Dengue Fever

Dengue fever is a mosquito-transmitted infection, with an escalating geographic distribution and disease burden because of factors including climate change, urbanisation and globalisation. Despite ongoing and often intensive vector control efforts implemented in many endemic countries, the incidence of dengue has increased thirty-fold worldwide over the past half-century, establishing it as the most rapidly spreading vector-borne disease. The rising burden of disease from dengue is further compounded by the absence of specific antiviral treatments, and the limitations of currently available vaccines. In light of these challenges, innovative strategies to enhance our understanding of dengue and accelerate the development of effective countermeasures are urgently needed. Controlled human infection (CHI) studies have emerged as a valuable tool in this endeavour, offering a unique platform for investigating the natural history of infectious diseases and evaluating the potential of novel interventions. CHI studies involve the deliberate inoculation of human volunteers with an infectious agent such as a virus, bacteria, or parasite. The strength of this study design is a result of their highly controlled nature, whereby carefully selected volunteers are exposed to standardised amounts of a well-characterised infectious agent. This enables exact longitudinal measurement of challenge agent replication kinetics, infectious shedding, immunological responses and clinical features, and contrasts with what is achievable through field trials of natural infection, including household contact studies. By inoculating all study participants with the same agent at the same dose and under the same conditions, confounding by strain, dose, and exposure is controlled. Host factors associated with inter-individual differences in clinical outcome and the effect of interventions can then be robustly inferred, along with the ability to connect detailed longitudinal data to the earliest time points after exposure, including prior to the onset of symptoms. Singapore, an equatorial city-state, is highly endemic for dengue, with the co-circulation of all four serotypes. The country boasts a well-established research infrastructure and considerable expertise in infectious diseases at institutions like NCID. Singapore also has a globally recognized vector control program and maintains extensive dengue surveillance data, providing a rich context for studying the disease. The strong research infrastructure and expertise at NCID, coupled with Singapore's commitment to public health and its history of effective disease surveillance and control, create a conducive environment for conducting high-quality and impactful dengue CHI studies. Findings from CHI studies conducted in Singapore are likely to be highly relevant to other endemic areas in Southeast Asia and globally. The specific dengue serotype dynamics in Singapore, including recent switches involving DEN1 and DEN3, make research on these serotypes particularly timely. Furthermore, Singapore has observed a shift in the average age of dengue patients towards older adults, who may be at higher risk of severe disease, making research in this context especially important. By developing a dengue controlled human infection model in Singapore through the DEN-CHIM-01 study we intend to enable: 1. A model of infection that can be used to assess the efficacy of new vaccines, treatments, and diagnostics in a dengue endemic setting. 2. Identification of the immune and other host factors, including ethnicity, associated with viral kinetics and dengue symptoms. 3. Provide the foundation for future development of a unique model of secondary dengue. The DEN-CHIM-01 study will use the optimised conditions established by our collaborators in the US to conduct a GMP rDEN3delta30 challenge study in seronegative volunteers. This study aims to investigate in the Singapore context the clinical, virologic and immunologic features of DEN3 infection and what immune, transcriptomic and genomic markers correlate with symptomology, viral kinetics and the immune response. The DEN-CHIM-01 study forms part of a wider programme of work in Singapore, both in dengue fever and using CHI studies as an experimental model to advance the development of therapeutics and vaccines. Experience from the Sing-CoV controlled human infection study (PI: A/Prof Barnaby Young) has informed development of this protocol, and agreements for sharing of samples and data with our scientific collaborators are in place. The DEN-CHIM-01 is a critical first step to conducting a follow up pilot clinical trial, DEN-CHIM-02, funded by the same grant. In DEN-CHIM-02 we plan to investigate the efficacy of a dengue vaccine at protecting against challenge with rDEN3delta30.

This Phase 1 study is designed to assess the safety, tolerability, and pharmacokinetics of single and multiple intravenous doses of BWC0977 when administered to healthy adult volunteers. This is a randomized double-blind, placebo-controlled, ascending dose, multi-cohort trial. A total of 64 healthy volunteers are expected to be enrolled in 8 Cohorts. The study will be conducted in two phases: A single ascending dose (SAD) phase, followed by a multiple ascending dose (MAD) phase. In SAD, participants in Cohorts 1 - 2 will receive one dose of BWC0977 or placebo. In MAD, participants in cohorts 3 - 7 will receive multiple doses of BWC0977 or placebo for 7-10 consecutive days (as per the schedule). In both parts, sequential cohorts will be exposed to increasing doses of BWC0977.

