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Lancet (London, England) Feb 2024Dengue, caused by four closely related viruses, is a growing global public health concern, with outbreaks capable of overwhelming health-care systems and disrupting... (Review)
Review
Dengue, caused by four closely related viruses, is a growing global public health concern, with outbreaks capable of overwhelming health-care systems and disrupting economies. Dengue is endemic in more than 100 countries across tropical and subtropical regions worldwide, and the expanding range of the mosquito vector, affected in part by climate change, increases risk in new areas such as Spain, Portugal, and the southern USA, while emerging evidence points to silent epidemics in Africa. Substantial advances in our understanding of the virus, immune responses, and disease progression have been made within the past decade. Novel interventions have emerged, including partially effective vaccines and innovative mosquito control strategies, although a reliable immune correlate of protection remains a challenge for the assessment of vaccines. These developments mark the beginning of a new era in dengue prevention and control, offering promise in addressing this pressing global health issue.
Topics: Animals; Humans; Dengue; Dengue Virus; Disease Outbreaks; Public Health; Vaccines; Aedes
PubMed: 38280388
DOI: 10.1016/S0140-6736(23)02576-X -
The New England Journal of Medicine Feb 2024Butantan-Dengue Vaccine (Butantan-DV) is an investigational, single-dose, live, attenuated, tetravalent vaccine against dengue disease, but data on its overall efficacy... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Butantan-Dengue Vaccine (Butantan-DV) is an investigational, single-dose, live, attenuated, tetravalent vaccine against dengue disease, but data on its overall efficacy are needed.
METHODS
In an ongoing phase 3, double-blind trial in Brazil, we randomly assigned participants to receive Butantan-DV or placebo, with stratification according to age (2 to 6 years, 7 to 17 years, and 18 to 59 years); 5 years of follow-up is planned. The objectives of the trial were to evaluate overall vaccine efficacy against symptomatic, virologically confirmed dengue of any serotype occurring more than 28 days after vaccination (the primary efficacy end point), regardless of serostatus at baseline, and to describe safety up to day 21 (the primary safety end point). Here, vaccine efficacy was assessed on the basis of 2 years of follow-up for each participant, and safety as solicited vaccine-related adverse events reported up to day 21 after injection. Key secondary objectives were to assess vaccine efficacy among participants according to dengue serostatus at baseline and according to the dengue viral serotype; efficacy according to age was also assessed.
RESULTS
Over a 3-year enrollment period, 16,235 participants received either Butantan-DV (10,259 participants) or placebo (5976 participants). The overall 2-year vaccine efficacy was 79.6% (95% confidence interval [CI], 70.0 to 86.3) - 73.6% (95% CI, 57.6 to 83.7) among participants with no evidence of previous dengue exposure and 89.2% (95% CI, 77.6 to 95.6) among those with a history of exposure. Vaccine efficacy was 80.1% (95% CI, 66.0 to 88.4) among participants 2 to 6 years of age, 77.8% (95% CI, 55.6 to 89.6) among those 7 to 17 years of age, and 90.0% (95% CI, 68.2 to 97.5) among those 18 to 59 years of age. Efficacy against DENV-1 was 89.5% (95% CI, 78.7 to 95.0) and against DENV-2 was 69.6% (95% CI, 50.8 to 81.5). DENV-3 and DENV-4 were not detected during the follow-up period. Solicited systemic vaccine- or placebo-related adverse events within 21 days after injection were more common with Butantan-DV than with placebo (58.3% of participants, vs. 45.6%).
CONCLUSIONS
A single dose of Butantan-DV prevented symptomatic DENV-1 and DENV-2, regardless of dengue serostatus at baseline, through 2 years of follow-up. (Funded by Instituto Butantan and others; DEN-03-IB ClinicalTrials.gov number, NCT02406729, and WHO ICTRP number, U1111-1168-8679.).
Topics: Adult; Child; Child, Preschool; Humans; Antibodies, Viral; Dengue; Dengue Vaccines; Dengue Virus; Double-Blind Method; Vaccination; Vaccines; Vaccines, Attenuated; Brazil; Vaccine Efficacy; Adolescent; Young Adult; Middle Aged; Follow-Up Studies
PubMed: 38294972
DOI: 10.1056/NEJMoa2301790 -
Journal of Water and Health Nov 2023Dengue virus is an arthropod-borne virus, transmitted by Aedes aegypti among humans. In this review, we discussed the epidemiology of dengue hemorrhagic fever (DHF) as... (Review)
Review
Dengue virus is an arthropod-borne virus, transmitted by Aedes aegypti among humans. In this review, we discussed the epidemiology of dengue hemorrhagic fever (DHF) as well as the disease's natural history, cycles of transmission, clinical diagnosis, aetiology, prevention, therapy, and management. A systematic literature search was done by databases such as PubMed and Google Scholar using search terms, 'dengue fever', 'symptoms and causes of dengue fever', 'dengue virus transmission', and 'strategies to control dengue'. We reviewed relevant literature to identify hazards related to DHF and the most recent recommendations for its management and prevention. Clinical signs and symptoms of dengue infection range from mild dengue fever (DF) to potentially lethal conditions like DHF or dengue shock syndrome (DSS). Acute-onset high fever, muscle and joint pain, myalgia, a rash on the skin, hemorrhagic episodes, and circulatory shock are among the most common symptoms. An early diagnosis is vital to lower mortality. As dengue virus infections are self-limiting, but in tropical and subtropical areas, dengue infection has become a public health concern. Hence, developing and executing long-term control policies that can reduce the global burden of DHF is a major issue for public health specialists everywhere.
