Curr Treat Options Infect Dis (2023) 15:27–52

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: [email protected]
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: [email protected]

Published online: 18 April 2023

© 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 host-
targeted 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)
28 

Introduction
Dengue fever (DF), caused by the dengue virus in the forest [4, 5] while in the urban cycle of transmis-
(DENV), is the world’s most prevalent and impor- sion, the virus is maintained within human popula-
tant arboviral infection. It is estimated that nearly tion aided by urban dwelling mosquitos such as Aedes
390 million infections occur annually, of which 96 aegypti [6]. As the geographical distributions of these
million manifest clinically [1]. DENV belongs to the vectors are expanding it is likely that DENV will spread
genus Flavivirus, which also comprises several other further [7]. There are 4 serotypes of DENV (DENV1-
clinically important human pathogens, such as Zika, 4), which makes it likely that an individual will be
Japanese encephalitis, West Nile, and Yellow Fever exposed to the virus multiple times in their lifetime
viruses, among others. The DENV genome consists [8]. Latest models of dengue transmission estimate
of a single-stranded positive-sense RNA that encodes that 4 million cases require hospitalization each year
for three structural (capsid, prM/M, and E) and seven [9] and account for an annual estimated cost of US
non-structural proteins that are translated during the $8.9 billion globally [10]. With an increase in urbani-
virus replication cycle [2]. The virus is spread by an zation and climate change supporting the spread of
infected mosquito bite during a blood meal and exists the mosquito vector, some models predict an increas-
in both sylvatic and urban ecosystems [3]. The sylvatic ing risk of DENV transmission, potentially impacting
cycle of DENV involves virus transmission between 6.1 billion people by 2080 [11].
non-human primates (NHP) and mosquitos prevalent

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 hepatomeg-
aly, 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 accumu-
lation 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 mul-
tiorgan 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. 29

Fig. 1  The clinical management and possible treatment options for dengue disease. Diagram was made using biore​nder.​com

Dengue risk factors

Secondary heterologous dengue infection is the most well-established risk fac-
tor for severe dengue. This is thought to be attributable to antibody-dependent
enhancement of infection (ADE), which occurs when viruses bound to sub-
neutralizing 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.
30 

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 recom-
mended 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 con-
cerns on the safety and efficacy of paracetamol in dengue patients [20•].
The study found that compared to placebo, administering 500 mg of par-
acetamol every 4 h (median dose was 1.5 g/day) when body temperature
exceeded 38 °C had significantly higher rate of transaminase elevation
(22% vs 10% in placebo; incidence rate ratio 3·77, 95% CI 1·36 − 10·46,
p = 0·011). Considering that hepatic dysfunction is a common complica-
tion of dengue and elevated liver transaminases are consistently associated
with severe dengue [21–24], this trial raises concerns of hepatotoxicity of
paracetamol, even at therapeutic doses, in a situation when the hepatocytes
are already stressed [25]. Moreover, paracetamol intake did not alter mean
and maximum body temperatures, duration of fever, length of hospitaliza-
tion, analgesic intake, and mean and maximum pain score, compared to
the placebo group, suggesting a lack of defervescent or analgesic benefit,
although the study was under-powered for assessment of this secondary
outcome. Since the current WHO guidelines contraindicate aspirin and
other non-steroidal anti-inflammatory drugs (NSAIDs) due to their anti-
platelet activity and bleeding risk and paracetamol is the only available
therapeutic option, caution should be exercised when prescribing paraceta-
mol and transaminase levels should be monitored.
Judicious fluid administration to ensure adequate tissue perfusion during
the critical phase of illness is the other arm of mainstay dengue management.
Oral rehydration with fluids other than plain water such as milk, fruit juice,
oral rehydration solution (ORS), rice or barley water, and isotonic electro-
lyte solution is recommended in cases of mild dengue fever in patients with
able oral intake [26, 27]. Hospitalization and intravenous (IV) fluid therapy
are recommended in cases of insufficient oral intake, emesis, a continuous
rise in hematocrit (HCT) of 10–20% despite oral rehydration, development
of warning signs, and in case of impending shock/shock [26]. Randomized
clinical trials (RCTs) have evaluated both crystalloids and colloids for pedi-
atric patients with DSS [28–30] and found no difference between the treat-
ment groups with regards to the need for rescue resuscitation with colloids or
shock recurrence [28]. However, in the case of profound shock when patients
have pulse pressure < 10 mm Hg, colloids are preferred since they have been
shown to restore cardiac index and hematocrit more rapidly than crystal-
loids [28–30]. Correspondingly, current WHO guidelines recommend vol-
ume replacement with isotonic crystalloid solutions as 10 ml/kg over 1 h
for patients with compensated shock and 20 ml/kg bolus over 15 min for
profound decompensated, hypovolemic shock, followed by a tapering fluid
Dengue: Update on Clinically Relevant Therapeutic Strategies and Vaccines Palanichamy Kala et al. 31