This is a multi-country, open label, two-arm, parallel-group, superiority, individually randomised clinical trial involving 2,606 febrile children per country (two countries, total n=5212). The trial will compare the performance of a point-of-care rapid triage test (POC-RTT) based on suPAR levels (i.e.suPARnostic®) (in combination with IMCI-based strategies, which are the SoC) to appropriately support admission/referral vs discharge decisions during the first clinical assessment of febrile children aged 2-\<60 months compared to the standard of care based on IMCI guidelines. Febrile children meeting the study eligibility criteria will be randomly allocated (1:1) to one of the two triaging approaches (arms): 1) IMCI-based standard of care (SoC); or 2) IMCI-enhanced by suPAR levels (SoC + suPAR POC). Blood will be collected from all participants and only those randomised to the intervention arm (arm 2) will have suPAR levels determined at the POC using suPARnostic® device. At baseline, all children will undergo two clinical assessments. Primary composite endpoint of "appropriateness of discharge" will be based on the first clinical assessment, which is more representative of real-world clinical practice. However, the ultimate decision on admission/referral vs discharge will be based on the second clinical assessment, which will ensure the safest possible clinical practice in the context of a clinical trial. 1. At baseline, during the first clinical assessment, all participants will be evaluated following the SoC based on IMCI guidelines, which will guide management decisions, including clinical diagnosis and treatment. This IMCI-guideline based evaluation during this first clinical assessment will be conducted by a health worker as per routine clinical practice in the outpatient departments of each study site. 1. In the participants randomised to the control arm, decision of admission/referral vs discharge home will be informed by IMCI-based evaluation alone (SoC). 2. In the participants randomised to the intervention arm, decision of admission/referral vs discharge home will be informed by IMCI-based evaluation enhanced by suPAR levels (SoC + suPAR POC). Clinicians will be instructed to admit for further observation any child with suPAR levels equal or superior to 4 ng/mL (except for confirmed malaria, that it will be equal or superior to 6 ng/mL), as these patients are at moderate or high risk of adverse outcomes and death. On the other hand, children with suPAR levels below 4 ng/mL (or below 6 ng/mL in case of confirmed malaria) will be eligible for discharge home at the criteria of the clinician, considering the signs and symptoms found, and based on IMCI guidelines. Hence, should clinicians in charge deem that any of these children still require admission, they will be instructed to continue with the admission regardless of suPAR levels. The study intervention will be implemented during the first clinical assessment, and consequently, primary composite endpoint of "appropriateness of discharge" will be based on the decision of admission/referral vs discharge home during this first clinical assessment, which is more representative of routine clinical practice in each study site. 2. All randomised participants will be also evaluated by an independent study physician in a second clinical assessment, for the implementation of a systematised clinical evaluation (IMCI-based) to uncover any danger signs or severity criteria potentially missed or misinterpreted during the first assessment. This second assessment will also include clinical variables of the clinical scores ED-PEWS, LqSOFA and LODS, as well as temperature and oxygen saturation measures. Hence, study clinicians during this second clinical assessment might be able to uncover more symptoms and signs that are admission criteria due to the tools available in the context of this clinical trial. Initially discharged patients from both arms showing a danger sign during this second assessment will be admitted, as well as those from the intervention arm with suPAR high-risk (red light) and moderate-risk (yellow light) levels, in case that the first clinician might not have adhered to the protocol during the first assessment. On the other hand, this second assessment will not overturn the decision of the first clinician if admission has been decided in case of low-risk (suPAR levels below 4 ng/mL; or below 6 ng/mL in case of confirmed malaria). This second clinical assessment will guide the ultimate decision on admission/referral vs discharge in order to ensure the safest possible clinical practice in the context of a clinical trial. Moreover, those participants with respiratory symptoms will be eligible for the respiratory tract infection (RTI) sub-study, where digital lung auscultations, a mid-turbinate nasal swab and a saliva sample will be collected. Throughout the study, all participants will receive treatment as per the routine clinical practice and SoC for each diagnosis at each study site, administered by clinical staff routinely working in the participating facilities. All participants will have follow-up evaluations by study clinicians on days 3 and 7 post-enrolment, or at any time in-between in case of clinical deterioration according to caregivers' evaluation. All participants will be also followed-up on day 28 for an interview to follow-up on serious adverse events (SAEs), as well as to collect information on secondary consultations and hospitalisation, or death. A follow-up extra visit at day 91 (month 3) can be conducted for an interview to ask for hospitalisation or death.

