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The 2015-16 Zika virus epidemic emerged in the Americas and rapidly spread throughout the region and beyond, showing the epidemic potential of this mosquito-borne Orthoflavivirus and its capacity to cause severe congenital malformations and neurological sequelae. WHO declared the Zika virus epidemic a public health emergency of international concern in 2016. Despite this declaration, there are no licensed Zika virus vaccines, therapeutics, or diagnostic tests appropriate for routine antenatal screening. To address this absence of essential tools to detect and mitigate the threat of future Zika virus outbreaks, a group of global experts developed a priority agenda for Zika virus research and development. This Series paper summarises crucial challenges and knowledge gaps and outlines a comprehensive strategy to advance research, surveillance, global capacity, policy, and investment for Zika virus preparedness and response., Competing Interests: Declaration of interests This project was supported by the Wellcome Trust, grant #226438/Z/22/Z, awarded to the Center for Infectious Disease Research and Policy at the University of Minnesota. ADTB and DWCB declare a subcontract from Hawaii Biotech related to testing of West Nile virus vaccine candidates in small animal models. EH declares grant U01 AI153416 from the National Institutes of Health (NIH). L-CN was the Chair of the Global Arbovirus Initiative Technical Advisory Group Meetings with WHO (2022–23). AIK declares a research grant from Takeda on Zika vaccine evaluation for which he is the principal investigator. IBR is a consultant to WHO (from June, 2018, to present). Wellcome programme staff served as members of the Zika Steering Group and participated in the project design, meetings, and reviews of manuscripts for publication. Wellcome Trust provided travel support to the December, 2023, meeting on Zika and arboviruses for EML, ADTB, DWCB, NB, EH, L-CN, TL, JES, JAM-R, ACB, AIK, JTO, AJM, AKU, and MTO. All other authors declare no competing interests. No authors were paid by a pharmaceutical company to write this Series paper. The authors alone are responsible for the views expressed in this Series paper and they do not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated. Mention of trade names is for information only and does not imply endorsement., (Copyright © 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objective: This study is a non-randomized pragmatic trial to assess the feasibility and acceptability of the Primary Care Intervention for Posttraumatic stress disorder (PCIP) (Srivastava et al., 2021), an Integrated Behavioral Health Care treatment for PTSD in adolescents., Method: Following routine clinic procedures, youth who were suspected of having trauma-related mental health symptoms were referred by their primary care providers to integrated care social workers for evaluation. The integrated care social workers referred the first 23 youth whom they suspected of having PTSD to the research study. Twenty youth consented to the study and 19 completed the pre-assessment (17 female; mean age = 19.32, SD = 2.11; range 14-22 years). More than 40% identified as Black and a third as Hispanic/Latinx. PCIP mechanisms and clinical outcomes were assessed pre- and post-treatment, and at one-month follow-up. Participants and therapists completed post-treatment qualitative interviews to assess feasibility and acceptability, and treatment sessions were audio recorded to assess fidelity., Results: Findings suggest high acceptability, satisfaction, and feasibility of the PCIP delivered in "real-life" safety net pediatric primary care. Integrated care social workers had high treatment fidelity. Despite the small sample size, there was significant improvement in symptom scores of anxiety (g = 0.68, p = 0.02) and substance use (g = 0.36, p = 0.04) from pre to post, and depression symptoms (g = 0.38, p = 0.04) from pre to follow-up. Qualitative data from patients who completed exit interviews and integrated social workers indicated high satisfaction with the treatment, with some participants reporting that the integrated intervention was more acceptable and less stigmatizing than seeking mental health care outside of primary care., Conclusions: The PCIP may improve treatment engagement and access for vulnerable youth. Promising findings of high acceptability, feasibility, and initial clinical effectiveness suggest that PCIP warrants larger-scale study as part of routine care in pediatric integrated care., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The first licensed dengue vaccine, CYD-TDV (Dengvaxia) is efficacious in seropositive individuals, but increases the risk for severe dengue in seronegative persons about two years after administration of the first dose. For countries considering the introduction of Dengvaxia, WHO recommends a pre-vaccination screening strategy whereby only persons with evidence of a past dengue infection would be vaccinated. Policy-makers need to consider the risk-benefit of vaccination strategies based on such screening tests, the optimal age to introduce the vaccine, communication and implementation strategies. To address these questions, the Global Dengue and Aedes-transmitted diseases Consortium (GDAC) organized a 3-day workshop in January 2019 with country representatives from Asia and Latin America. The meeting discussions highlighted many challenges in introducing Dengvaxia, in terms of screening test characteristics, costs of such tests combined with a 3-dose schedule, logistics, achieving high coverage rates, vaccine confidence and communication; more challenges than for any other vaccine introduction programme. A screening test would require a high specificity to minimize individual risk, and at the same time high sensitivity to maximize individual and population benefit. The underlying seroprevalence dependent positive predictive value is the best indicator for an acceptable safety profile of a pre-vaccination screening strategy. The working groups discussed many possible implementation strategies. Addressing the bottlenecks in school-based vaccine introduction for Dengvaxia will also benefit other vaccines such as HPV and booster doses for tetanus and pertussis. Levels of public trust are highly variable and context specific, and understanding of population perceptions and concerns is essential to tailor interventions, monitor and mitigate risks., (Copyright © 2019.)