regimen supplemented with bolus colloid solutions as necessary [26, 27].

However, there have been limited clinical trials with evidence to support
the current WHO fluid resuscitation regimen recommendations for patients
during the critical phase of the illness. This is concerning, particularly in
the evidence of observational studies reporting longer duration of IV fluid
therapy, greater amounts of IV fluid therapy, and IV fluid bolus as independ-
ent risk factors for respiratory distress with fluid accumulation [31], a poten-
tial iatrogenic complication of dengue supportive treatment. Therein, fluid
regimens that taper and restrict fluids as needed during the recovery phase of
dengue are necessary to prevent fluid overload complications (Fig. 1). Cur-
rently, several RCTs have been registered to evaluate WHO-recommended
fluid regimens for dengue patients with warning signs and for patients in the
early stages of DHF: CTRI/2019/09/021026 aims to compare need-based vs
guidelines-based fluid administration in dengue patients with warning signs;
CTRI/2020/01/022694 aims to evaluate respiratory distress in children with
dengue warning signs receiving current WHO-recommended fluid regimen vs
an alternate tapering fluid regimen. Administration of albumin in crystalloid
refractory shock was associated with shock resolution with reduced fluid over-
load symptoms in an observational study [32]. RCTs (CTRI/2018/03/012781
and NCT04076254) have been registered to evaluate the efficacy of albumin
administration in addition to normal (0.9%) saline for effective fluid resus-
citation of severe dengue patients. A multi-center double-blind parallel group
RCT has also been registered (SLCTR/2022/003) in Sri Lanka to evaluate the
effectiveness of Dextran 40 compared to 0.9% saline in preventing dengue
shock in the early leakage phase of DHF. Results from these on-going trials
will be important to identify the most effective fluid therapy with a reduced
risk of iatrogenic complications for dengue case management. Additional
considerations for fluid replacement have been reviewed elsewhere [33].
In the context of hypotensive shock without a rise in hematocrit, signifi-
cant internal bleeding should be suspected. Current guidelines are to trans-
fuse aliquots of 10 ml/kg of whole blood or 5 ml/kg of packed red blood
cells and monitor the clinical response and posttransfusion hematocrit [26,
27]. Thrombocytopenia (platelet count below 100 × ­109/L) is a hallmark of
dengue infection and has been shown to have various etiologies including
enhanced platelet clearance [34•, 35]. Low platelet levels are associated with
severity of dengue disease [34•, 35–37] since thrombocytopenia can precipi-
tate hemorrhage. As per current guidelines, strict bed rest, and avoidance of
NSAIDs or any source of trauma have been the only courses of action advised
for patients with severe thrombocytopenia (platelet count below 20 × ­109/L)
since a RCT (NCT01030211) found that prophylactic platelet transfusion was
not superior to supportive care in preventing bleeding and, in fact, increased
adverse reactions [26, 38]. As such, effective drugs to treat thrombocytope-
nia are needed. A recent phase II open-labeled RCT evaluating the efficacy
of eltrombopag to correct thrombocytopenia in moderate to severe dengue
patients with platelet counts below 100 × ­109/L (SLCTR/2019/037) shows
potential [39•]. Administration of 25 mg of eltrombopag, a thrombopoietin
receptor agonist that stimulates megakaryopoiesis [40], in a short regimen for
three days, was shown to significantly augment platelet recovery and increase
platelet count to above the lower normal limit (LNL) (150 × ­109/L) in 91% of
32 