The main aim of this study is to collect more information on the effectiveness of TDV when used in a pilot public vaccination program for children and adolescents participating in a community-based cohort in Southeast Asian countries with high dengue transmission, specifically Thailand, Indonesia, and Malaysia where TDV is already approved for use. The study will include cohort participants (individual follow-up of 3 years) who may or may not later be vaccinated with TDV as part of a pilot public vaccination program in the study countries. The study will investigate if cohort participants who were vaccinated with TDV have less hospital stays due to dengue than cohort participants who were not vaccinated with TDV. The study will also provide further information on the effectiveness of TDV against the least common dengue virus serotypes (DENV-3 and DENV-4).

Dengue fever is caused by an infection with the dengue virus. Vaccination with Dengue Tetravalent Vaccine (TDV) can help prevent dengue fever. The purpose of this study is to collect information of vaccination with TDV when given to children younger than 2 years. The main aims of this study are to learn how safe the vaccine is and how well it works to activate a young child's immune system (this is called immunogenicity). Children between the age of 6 and 21 months will receive two vaccinations with either TDV or placebo 3 months apart. Blood samples will be taken before and after the vaccination as well as throughout the study. These are necessary to check how well the vaccine works to activate the immune system. During the study, participants will visit their study clinic 8 times for vaccinations, blood draws and health checks.

Dengue fever is caused by an infection with the dengue virus. Vaccination with Dengue Tetravalent Vaccine (TDV) can help prevent dengue fever. Researchers have seen that dengue fever now also happens more often in elderly persons. The main aim of this study is to learn more about the side effects of TDV in adult (45 - 60 years) and elderly (60 - 79 years) persons and about TDV's ability to create an immune response in adult and elderly persons. Another aim is to learn about the side effects of TDV in adult and elderly persons in endemic countries who have one or more additional medical conditions (called comorbidities) such as diabetes mellitus, hypertension or a chronic kidney condition. In this study, participants will receive 2 vaccinations with TDV (the second 3 months after the first). During the study, participants will visit their study clinic 5 times.

This is a randomized, participant- and investigator- blinded, placebo-controlled study to investigate the efficacy and safety of EYU688 administered orally in patients with dengue fever. Due to the different PK sampling schedules applied, the study consists of two cohorts run in parallel (intensive PK \[cohort 1\] and sparse PK sampling \[cohort 2\]).

The main aim of this study is to collect the number and type of medical problems (adverse events) after vaccination with QDENGA in Malaysia and to learn more about such medical problems after vaccination. Another aim of this study is to collect the number of persons vaccinated with QDENGA who need to stay in the hospital because of severe dengue fever. No vaccination will be given as part of this study. The study will only collect data of persons already vaccinated with QDENGA who agree to participate.

Prospective, longitudinal studies of people with acute infections are essential to understand risk factors, clinical manifestations, pathobiology, and management strategies. Observational studies can provide data necessary to select interventions and strategies for testing in clinical trials and to develop key design features of trials. Observational studies can be particularly important for establishing an early knowledge base after emergence of a new pathogen, as illustrated by the recent emergence of influenza A (H1N1), SARS-CoV-2, and Mpox. This observational study protocol describes collection of data and biospecimens from sites across the world for characterizing acute infections in hospitalized patients. The protocol is designed to study respiratory infections, infections outside the respiratory tract, established infectious diseases, and emerging infectious diseases. Data generated in this study will be used to efficiently characterize acute infectious diseases and plan future clinical trials.

The AnovaOS™ Network Powered Patient Registry may be used to inform the development and conduct of clinical trials and observational studies designed to better understand, prevent, diagnose, treat, ameliorate or cure disease. The AnovaOS™ Network Powered Patient Registry may additionally be used to expedite identification and recruitment of participants for clinical trials of promising therapeutics and observational studies.