Dengue: Update on Clinically Relevant Therapeutic Strategies and Vaccines

Curr Treat Options Infect Dis DOI 10.1007/s40506-023-00263-w Dengue: Update on Clinically Relevant Therapeutic Strategies and Vaccines Monica Palanichamy Kala1 Ashley L. St. John1,2,3,4*, Abhay P. S. Rathore4*, Address *,1 Program in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, 8 College Rd., Level 9, Singapore 169857, Singapore Email: 2 Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore 3 SingHealth Duke-NUS Global Health Institute, Singapore, Singapore *,4 Department of Pathology, Duke University Medical Center, 207 Research Rd, Durham, NC 27705, USA Email: © The Author(s) 2023 Keywords Dengue fever · Vascular leakage · Therapeutics · Vaccines · Metabolic disorders · Mast cells Opinion statement Dengue viruses (DENV) continue to circulate worldwide, resulting in a significant burden on human health. There are four antigenically distinct serotypes of DENV, an infection of which could result in a potentially life-threatening disease. Current treatment options are limited and rely on supportive care. Although one dengue vaccine is approved for dengue-immune individuals and has modest efficacy, there is still a need for therapeutics and vaccines that can reduce dengue morbidities and lower the infection burden. There have been recent advances in the development of promising drugs for the treatment of dengue. These include direct antivirals that can reduce virus replication as well as hosttargeted drugs for reducing inflammation and/or vascular pathologies. There are also new vaccine candidates that are being evaluated for their safety and efficacy in preventing dengue disease. This review highlights nuances in the current standard-of-care treatment of dengue. We also discuss emerging treatment options, therapeutic drugs, and vaccines that are currently being pursued at various stages of preclinical and clinical development. Vol.:(0123456789)  Introduction Dengue fever (DF), caused by the dengue virus (DENV), is the world’s most prevalent and important arboviral infection. It is estimated that nearly 390 million infections occur annually, of which 96 million manifest clinically [1]. DENV belongs to the genus Flavivirus, which also comprises several other clinically important human pathogens, such as Zika, Japanese encephalitis, West Nile, and Yellow Fever viruses, among others. The DENV genome consists of a single-stranded positive-sense RNA that encodes for three structural (capsid, prM/M, and E) and seven non-structural proteins that are translated during the virus replication cycle [2]. The virus is spread by an infected mosquito bite during a blood meal and exists in both sylvatic and urban ecosystems [3]. The sylvatic cycle of DENV involves virus transmission between non-human primates (NHP) and mosquitos prevalent in the forest [4, 5] while in the urban cycle of transmission, the virus is maintained within human population aided by urban dwelling mosquitos such as Aedes aegypti [6]. As the geographical distributions of these vectors are expanding it is likely that DENV will spread further [7]. There are 4 serotypes of DENV (DENV14), which makes it likely that an individual will be exposed to the virus multiple times in their lifetime [8]. Latest models of dengue transmission estimate that 4 million cases require hospitalization each year [9] and account for an annual estimated cost of US $8.9 billion globally [10]. With an increase in urbanization and climate change supporting the spread of the mosquito vector, some models predict an increasing risk of DENV transmission, potentially impacting 6.1 billion people by 2080 [11]. Dengue clinical course The clinical course of DF begins with common flu-like symptoms, including fever, nausea, myalgia, and headache [12]. Although DF is a self-limiting mild disease, some patients will develop the severe form of the disease, characterized by plasma leakage, hemorrhaging, and shock [12]. According to the 2009 WHO revised guidelines, dengue disease is categorized as DF, DF with warning signs, and severe dengue [13] (Fig. 1). Some of the warning signs include hepatomegaly, abdominal pain, mucosal bleeding, and increasing hematocrit concurrent with rapidly declining platelets [13]. In general, there are three phases of dengue disease—the febrile phase when viremia is high, the critical phase when fever and viremia are resolving, but the patient may experience thrombocytopenia and or plasma leakage that manifests as hemoconcentration and fluid accumulation in tissues in severe cases, and, finally, the convalescent phase with fluid reabsorption and recovery [13] (Fig. 1). During the critical phase, if vascular complications and hemorrhage occur, the disease may also be called dengue hemorrhagic fever (DHF). If left untreated, patients with DHF can develop multiorgan failure and shock, known as dengue shock syndrome (DSS) [13]. Case fatality rates (CFRs) vary among countries but can be as high as 10–15% in some and < 1% in others, depending mostly on access to and quality of healthcare [14, 15]. Dengue: Update on Clinically Relevant Therapeutic Strategies and Vaccines Palanichamy Kala et al. Fig. 1  The clinical management and possible treatment options for dengue disease. Diagram was made using biorender.com Dengue risk factors Secondary heterologous dengue infection is the most well-established risk factor for severe dengue. This is thought to be attributable to antibody-dependent enhancement of infection (ADE), which occurs when viruses bound to subneutralizing antibodies are opsonized by immune cells like dendritic cells, monocytes/macrophages through Fc receptor, which then results in increased virus production [8]. Moreover, cross-reactive non-neutralizing heterotypic antibodies can also lead to increased antibody dependent cellular cytotoxicity (ADCC) and excessive activation of mast cells, resulting in release of vasoactive mediators that have been shown to promote dengue vascular pathology [16, 17•, 18]. Other risk factors (reviewed elsewhere [19]) include host factors like pre-existing metabolic diseases, age, gender, and HLA type; and may also include viral factors like viral load, NS1 antigenemia. Healthcare quality and access also influence the risk for disease progression.  Updates in dengue supportive care In the absence of targeted dengue therapeutics, good supportive care, with treatment for symptom management and fluid administration, is the cornerstone of clinical management of dengue (Fig. 1). WHO guidelines recommend acetaminophen or paracetamol for antipyretics, with a recommended dose of 10 mg/kg/dose. The maximum dose for adults is 4 g/day and a frequency of not less than 6 h [13]. However, a recent double-blind, randomized, placebo controlled clinical trial (NCT02833584) raises concerns on the safety and efficacy of paracetamol in dengue patients [20•]. The study found th (...truncated)