Vaccine Dengvaxia Research Articles

Exploring the Targets of Dengue Virus and Designs of Potential Inhibitors.

Dengue, a mosquito-borne viral disease spread by the dengue virus (DENV), has become one of the most alarming health issues in the global scenario in recent days. The risk of infection by DENV is mostly high in tropical and subtropical areas of the world. The mortality rate of patients affected with DENV is ever-increasing, mainly due to a lack of anti-dengue viral-specific synthetic drug components. Repurposing synthetic drugs has been an effective tool in combating several pathogens, including DENV. However, only the Dengvaxia vaccine has been developed so far to fight against the deadly disease despite the grave situation, mainly because of the limitations of understanding the actual pathogenicity of the disease. To address this particular issue and explore the actual disease pathobiology, several potential targets, like three structural proteins and seven non-structural (NS) proteins, along with their inhibitors of synthetic and natural origin, have been screened using docking simulation. Exploration of these targets, along with their inhibitors, has been extensively studied in culmination with molecular docking-based screening to potentiate the treatment. These screened inhibitors could possibly be helpful for the designing of new congeneric potential compounds to combat dengue fever and its complications.

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.

Exploring the therapeutic potential of DV-B-120 as an inhibitor of dengue virus infection.

Dengue fever, an infectious disease prevalent in subtropical and tropical regions, currently lacks effective small-molecule drugs as treatment. In this study, we used a fluorescence peptide cleavage assay to screen seven compounds to assess their inhibition of the dengue virus (DENV) NS2B-NS3 protease. DV-B-120 demonstrated superior inhibition of NS2B-NS3 protease activity and lower toxicity compared to ARDP0006. The selectivity index of DV-B-120 was higher than that of ARDP0006. In vivo assessments of the antiviral efficacy of DV-B-120 against DENV replication demonstrated delayed mortality of suckling mice treated with the compound, with 60-80% protection against life-threatening effects, compared to the outcomes of DENV-infected mice treated with saline. The lower clinical scores of DENV-infected mice treated with DV-B-120 indicated a reduction in acute-progressive illness symptoms, underscoring the potential therapeutic impact of DV-B-120. Investigations of DV-B-120's ability to restore the antiviral type I IFN response in the brain tissue of DENV-infected ICR suckling mice demonstrated its capacity to stimulate IFN and antiviral IFN-stimulated gene expression. DV-B-120 not only significantly delayed DENV-2-induced mortality and illness symptoms but also reduced viral numbers in the brain, ultimately restoring the innate antiviral response. These findings strongly suggest that DV-B-120 holds promise as a therapeutic agent against DENV infection and highlight its potential contribution in addressing the current lack of effective treatments for this infectious disease.IMPORTANCEThe prevalence of dengue virus (DENV) infection in tropical and subtropical regions is escalating due to factors like climate change and mosquito vector expansion. With over 300 million annual infections and potentially fatal outcomes, the urgent need for effective treatments is evident. While the approved Dengvaxia vaccine has variable efficacy, there are currently no antiviral drugs for DENV. This study explores seven compounds targeting the NS2B-NS3 protease, a crucial protein in DENV replication. These compounds exhibit inhibitory effects on DENV-2 NS2B-NS3, holding promise for disrupting viral replication and preventing severe manifestations. However, further research, including animal testing, is imperative to assess therapeutic efficacy and potential toxicity. Developing safe and potent treatments for DENV infection is critical in addressing the rising global health threat posed by this virus.

Single dose of Dengvaxia vaccine: is it a cause for alarm?

Single dose of Dengvaxia vaccine: is it a cause for alarm?

Amazon Plant‐Derived Compounds Suppressing Dengue NS5 Protein: Insights from Computational Drug Development and Network Pharmacology Approach

