent vaccine, has shown promise in preventing dengue fever, but challenges such as vaccine acceptance and accessibility need to be addressed. Global urbanization contributes to the disease's spread, which is influenced by factors such as population density, cultural beliefs, water storage practices, hygiene, and water supply accessibility. Future prevention strategies must focus on government intervention, community practices, and innovative vector control measures to mitigate the spread of DENV in Nigeria. This study will serve as a valuable reference for policymakers, researchers, and clinicians in the management and control of DENV in Nigeria and Africa as a whole.

Immunity to Non-Dengue Flaviviruses Impacts Dengue Virus Immunoglobulin G Enzyme-Linked Immunosorbent Assay Specificity in Cambodia.

Seroprevalence studies are the standard for disease surveillance, and serology determined eligibility for the first dengue vaccine. Expanding flavivirus co-circulation and vaccination complicate testing. We evaluate the accuracy of a common dengue virus serological assay, examine immunity to non-dengue flaviviruses as a contributor to decreased performance, and assess whether alternative cut points may improve assay performance. Children (n = 770) aged 2-9 years in Kampong Speu, Cambodia were enrolled in a prospective longitudinal study, and PanBio indirect dengue virus immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA) was performed. Plaque reduction neutralization tests (PRNTs) using dengue viruses were performed on a subset to assess the accuracy of the IgG ELISA, and PRNTs with Zika, Japanese encephalitis, and West Nile viruses evaluated immunity to non-dengue flaviviruses. Receiver operating curve analysis identified an alternative cut point to improve IgG ELISA accuracy. The dengue IgG ELISA had a lower specificity than previously reported (58% vs 93%-100%). Of those with false-positive IgG results, 46% had detectable neutralizing antibodies against other flaviviruses including 14% against West Nile virus. A higher IgG cut point improved the test accuracy in this population. Physicians and public health authorities should be alert for West Nile in Cambodia. Immunity to non-dengue flaviviruses can impact dengue surveillance. NCT03534245.

Vaccination against dengue fever for travellers.

Dengue fever, endemic to most tropical and subtropical countries, is a major cause of illness in travellers, but severe dengue, hospitalisation and death are considered rare in this population. Two vaccines against dengue fever, Dengvaxia®and Qdenga®, are available. While there is no recommendation for the use of Dengvaxia®in travellers, Qdenga®has been licensed for travellers in many European countries since December 2022, most recently (29 July 2024) in Switzerland by Swissmedic. The Swiss Expert Committee for Travel Medicine (ECTM), having assessed available data on the Qdenga®vaccine, issues the following recommendations: (1) Vaccination against dengue fever virus with Qdenga®is not recommended for persons with no previous dengue fever infection. (2) Vaccination with Qdenga®may be recommended for travellers aged 6 years and older who have evidence of previous dengue infection, defined as (a) a laboratory-confirmed dengue infection (PCR, antigen or seroconversion)or(b) a compatible history of dengue infection with a positive IgG serological test AND expected exposure to a region with significant dengue transmission. Travel medicine advisors should provide clear information in accessible language on the complexity of dengue vaccines and the risk/benefit evaluation for their use in travellers.

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 fever vaccination - safe protection against a spreading disease for travellers?

Dengue fever vaccination - safe protection against a spreading disease for travellers?

An In Silico Design of a Vaccine against All Serotypes of the Dengue Virus Based on Virtual Screening of B-Cell and T-Cell Epitopes.

Dengue virus poses a significant global health challenge, particularly in tropical and subtropical regions. Despite the urgent demand for vaccines in the control of the disease, the two approved vaccines, Dengvaxia and TV003/TV005, there are current questions regarding their effectiveness due to an increased risk of antibody-dependent enhancement (ADE) and reduced protection. These challenges have underscored the need for further development of improved vaccines for Dengue Virus. This study presents a new design using an in silico approach to generate a more effective dengue vaccine. Initially, our design process began with the collection of Dengue polyprotein sequences from 10 representative countries worldwide. And then conserved fragments of viral proteins were retrieved as the bases for epitope screening. The selection of epitopes was then carried out with criteria such as antigenicity, immunogenicity, and binding affinity with MHC molecules, while the exclusion criteria were according to their allergenicity, toxicity, and potential for antibody-dependent enhancement. We then constructed a core antigen with the selected epitopes and linked the outcomes with distinct adjuvant proteins, resulting in three candidate vaccines: PSDV-1, PSDV-2, and PSDV-3. Among these, PSDV-2 was selected for further validation due to its superior physicochemical and structural properties. Extensive simulations demonstrated that PSDV-2 exhibited strong binding to pattern recognition receptors, high stability, and robust immune induction, confirming its potential as a high-quality vaccine candidate. For its recombinant expression, a plasmid was subsequently designed. Our new vaccine design offers a promising additional option for Dengue virus protection. Further experimental validations will be conducted to confirm its protective efficacy and safety.