patients on day-7 post enrollment, compared to 55% in the control group.

Moreover, eltrombopag abated bleeding manifestations in 93% of grade II
DHF patients by day-7, while intermittent bleeding with low platelet counts
was still observed in 40% of patients in the control group. Eltrombopag also
had a favorable safety profile with no thrombosis and no increase in adverse
events (vomiting, diarrhea) compared to the control group. These results
suggest that eltrombopag may be a therapeutic option for thrombocytopenia
and for abating bleeding manifestations in dengue patients.
It is to be noted that previous interventional [38, 41] and retrospective
studies [42] have shown that increasing platelet counts via transfusion neither
prevented the development of severe bleeding nor shortened time to cessation
of bleeding. Analysis of patient samples and supporting in vitro studies sug-
gest that this could be due to DENV infection and the subsequent activation
and consumption of platelets, resulting in increased thrombus formation
[43]. Therefore, increasing platelet count may not necessarily contribute to
bleeding resolution and could result in increased intravascular coagulation
since platelet activating factors may still be present in the circulation [44].
More trials are needed to understand the clinical efficacy of adding platelets,
including through mechanisms to increase platelet production. Specifically
the rate of prevention of severe bleeding, rate of bleeding resolution, and
normalization of other coagulation abnormalities reported during DHF [44]
should be evaluated.
Desialylation or removal of sialic acid on platelet membrane by endog-
enous neuraminidase, induced by binding of von Willebrand factor (VWN)
to platelets, has been suggested as possible mechanism for increased platelet
clearance in dengue patients [45]. Based on this, oseltamivir, a neuraminidase
inhibitor that is commonly administered for influenza [45] was tested as a
potential therapeutic for thrombocytopenia in a phase 2, TOTO trial (Treat-
ment Of Thrombocytopenia with Oseltamivir in acute dengue virus infection:
a randomized, placebo controlled, multicenter trial) conducted in Indonesia
(ISRCTN35227717) [46]. Unfortunately, the drug was found to be ineffective
for both platelet recovery and preventing plasma leakage in patients with
acute dengue with moderate to severe thrombocytopenia. This indicates that
while many drugs may show potential as dengue therapeutics in preclinical
development, proof of concept testing with clinical trials with predefined
primary and secondary clinical outcomes is important.

Development of therapeutics targeting dengue virus

Considering that a higher viral burden could promote severe dengue disease
[47, 48], identification of DENV-specific antivirals has been an important
focus of research for dengue therapeutics. So far, clinical trials with repur-
posed drugs with antiviral activity in pre-clinical studies like balapiravir [49],
chloroquine [50], lovastatin [51], and celgosivir [52] did not show any effi-
cacy in reducing viremia nor beneficial clinical outcomes. In this section, we
describe both direct-acting and host factors-targeting antivirals that show the
Table 1.  Summary of dengue therapeutics in advanced stages of clinical testing