AbstractDengue, a life‐threatening Flavivirus infection, is rampant across 128 tropical and subtropical regions, annually afflicting millions and causing 20,000 deaths due to inadequate treatments. Despite the FDA‐approved Dengvaxia vaccine, its limitations necessitate novel drug development. Notably, the enzymatic nature of the NS5 protein (PDB ID: 3p97) within DENV, responsible for viral RNA synthesis, makes it a prime drug target. Employing Pharmacoinformatics, Molecular Dynamics Simulations, Quantum Mechanics, and network pharmacology, we screened compounds from NuBBE, the Brazilian Amazon Plant Database, along with reported dengue compounds. Docking yielded promising scores (−11.1 to −2.8) and (−11 to −3.1) kcal/mol, respectively. From 1310 phytochemicals, top compounds emerged: Ramosin, Pectolinarin, hinokinin, and sesamin, boasting scores of −11, −11, −9.7, and −9.6, surpassing Acetaminophen's −5.8. Validated post‐docking interactions used 100 ns Molecular Dynamics Simulations and quantum mechanics. Pharmacokinetics and Toxicity analysis aligned with ADME norms, showing no undue toxicity. Network pharmacology unveiled connections between bioactive chemicals and disease targets. This investigation uncovers the potential of these compounds to inhibit DENV‐3 NS5 protein. In vitro, in vivo, and cell line assays are crucial next steps for specific anti‐dengue drug development.

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.

Dengue vaccines, a time for cautious optimism?

Vaccine could take a central role in the strategy to reduce the burden of dengue. The development of an effective and safe vaccine must address various immunological challenges. Several vaccines are currently in development. To date, two live-attenuated vaccines have been deployed. Both have an effectiveness that varies depending on the serotypes. The deployment of the Dengvaxia vaccine, which began in 2015, was marked by a major safety alert leading to its use being restricted to previously dengue-seropositive people over 9 years old. The Qdenga vaccine is currently being deployed. There is for now insufficient data to ensure its safety in seronegative people. Some travelers, who have previously been infected with dengue, are a group for whom a vaccination recommendation applies.

(Re)building Trust in Public Health Through Responsible Science Communication

Abstract Effective science communication is essential in public health, as evidenced by the aftermath of the Dengvaxia vaccine controversy in the Philippines, where inadequate communication resulted in widespread vaccine hesitancy. This article highlights the need for improved strategies for communication while examining the implications of inadequate science communication on public health outcomes. It argues for a more engaging and inclusive approach to public health communication, emphasizing that effective communication goes beyond simply disseminating knowledge to include promoting community engagement and conversation. Finally, it advocates for rebuilding trust in public health institutions through better science communication and responsive public health practices by addressing the root causes of public skepticism and improving community involvement.

Dengue virus and vaccines: A review

Dengue disease is a significant global health issue with nearly 400 million infections per year. Therefore, it is vital to developed a universal dengue vaccine. However, developing such a vaccine faces major challenges including risk of ADE, lack of predictive animal models, and insufficient immunological correlates of protection. First licensed dengue vaccine Dengvaxia showed increased risk of severe dengue likely due to ADE from imbalanced immunity against the four dengue serotypes. This review summarizes current dengue vaccine candidates like Dengvaxia, TAK-003, and TV003/TV005. It highlights the mechanisms and implications of ADE in vaccine-induced immune responses. Potential innovative solutions are discussed including focusing on highly neutralizing epitopes like envelope domain III and leveraging new vaccine platforms such as virus-like particles and mRNA vaccines. These approaches may improve the quality of neutralizing antibodies over cross-reactive enhancement-prone responses. However, definitive immunological correlates for protection remain unknown. Continued research is urgently needed to enable universal dengue vaccine that provides long-lasting immunity against all serotypes without risk of ADE.