The Strategic Advisory Group of Experts (SAGE) on Immunization advises WHO on global policies for vaccines. In April, 2016, SAGE issued recommendations on the use of the first licenced dengue vaccine, CYD-TDV. In November, 2017, a retrospective analysis of clinical trial data, stratifying participants according to their dengue serostatus before the first vaccine dose, showed that although in high seroprevalence settings the vaccine provides overall population benefit, there was an excess risk of severe dengue in seronegative vaccinees. SAGE's working group on dengue vaccines met to discuss the new data and mainly considered two vaccination strategies: vaccination of populations with dengue seroprevalence rates above 80% or screening of individuals before vaccination, and vaccinating only seropositive individuals. We report on the deliberations that informed the recommendation of the pre-vaccination screening strategy, in April, 2018. Important research and implementation questions remain for CYD-TDV, including the development of a highly sensitive and specific rapid diagnostic test to determine serostatus, simplified immunisation schedules, and assessment of the need for booster doses., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Dengue infection is the most common mosquito-borne viral disease worldwide, but no suitable antiviral drugs are available. We tested the α-glucosidase inhibitor celgosivir as a treatment for acute dengue fever., Methods: To establish eligibility for inclusion in a phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial, individuals aged 21-65 years who had had a fever (≥38°C) for less than 48 h, met at least two criteria indicating probable dengue infection, and had a positive result on a dengue point-of-care test kit or PCR assay were referred for screening at a centre in Singapore between July 30, 2012, and March 4, 2013. Using a web-based system, we randomly assigned patients who met full inclusion criteria after screening (1:1; random permuted block length four) to celgosivir (initial 400 mg loading dose within 6 h of randomisation, followed by 200 mg every 12 h for a total of nine doses) or matched placebo. Patients and the entire study team were masked to group assignment. The primary endpoints were mean virological log reduction (VLR) from baseline for days 2, 3, and 4, and area under the fever curve (AUC) for a temperature above 37°C from 0 h to 96 h. Efficacy analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01619969., Findings: We screened 69 patients and randomly assigned 50 (24 to celgosivir, 26 to placebo). Mean VLR was greater in the celgosivir group (-1·86, SD 1·07) than in the placebo group (-1·64, 0·75), but the difference was non-significant (-0·22, 90% CI -0·65 to 0·22; one-sided p=0·203). The mean AUC was also higher in the celgosivir group (54·92, SD 31·04) than in the placebo group (40·72, 18·69), but again the difference was non-significant (14·20, 90% CI 2·16-26·25; one-sided p=0·973). We noted similar incidences of adverse events between groups., Interpretation: Although generally safe and well tolerated, celgosivir does not seem to reduce viral load or fever burden in patients with dengue., Funding: STOP Dengue Translational Clinical Research., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Neurological manifestations due to Dengue virus (DENV) infection are atypical and uncommon. Genomic information of clinically characterised, neurotrophic DENV in humans is extremely limited albeit their importance in deciphering the pathogenicity is substantial. Here, we report a rare case of fatal DENV-4 infection complicated with encephalitis and multi-organ failure. The clinical presentation was unusual due to its rapid onset of encephalitis despite a very low virus titre. Full genomes of serum and CSF-derived viruses shared 99.99% similarity, indicating the virus dissemination across blood-brain barrier. Even though virus genomes did not reveal any of the neurotrophic substitutions of DENV documented so far, case isolates possessed a combination of 8 novel amino acid alterations, predominantly distributed in non-structural genes of DENV-4., (Copyright © 2013. Published by Elsevier B.V.)