Drug name Target Pre-clinical data Clinical data

Treatment options with possible benefits

JNJ-64281802 NS4B inhibitor that inhibits viral replication Antiviral activity in vitro was shown for its Clinical trials for dengue prophylaxis in
analog, JNJ-A07. Decrease in viremia, viral healthy individuals (NCT05201794) as well
burden, and inflammatory cytokines, and as for dengue therapy in patients with
improved survival in immunocompromised confirmed dengue fever (NCT04906980)
mouse model of DENV infection [53•] are in progress
Ivermectin Antiviral agent that inhibits host nuclear Reduced viral replication in vitro [56, 57] Randomized double-blind placebo-con-
import receptors trolled trial (n = 203) showed faster NS1
antigenemia clearance but no improve-
ment in virological or clinical efficacy
(NCT02045069) [58•]
AT-752 Guanosine nucleotide analog inhibiting NS5 Reduced viremia on certain days and Phase 1 (NCT05366439) and phase 2
RdRp function, inhibits viral replication improved survival in immunocompromised (NCT05466240) clinical trials are in
mice models infected with DENV [63] progress
Doxycycline Tetracycline class antibiotic, inhibits viral Antiviral activity against all four DENV One randomized clinical trial (n = 231)
entry and replication by inhibiting NS2B- serotypes in vitro [64] showed reduction in inflammatory
NS3 cytokines and another case control study
(n = 120) showed faster platelet recovery,
leukocyte count, and reduced length of
hospitalization. Clinical trials to test effi-
cacy of doxycycline as a dengue therapeu-
tic in pediatric (CTRI/2018/01/011548)
and adult (CTRI/2021/09/036661) popu-
lations are on-going
Dengue: Update on Clinically Relevant Therapeutic Strategies and Vaccines

Eltrombopag Thrombopoietin receptor agonist Nil Randomized open-label placebo-controlled

trial (n = 101) showed improved platelet
recovery, increased platelet count, and
reduced bleeding manifestations in grade
II DHF patients (SLCTR/2019/037) [39•]
UV-4B Endogenous alpha glucosidase inhibitor Antiviral activity in vitro [70] and in vivo [71] Phase 1a clinical trial (NCT02061358) with
healthy subjects indicated that a single
dose up to 1000 mg of UV-4B was safe
and well tolerated [72]
Palanichamy Kala et al.

Zanamivir Neuraminidase inhibitor to block desialyla- Reduction in DENV2 NS1-induced endothelial Clinical trial to test efficacy against vascular
tion on platelet membrane hyperpermeability and vascular leakage leakage (NCT04597437) is currently on-going
in vitro [73]
33
Table 1.  (continued)
34


Drug name Target Pre-clinical data Clinical data

VIS513 Pan-serotype anti-DENV monoclonal anti- Diminished circulating infectious DENV in Clinical trial in progress
body NHPs [88], and reduced viral load with (CTRI/2021/07/035290)
improved survival in immunocompromised
mice models of DENV infection [87]
Ketotifen Prevent mast cell degranulation and release Reduced vascular leakage in mouse models Clinical trial in progress (NCT02673840)
of vasoactive products of DENV infection [16, 18]
Montelukast Cysteinyl leukotriene receptor antagonist Reduced vascular leakage in mouse models One randomized open-label clinical trial
of DENV infection [18] (n = 200) reported reduced incidence
and relative risk of DSS (narrow pulse
pressure < 20 mmHg and hypotension for
age) [95]. A randomized, double-blind,
placebo controlled, superiority trial
(NCT04673422) to test efficacy of mon-
telukast is currently on-going
Rupatadine Dual PAF and histamine-1-receptor antago- Reduced vascular leakage in mouse model Randomized placebo-controlled trial
nist of DENV infection [94] (n = 183) did not show reduction in leak-
age, but improved platelet counts and
liver enzyme values (SLCTR/2014/023)
[94]
Metformin Oral anti-hyperglycemic agent, AMPK activa- Antiviral effect in DENV infected cells A retrospective study (n = 223) showed
tor in vitro [101] decreased risk of severe dengue with
metformin use in dengue patients with
diabetes [103•]. Clinical trial in progress
(NCT04377451) [104]
Carica papaya Anti-inflammatory agent, augments Reduced production of proinflammatory Three randomized controlled trials showed
leaf extract megakaryocyte development and platelet cytokines [118] and increased platelet an improvement in platelet counts
formation count in vivo [119] [106–108]
Vitamin E Unclear mechanism. Can act as an antioxi- Nil Randomized placebo-controlled trials
dant showed faster platelet recovery (n = 66)
[114] and reduced liver enzyme derange-
ment (n = 127) (SLCTR/2015/012) [113]
Vitamin D Unclear mechanism. Can increase calcium Reduced viral replication and inflammatory Randomized clinical trial (n = 124) showed
availability for immune cell activation cytokines production in vitro [120] reduced relative risk for DHF (P, signifi-
cance for trend was 0.0588) [115]
Table 1.  (continued)
Drug name Target Pre-clinical data Clinical data
Vitamin C Unclear mechanism. Can act as an antioxi- Nil Retrospective study (n = 200) found
dant improved platelet recovery and reduced
hospitalization duration in treat-
ment group [117]. Clinical trials for
Vitamin C alone (SLCTR/2017/028)
and in combination with Vitamin B1
(CTRI/2019/09/021244) are in progress
Zinc Unclear mechanism Nil Randomized double-blind placebo-con-
trolled trial (n = 50) (TCTR20151110001)
showed reduced hospitalization duration,
but no improvement in other clinical or
laboratorical outcomes [116]
Treatment options without support for benefits