Dengue Fever: Etiology, Diagnosis, Prevention and Treatment

Dengue fever (break-bone fever) is a viral disease transmitted by Aedes mosquitoes. It is caused by the Dengue virus, which is a single positive-stranded RNA virus belonging to the Flaviviridae family. Dengue fever is prevalent in tropical and subtropical areas and is a significant public health concern in many countries, including`g Nigeria. The disease is characterized by symptoms such as high fever, headache, body aches, nausea, vomiting, swollen glands, and rash. In severe cases, dengue fever can lead to complications such as bleeding, organ impairment, and dengue shock syndrome. Diagnosing dengue fever can be challenging, especially in areas where it is endemic. In endemic locations, diagnosis is often made clinically based on the patient's reported symptoms and a physical examination. Tourniquet testing, which involves applying a blood pressure cuff and counting any petechial hemorrhages, can help in the diagnosis. Laboratory methods, including full blood count, cell culture, nucleic acid identification (PCR), and serology, can be used to confirm the diagnosis. Preventing dengue fever involves controlling the mosquito vector and protecting oneself from mosquito bites. Measures such as eliminating mosquito breeding sites, using insect repellents, wearing protective clothing, and using bed nets can help prevent mosquito bites. Vaccination against dengue is also available, with the Dengvaxia vaccine being used in some countries. There is no specific antiviral treatment for dengue fever. Management focuses on supportive care, maintaining a healthy fluid balance, and relieving symptoms such as fever and pain. Severe cases may require hospitalization and intensive medical care. In Nigeria, dengue fever is often misdiagnosed or overlooked due to similarities with other febrile illnesses like malaria. This can lead to underreporting and inadequate management of dengue cases. Increasing awareness among healthcare professionals and the general population is crucial for early detection and appropriate management of dengue fever in Nigeria. In conclusion dengue fever is a viral disease transmitted by mosquitoes, primarily Aedes species. It is a significant global health concern, including in Nigeria. Early diagnosis, prevention measures, and supportive care are essential in managing dengue fever and reducing its impact on public health. This review is aimed at discussing the current issues of Dengue fever with focus on Nigeria.

Molecular Mechanisms of Antiviral Agents against Dengue Virus.

Dengue is a major global health threat causing 390 million dengue infections and 25,000 deaths annually. The lack of efficacy of the licensed Dengvaxia vaccine and the absence of a clinically approved antiviral against dengue virus (DENV) drive the urgent demand for the development of novel anti-DENV therapeutics. Various antiviral agents have been developed and investigated for their anti-DENV activities. This review discusses the mechanisms of action employed by various antiviral agents against DENV. The development of host-directed antivirals targeting host receptors and direct-acting antivirals targeting DENV structural and non-structural proteins are reviewed. In addition, the development of antivirals that target different stages during post-infection such as viral replication, viral maturation, and viral assembly are reviewed. Antiviral agents designed based on these molecular mechanisms of action could lead to the discovery and development of novel anti-DENV therapeutics for the treatment of dengue infections. Evaluations of combinations of antiviral drugs with different mechanisms of action could also lead to the development of synergistic drug combinations for the treatment of dengue at any stage of the infection.

Philippine immunization coverage and dengvaxia: An infodemiological study.

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. 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. 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. There was no significant correlation between web-based interest in dengvaxia, the vaccines in the NIP, and national immunization coverage.

Filipinos' COVID-19 vaccine hesitancy comments in TikTok videos: A manifest content analysis.

Vaccine hesitancy is one of the top 10 threats to world health. The ongoing pandemic highlighted this health threat. The COVID-19 vaccine hesitancy remains underreported in the Philippines. Thus, this study aimed to describe and analyze the comments of Filipinos in TikTok videos about COVID-19 vaccine hesitancy. Manifest content analysis. A total of 25 TikTok videos and their comments (n=4564) were analyzed. We collected data between July 2021 and October 2021. Bengtsson's approach to content analysis was utilized to analyze the data. Data were validated using member-checking and intercoder reliability. This study afforded three themes of COVID-19 vaccine hesitancy: (a) fear and mistrust (subthemes: influence of Dengvaxia vaccine, the influence of people who refuse to be vaccinated, lack of trust in the government, lack of trust in healthcare workers, doubts on vaccines' effectiveness), (b) misinformation and disinformation (subthemes: misbeliefs, insufficient knowledge), and (c) adamant attitudes (subthemes: unwillingness to be vaccinated, picky on vaccine brand). Our study established Filipinos' diverse reasons for COVID-19 vaccine hesitancy. TikTok, as a social media platform, is used for COVID-19 vaccinediscussions and thedissemination of misinformation. To prepare for the next pandemic or public health disaster, the government, HCWs, and the public must efficiently convey timely, accurate health information and dispel misinformation on social media platforms.