Dengue fever, a vector-borne disease, has caused tremendous burden to countries in the tropics and sub tropics. Over the past 20 years, dengue epidemics have become more widespread, severe and frequent. This study aims to understand the dynamics of dengue viruses in cosmopolitan Singapore. Envelope protein gene sequences of all four dengue serotypes (DENV-1-DENV-4) obtained from human sera in Singapore (2008-2010) revealed that constant viral introductions and in situ evolution contribute to viral diversity in Singapore and play important roles in shaping the epidemiology of dengue in the island state. The diversity of dengue viruses reported here could be a reflection of the on-going dengue situation in the region given Singapore's location in a dengue hyperendemic region and its role as the regional hub for travels and trade. Though cosmopolitan genotype of DENV-2 has remained as the predominant strain circulating in Singapore, we uncovered evidence of in situ evolution which could possibly result in viruses with improved fitness. While we have previously shown that a switch in the predominant dengue serotype could serve as a warning for an impending outbreak, our current data shows that a replacement of a predominant viral clade, even in the absence of a switch in predominant serotype, could signal a possible increase in dengue transmission. The circulating dengue viruses in Singapore are highly diverse, a situation which could offer ample opportunities for selection of strains of higher fitness, thus increasing the risk of outbreaks despite a low Aedes population., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Infection with dengue virus is a major public health problem in the Asia-Pacific region and throughout tropical and sub-tropical regions of the world. Vaccination represents a major opportunity to control dengue and several candidate vaccines are in development. Experts in dengue and in vaccine introduction gathered for a two day meeting during which they examined the challenges inherent to the introduction of a dengue vaccine into the national immunisation programmes of countries of the Asia-Pacific. The aim was to develop a series of recommendations to reduce the delay between vaccine licensure and vaccine introduction. Major recommendations arising from the meeting included: ascertaining and publicising the full burden and cost of dengue; changing the perception of dengue in non-endemic countries to help generate global support for dengue vaccination; ensuring high quality active surveillance systems and diagnostics; and identifying sustainable sources of funding, both to support vaccine introduction and to maintain the vaccination programme. The attendees at the meeting were in agreement that with the introduction of an effective vaccine, dengue is a disease that could be controlled, and that in order to ensure a vaccine is introduced as rapidly as possible, there is a need to start preparing now., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Chikungunya fever has caught fresh attention as it raves around the globe. Since the first report of a major outbreak in Kenya in 2004, the disease has travelled across the Indian Ocean to the Indian subcontinent and subsequently to south-east Asia, resulting in millions of cases. Incidentally, the pandemic is panning out in a post-genomic era equipped with advanced molecular and bioinformatics tools that have facilitated the tracing, tracking and dissection of the Chikungunya virus (CHIKV). The rapidly accumulated data and information have offered us a glimpse of the evolution and adaptation of the virus as the pandemic unfolds. This paper reviews the history of the disease and current knowledge of the evolution of CHIKV. The virus is known to have emerged from the sylvatic cycle in Africa, resulting in three genotypes - Western African, Eastern/Central African and Asian. Evidence from Asia suggests that the virus has the potential to return to the forest. Integrating genetic signatures with spatial and temporal data, we present a network that shows the possible geographical routes of the recent spread of CHIKV. Though evolutionary constrains are imposed on arboviruses by their obligations to fulfil the biological criteria of two different hosts (vertebrates and mosquitoes) during the transmission cycle, CHIKV has accumulated biologically important mutations that facilitated the recently changed epidemiology. It is evident that the virus has adapted to Ae. albopictus, without compromising its fitness in Ae. aegypti and the human host. Besides the E1-A226V and E2-I211T mutations that have led to the virus' adaptation to Ae. albopictus, we discuss the possible initial adaptation to urban Ae. aegypti and the role of environmental factors. CHIKV may continue to scorch regions with competent vectors, especially Ae. albopictus and a susceptible human population. A preemptive approach is necessary to combat this disease with very high epidemic potential., (Copyright 2010 Elsevier B.V. All rights reserved.)