Paracetamol Anti-pyretic Nil Randomized double-blind placebo-con-

trolled trial (n = 123) showed worse liver
enzyme derangements in the treatment
group, with no improvement in other
clinical or laboratorical parameters.
(NCT02833584) [20•]
Oseltamivir Neuraminidase inhibitor to block desialyla- One ex vivo study showed that oseltamivir Randomized double-blind placebo-controlled
tion on platelet membrane reduced desialylation on platelets from trial (n = 70) did not show improvement in
healthy donors [45] platelet recovery or plasma leakage param-
eters (ISRCTN35227717) [46]
Dengue: Update on Clinically Relevant Therapeutic Strategies and Vaccines
Palanichamy Kala et al.
35
36 

most potential as dengue therapeutics and are in advanced stages of clinical

testing. These have also been summarized in Table 1 and Fig. 1.
A direct-acting dengue therapeutic with promising preclinical data is the
JNJ-A07, NS4B inhibitor developed by Janssen Pharmaceuticals [53•]. The
drug was identified from a set of 2000 related molecules that were generated
by modifying the structure of a ketoindole compound that showed inhibi-
tion against DENV2 infection [54]. The drug inhibited DENV replication
complex formation by inhibiting the interaction between the NS4B protein,
a multi-transmembrane protein at the endoplasmic reticulum, and NS3, a
serine protease-helicase [55]. JNJ-A07 showed antiviral activity against all four
dengue serotypes as well as 21 clinical isolates in vitro. Immunocompromised
murine models infected with lethal as well as sub-lethal DENV2 doses and
in models of antibody-dependent enhancement showed rapid decrease in
viremia and viral burden in organs, regardless of whether JNJ-A07 treatment
was started at the onset of infection or a delayed treatment. Reduction in
pro-inflammatory cytokines like IL-18, IFN-γ, TNF, and IL-6 and increase
in survival percentage were also observed in the drug-treated infected mice.
Hemoconcentration or fluid accumulation in tissues and immune response
parameters such as neutralizing antibody titers following infection in the
drug-treated group were not assessed. This is important since the rapid sup-
pression of viremia by the drug could lead to weakened antibody produc-
tion that could precipitate severe dengue in a subsequent dengue infection.
Currently, JNJ-64281802, an analog of JNJ-A07, has been registered for two
phase 2, randomized, double-blind, placebo-controlled clinical trials to study
its efficacy for dengue prophylaxis in healthy individuals (NCT05201794)
as well as for dengue therapeutics in patients with confirmed dengue fever
(NCT04906980).
Ivermectin, a broad-spectrum antiparasitic drug against helminth infec-
tion, has been previously shown to inhibit all four dengue serotypes in vitro
by inhibiting the host nuclear import proteins that were important for nuclear
localization of the dengue NS5 protein with RNA-dependent RNA polymerase
(RdRp) function [56, 57]. A phase 2/3 randomized, double-blind, placebo-
controlled trial (NCT02045069) was conducted to study the efficacy of a
once-daily dose of ivermectin 400 μg/kg for 2–3 days in adult dengue patients
[58•]. Interestingly, the study reported faster NS1 antigenemia clearance upon
ivermectin treatment, with no difference in viremia, viral clearance, or any
beneficial clinical outcomes including fever, DHF incidence, hospitalization,
pleural effusion, hemoconcentration, or fluid requirements [58•]. High NS1
levels have been previously shown to be a risk factor for the development
of dengue hemorrhagic fever [59] since it can induce pathologic comple-
ment activation [60] as well as independently induce vascular leakage [61]
by disrupting the endothelial glycocalyx [62]. Hence, while this current trial
did not report any clinical efficacy at this dosing regimen, further studies
to understand the pharmacodynamics of ivermectin and its mechanism of
action with regards to NS1 are warranted.
AT-752, an orally available guanosine nucleotide analog recently devel-
oped by Atea Pharmaceuticals, also functions by targeting the RdRp func-
tion of the NS5 protein [63]. The drug functions by metabolizing into an
active triphosphate metabolite, AT-9010, intracellularly, which acts as a GTP
Dengue: Update on Clinically Relevant Therapeutic Strategies and Vaccines Palanichamy Kala et al. 37