Topics: Humans; Severe Dengue; Dengue; Dengue Virus; Disease Outbreaks; Public Health
PubMed: 38017595
DOI: 10.2166/wh.2023.114 -
Molecular Cell Aug 2023Dengue is a mosquito-borne viral infection caused by dengue virus (DENV), a member of the flaviviruses. The DENV genome is a 5'-capped positive-sense RNA with a unique...
Dengue is a mosquito-borne viral infection caused by dengue virus (DENV), a member of the flaviviruses. The DENV genome is a 5'-capped positive-sense RNA with a unique 5'-stem-loop structure (SLA), which is essential for RNA replication and 5' capping. The virus-encoded proteins NS5 and NS3 are responsible for viral genome replication, but the structural basis by which they cooperatively conduct the required tasks has remained unclear. Here, we report the cryoelectron microscopy (cryo-EM) structures of SLA-bound NS5 (PC), NS3-bound PC (PC-NS3), and an RNA-elongating NS5-NS3 complex (EC). While SLA bridges the NS5 methyltransferase and RNA-dependent RNA polymerase domains in PC, the NS3 helicase domain displaces it in elongation complex (EC). The SLA- and NS3-binding sites overlap with that of human STAT2. These structures illuminate the key steps in DENV genome replication, namely, SLA-dependent replication initiation, processive RNA elongation, and 5' capping of the nascent genomic RNA, thereby providing foundations to combat flaviviruses.
Topics: Animals; Humans; Dengue Virus; Cryoelectron Microscopy; Binding Sites; RNA-Dependent RNA Polymerase; RNA Caps; Viral Nonstructural Proteins; Virus Replication; RNA, Viral
PubMed: 37478848
DOI: 10.1016/j.molcel.2023.06.023 -
The New England Journal of Medicine Feb 2024
Topics: Humans; Dengue; Dengue Vaccines; Dengue Virus; Vaccines, Attenuated
PubMed: 38294979
DOI: 10.1056/NEJMe2314240 -
MBio Oct 2023Dengue virus (DENV) is a major human pathogen that can cause hemorrhagic fever and shock syndrome. One important factor of DENV pathogenicity is non-structural protein 1...
Dengue virus (DENV) is a major human pathogen that can cause hemorrhagic fever and shock syndrome. One important factor of DENV pathogenicity is non-structural protein 1 (NS1), a glycoprotein that is secreted from infected cells. Here we study the mode of action of the widely used drug ivermectin, used to treat parasitic infections and recently shown to lower NS1 blood levels in DENV-infected patients. We found that ivermectin blocks the nuclear transport of transcription factors required for the expression of chaperones that support the folding and secretion of glycoproteins, including NS1. Impairing nuclear transport of these transcription factors by ivermectin or depleting them from infected cells dampens NS1 folding and thus its secretion. These results reveal a novel mode of action of ivermectin that might apply to other flaviviruses as well.
Topics: Humans; Dengue Virus; Dengue; Endoplasmic Reticulum Chaperone BiP; Ivermectin; Karyopherins; Molecular Chaperones; Transcription Factors; Viral Nonstructural Proteins
PubMed: 37702492
DOI: 10.1128/mbio.01441-23 -
The Lancet. Global Health Feb 2024About half of the world's population lives in dengue-endemic areas. We aimed to evaluate the long-term efficacy and safety of two doses of the tetravalent dengue vaccine... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
About half of the world's population lives in dengue-endemic areas. We aimed to evaluate the long-term efficacy and safety of two doses of the tetravalent dengue vaccine TAK-003 in preventing symptomatic dengue disease of any severity and due to any dengue virus (DENV) serotypes in children and adolescents.
METHODS
In this ongoing double-blind, randomised, placebo-controlled trial, we enrolled healthy participants aged 4-16 years at 26 medical and research centres across eight dengue-endemic countries (Brazil, Colombia, Dominican Republic, Nicaragua, Panama, Philippines, Sri Lanka, and Thailand). The main exclusion criteria were febrile illness (body temperature ≥38°C) at the time of randomisation, hypersensitivity or allergy to any of the vaccine components, pregnancy or breastfeeding, serious chronic or progressive disease, impaired or altered immune function, and previous receipt of a dengue vaccine. Participants were randomly assigned 2:1 (stratified by age and region) using an interactive web response system and dynamic block assignment to receive two subcutaneous doses of TAK-003 or placebo 3 months apart. Investigators, participants, and their parents or legal guardians were blinded to group assignments. Active febrile illness surveillance and RT-PCR testing of febrile illness episodes were performed for identification of virologically confirmed dengue. Efficacy outcomes were assessed in the safety analysis set (all randomly assigned participants who received ≥1 dose) and the per protocol set (all participants who had no major protocol violations), and included cumulative vaccine efficacy from first vaccination to approximately 4·5 years after the second vaccination. Serious adverse events were monitored throughout. This study is registered with ClinicalTrials.gov, NCT02747927.