Role of the dengue vaccine TAK-003 in an outbreak response: Modeling the Sri Lanka experience.

Outbreaks of dengue can overburden hospital systems, drastically reducing capacity for other care. The 2017 dengue serotype 2 (DENV-2) outbreak in Sri Lanka coincided with vaccination in an ongoing phase 3 efficacy trial of a tetravalent dengue vaccine, TAK-003 (NCT02747927). Here, we present data on the efficacy of TAK-003 following two doses of the vaccine administered 3 months apart in participants aged 4-16 years in Sri Lanka. In addition, we have used the 2017 outbreak dynamics to model the potential impact of TAK-003 on virologically confirmed dengue (VCD) cases and hospitalizations during an outbreak situation. Modeling was performed using an age-structured, host-vector, spatial and stochastic transmission model, assuming 65% vaccine coverage and 30 days until initiation of vaccination. Efficacy of TAK-003 against VCD and hospitalized VCD cases was based on data against DENV-2 from the first year of the phase 3 trial. Vaccine efficacy and safety findings in Sri Lanka were in line with those of the overall trial population. The efficacy estimates in Sri Lanka up to the first 12 months after the second dose of TAK-003 were 94.7% and 95.7% against VCD and hospitalized VCD cases, respectively. Modeling of the trial data over an extended geographic area showed a substantial reduction in cases and a flattening of outbreak curves from TAK-003 use. The baseline vaccination scenario (initiation at 30 days, 65% target coverage, vaccine effective at 14 days, 70% hospitalization rate, VE of 95% for VCD and 97% for hospitalized VCD, and 47% for asymptomatic) resulted in a 69.1% reduction in VCD cases and 72.7% reduction in VCD hospitalizations compared with no vaccination. An extreme high scenario (vaccination initiated at Day 15, 80% coverage rate, baseline VE) resulted in 80.3% and 82.3% reduction in VCD and VCD hospitalizations, respectively. Vaccine performance, speed of vaccination campaign initiation, and vaccine coverage were key drivers in reducing VCD cases and hospitalizations. Overall, the study and modeling results indicate that TAK-003 has the potential of meaningful utility in dengue outbreaks in endemic areas.

An effective pan-serotype dengue vaccine and enhanced control strategies could help in reducing the severe dengue burden in Bangladesh-A perspective.

Dengue is an important vector-borne disease occurring globally. Dengue virus (DENV) infection can result in a potentially life-threatening disease. To date, no DENV-specific antiviral treatment is available. Moreover, an equally effective pan-serotype dengue virus vaccine is not available. Recently, two DENV vaccines, Dengvaxia and Qdenga, were licensed for limited use. However, none of them have been approved in Bangladesh. DENV is transmitted by Aedes mosquitoes, and global warming caused by climate change favoring Aedes breeding plays an important role in increasing DENV infections in Bangladesh. Dengue is a serious public health concern in Bangladesh. In the year 2023, Bangladesh witnessed its largest dengue outbreak, with the highest number of dengue cases (n = 321,179) and dengue-related deaths (n = 1,705) in a single epidemic year. There is an increased risk of severe dengue in individuals with preexisting DENV-specific immunoglobulin G if the individuals become infected with different DENV serotypes. To date, vector control has remained the mainstay for controlling dengue; therefore, an immediate, strengthened, and effective vector control program is critical and should be regularly performed for controlling dengue outbreaks in Bangladesh. In addition, the use of DENV vaccine in curbing dengue epidemics in Bangladesh requires more consideration and judgment by the respective authority of Bangladesh. This review provides perspectives on the control and prevention of dengue outbreaks. We also discuss the challenges of DENV vaccine use to reduce dengue epidemics infection in Bangladesh.

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.