Generation of soluble, cleaved, well-ordered, native-like dimers of dengue virus 4 envelope protein ectodomain (sE) suitable for vaccine immunogen design

Dengue virus is transmitted by Aedes mosquitoes and dengue is endemic in many regions of the world. Severe dengue results in complications that may lead to death. Although some vaccine candidates are in clinical trials and one vaccine Dengvaxia, with restricted efficacy, is available, there are currently no specific therapies to completely prevent or treat dengue. The dengue virus structural protein E (envelope) exists as a head-to-tail dimer on mature virus, is targeted by broadly neutralizing antibodies and is suitable for developing vaccine immunogens. Here, we have used a redesigned dengue prME expression construct and immunoaffinity chromatography with conformational/quaternary antibody A11 to purify soluble DENV4 sE(A259C) (E ectodomain) dimers from mammalian expression system to ~99 % purity. These dimers retain glycosylation reported for native DENV E, display the three major broadly neutralizing antibody epitopes, and form well-ordered structure. This strategy can be used for developing subunit vaccine candidates against dengue and other flaviviruses.

Short communication: Feasibility of dengue vaccine to infect different human cell lines: An alternative potency test using HEK293T cells.

Dengue is caused by an arbovirus that belongs to the Flaviviridae family and there are four distinct, but close related, circulating serotypes. Dengue disease is of great importance for global public health, with vaccination being its main prophylactic measure. However, there is a paucity of biological models for evaluating tetravalent dengue vaccines. The aim of this study was to evaluate the susceptibility of human cell lines HEK293T and THP-1 to a commercial dengue vaccine and test the feasibility of this approach in the development of a potency assay with human cell lines, as a methodological alternative to the golden standard potency assay with VERO cells. In this context, we used a batch of the commercial vaccine Dengvaxia® (CYD-TDV) for the infection tests. We evaluated the presence of the vaccine virus in THP-1 cells, differentiated into macrophages (dTHP-1), and in HEK293T by confocal microscopy, using 4G2 pan-flavivirus antibody. Vaccine infectivity and potency were determined by immunocolorimetric assay using monoclonal antibodies specific for each serotype. The results indicated that the human strain HEK293T was responsive to the tetravalent vaccine, as shown by the presence of virus particles in the cell cytoplasm in a pattern similar to the one observed with VERO cells. Moreover, it was possible to determine the infectivity and potency values of each vaccine virus serotype in the HEK293T, with serotype 4 prevailing over the others. Thus, the human cell line HEK293T provides a potential candidate to be used in assays to determine potency and identity of tetravalent dengue vaccines.

March 2019 dengue fever outbreak at the Kenyan south coast involving dengue virus serotype 3, genotypes III and V.

The first description of a disease resembling dengue fever (DF) was in the 15th century slave trade era by Spanish sailors visiting the Tanzania coast. The disease, then associated with evil spirits is now known to be caused by four serotypes of dengue virus (DENV1-4) that are transmitted by Aedes mosquitoes. Kenya has experienced multiple outbreaks, mostly associated with DENV-2. In this study, plasma samples obtained from 37 febrile patients during a DF outbreak at Kenya's south coast in March 2019 were screened for DENV. Total RNA was extracted and screened for the alpha- and flavi-viruses by real-time polymerase chain reaction (qPCR). DENV-3 was the only virus detected. Shotgun metagenomics and targeted sequencing were used to obtain DENV whole genomes and the complete envelope genes (E gene) respectively. Sequences were used to infer phylogenies and time-scaled genealogies. Following Maximum likelihood and Bayesian phylogenetic analysis, two DENV-3 genotypes (III, n = 15 and V, n = 2) were found. We determined that the two genotypes had been in circulation since 2015, and that both had been introduced independently. Genotype III's origin was estimated to have been from Pakistan. Although the origin of genotype V could not be ascertained due to rarity of these sequences globally, it was most related to a 2006 Brazilian isolate. Unlike genotype III that has been described in East and West Africa multiple times, this was the second description of genotype V in Kenya. Of note, there was marked amino acid variances in the E gene between study samples and the Thailand DENV-3 strain used in the approved Dengvaxia vaccine. It remains to be seen whether these variances negatively impact the efficacy of the Dengvaxia or future vaccines.

Dengue Vaccine: Recommendations of the Advisory Committee on Immunization Practices, United States, 2021.