FINDINGS
Between Sept 7, 2016, and March 31, 2017, 20 099 participants were randomly assigned (TAK-003, n=13 401; placebo, n=6698). 20 071 participants (10 142 [50·5%] males; 9929 [49·5%] females; safety set) received TAK-003 or placebo, with 18 257 (91·0%) completing approximately 4·5 years of follow-up after the second vaccination (TAK-003, 12 177/13 380; placebo, 6080/6687). Overall, 1007 (placebo: 560; TAK-003: 447) of 27 684 febrile illnesses reported were virologically confirmed dengue, with 188 cases (placebo: 142; TAK-003: 46) requiring hospitalisation. Cumulative vaccine efficacy was 61·2% (95% CI 56·0-65·8) against virologically confirmed dengue and 84·1% (77·8-88·6) against hospitalised virologically confirmed dengue; corresponding efficacies were 53·5% (41·6-62·9) and 79·3% (63·5-88·2) in baseline seronegative participants (safety set). In an exploratory analysis, vaccine efficacy was shown against all four serotypes in baseline seropositive participants. In baseline seronegative participants, vaccine efficacy was shown against DENV-1 and DENV-2 but was not observed against DENV-3 and low incidence precluded evaluation against DENV-4. During part 3 of the trial (approximately 22-57 months after the first vaccination), serious adverse events were reported for 664 (5·0%) of 13 380 TAK-003 recipients and 396 (5·9%) of 6687 placebo recipients; 17 deaths (6 in the placebo group and 11 in the TAK-003 group) were reported, none were considered study-vaccine related.
INTERPRETATION
TAK-003 demonstrated long-term efficacy and safety against all four DENV serotypes in previously exposed individuals and against DENV-1 and DENV-2 in dengue-naive individuals.
FUNDING
Takeda Vaccines.
TRANSLATIONS
For the Portuguese, Spanish translations and plain language summary of the abstract see Supplementary Materials section.
Topics: Adolescent; Child; Female; Humans; Male; Dengue; Dengue Vaccines; Dengue Virus; Double-Blind Method; Hypersensitivity; Vaccination; Child, Preschool
PubMed: 38245116
DOI: 10.1016/S2214-109X(23)00522-3 -
Acta Medica Portuguesa Feb 2024Dengue is a vector-borne disease that has a significant impact on global public health. The vector mosquito belongs to the genus Aedes. Two species play a key role in... (Review)
Review
Dengue is a vector-borne disease that has a significant impact on global public health. The vector mosquito belongs to the genus Aedes. Two species play a key role in human transmission: Ae. aegypti, which has adapted to the urban environment of highly populated areas in tropical and subtropical countries, leading to a dramatic increase in dengue cases over the years, and Ae. albopictus, which poses a potential threat to temperate climate countries due to its ability to adapt to colder climates. The disease is widespread across the world, posing a risk to nearly half of the world's population. Although most cases are asymptomatic, dengue causes a burden on healthcare systems and mainly affects the younger population. The disease is also spreading to temperate climate countries, thus becoming a global threat. Vector control measures and vaccine development have been the main prevention strategies, as there is still no effective treatment for the disease.
Topics: Animals; Humans; Dengue; Dengue Virus; Mosquito Vectors; Aedes
PubMed: 38309298
DOI: 10.20344/amp.20569 -
Nature Immunology Dec 2023Severe dengue (SD) is a major cause of morbidity and mortality. To define dengue virus (DENV) target cells and immunological hallmarks of SD progression in children's...
Severe dengue (SD) is a major cause of morbidity and mortality. To define dengue virus (DENV) target cells and immunological hallmarks of SD progression in children's blood, we integrated two single-cell approaches capturing cellular and viral elements: virus-inclusive single-cell RNA sequencing (viscRNA-Seq 2) and targeted proteomics with secretome analysis and functional assays. Beyond myeloid cells, in natural infection, B cells harbor replicating DENV capable of infecting permissive cells. Alterations in cell type abundance, gene and protein expression and secretion as well as cell-cell communications point towards increased immune cell migration and inflammation in SD progressors. Concurrently, antigen-presenting cells from SD progressors demonstrate intact uptake yet impaired interferon response and antigen processing and presentation signatures, which are partly modulated by DENV. Increased activation, regulation and exhaustion of effector responses and expansion of HLA-DR-expressing adaptive-like NK cells also characterize SD progressors. These findings reveal DENV target cells in human blood and provide insight into SD pathogenesis beyond antibody-mediated enhancement.
Topics: Child; Humans; Severe Dengue; Dengue; Dengue Virus; B-Lymphocytes; Killer Cells, Natural
PubMed: 37872316
DOI: 10.1038/s41590-023-01654-3 -
Medicina 2024
Topics: Humans; Dengue; Dengue Virus
PubMed: 38683527
DOI: No ID Found