SummaryDengue is a vectorborne infectious disease caused by dengue viruses (DENVs), which are predominantly transmitted by Aedes aegypti and Aedes albopictus mosquitos. Dengue is caused by four closely related viruses (DENV-1–4), and a person can be infected with each serotype for a total of four infections during their lifetime. Areas where dengue is endemic in the United States and its territories and freely associated states include Puerto Rico, American Samoa, the U.S. Virgin Islands, the Federated States of Micronesia, the Republic of Marshall Islands, and the Republic of Palau. This report summarizes the recommendations of the Advisory Committee on Immunization Practices (ACIP) for use of the Dengvaxia vaccine in the United States. The vaccine is a live-attenuated, chimeric tetravalent dengue vaccine built on a yellow fever 17D backbone. Dengvaxia is safe and effective in reducing dengue-related hospitalizations and severe dengue among persons who have had dengue infection in the past. Previous natural infection is important because Dengvaxia is associated with an increased risk for severe dengue in those who experience their first natural infection (i.e., primary infection) after vaccination. Dengvaxia was licensed by the Food and Drug Administration for use among children and adolescents aged 9–16 years (referred to in this report as children). ACIP recommends vaccination with Dengvaxia for children aged 9–16 having evidence of a previous dengue infection and living in areas where dengue is endemic. Evidence of previous dengue infection, such as detection of anti-DENV immunoglobulin G with a highly specific serodiagnostic test, will be required for eligible children before vaccination.

Evaluation of the extended efficacy of the Dengvaxia vaccine against symptomatic and subclinical dengue infection.

More than half of the world's population lives in areas at risk for dengue virus infection. A vaccine will be pivotal to controlling spread, however, the only licensed vaccine, Dengvaxia, has been shown to increase the risk of severe disease in a subset of individuals. Vaccine efforts are hampered by a poor understanding of antibody responses, including those generated by vaccines, and whether antibody titers can be used as a marker of protection from infection or disease. Here we present the results of an ancillary study to a phase III vaccine study (n = 611). All participants received three doses of either Dengvaxia or placebo and were followed for 6 years. We performed neutralization tests on annual samples and during confirmed dengue episodes (n = 16,508 total measurements). We use mathematical models to reconstruct long-term antibody responses to vaccination and natural infection, and to identify subclinical infections. There were 87 symptomatic infections reported, and we estimated that there were a further 351 subclinical infections. Cumulative vaccine efficacy was positive for both subclinical and symptomatic infection, although the protective effect of the vaccine was concentrated in the first 3 years following vaccination. Among individuals with the same antibody titer, we found no difference between the risk of subsequent infection or disease between placebo and vaccine recipients, suggesting that antibody titers are a good predictor of both protection and disease risk.

Vaccine Hesitancy and the Cultural Politics of Trust in the Dengvaxia Controversy: A Critical Discourse-Ethnographic Study of Online News Content, Producers, and Audiences

Vaccine hesitancy refers to the delay in acceptance or refusal of vaccination despite vaccine availability. At its very core lies the problem of trust. Yet, there is very little research on the role of trust in vaccine hesitancy, particularly concerning its ideological dimension. This research aims to describe and explore how the online news discourse on the Dengvaxia vaccine controversy legitimizes a particular trust culture in Philippine society. For this purpose, the research adopts the theory of social trust propounded by the Polish sociologist Piotr Sztompka and links it to the study of news media using critical discourse analysis. This research is an interdisciplinary project that adopts various concepts and lenses from sociology, linguistics, media studies, and public health.

Relative contribution of nonstructural protein 1 in dengue pathogenesis.

Dengue is a major public health concern in the tropical and subtropical world, with no effective treatment. The controversial live attenuated virus vaccine Dengvaxia has boosted the pursuit of subunit vaccine approaches, and nonstructural protein 1 (NS1) has recently emerged as a promising candidate. However, we found that NS1 immunization or passive transfer of NS1 antibodies failed to confer protection in symptomatic dengue mouse models using two non-mouse-adapted DENV2 strains that are highly virulent. Exogenous administration of purified NS1 also failed to worsen in vivo vascular leakage in sublethally infected mice. Neither method of NS1 immune neutralization changed the disease outcome of a chimeric strain expressing a vascular leak-potent NS1. Instead, virus chimerization involving the prME structural region indicated that these proteins play a critical role in driving in vivo fitness and virulence of the virus, through induction of key proinflammatory cytokines. This work highlights that the pathogenic role of NS1 is DENV strain dependent, which warrants reevaluation of NS1 as a universal dengue vaccine candidate.