analog and is incorporated into RNA by RdRp, therein inhibiting viral replica-
tion. Correspondingly, AT-281, the prodrug of AT-752 inhibited DENV2 and
DENV3 in vitro and AT-752 showed reduced viremia (albeit only at day 6 and
8 post infection) and improved survival in DENV2-infected immunocompro-
mised mice. Currently, the drugs are in phase 1 (NCT05366439) and phase
2 (NCT05466240) double-blind, randomized, placebo-controlled studies to
assess the safety and antiviral activity in the dengue human challenge model
and in dengue patients, respectively.
Doxycycline, a broad-spectrum tetracycline-class antibiotic and antima-
larial, has shown some efficacy as an antiviral against DENV1-4 in vitro by
inhibiting NS2B-NS3 protease activity, resulting in reduced viral entry and
replication [64]. A randomized clinical trial (with no placebo control arm)
in Brazil, testing doxycycline for its efficacy as an anti-inflammatory drug
in dengue infection showed reduction in pro-inflammatory cytokines IL-6
and TNF in the treatment group compared to patients receiving standard
symptomatic and supportive care [65]. A case–control study in India showed
that doxycycline-treated dengue patients showed faster recovery of platelet
and leukocyte counts and reduced hospital stay [66]. However, these studies
so far have not been robust double-blind randomized placebo-controlled
clinical trials with defined end point measurements. One such clinical trial
(CTRI/2018/01/011548) is currently registered in India to study the efficacy of
doxycycline as a dengue antiviral in a pediatric population and could clarify
whether doxycycline has use as dengue therapeutic.
DENV infection and replication also require host factors that could be
potential drug targets. N-linked glycosylation of viral proteins (pre-membrane
(prM) and envelope (E) proteins) mediated by host α- glucosidase in the
endoplasmic reticulum is important for viral assembly and subsequent release
of mature, infectious DENV particles [67]. Celgosivir, an alpha-glucosidase
inhibitor, had impaired folding and trapping of NS1 and significant antivi-
ral activity when tested in vivo in mouse models of dengue infection [68].
Although the previous trial did not meet its primary outcome of reducing
viremia or fever, subsequent evaluation of the pharmacokinetic endpoints
of the trial inferred that a revised dosing regimen that would increase the
steady-state trough concentrations of the drug in the patient serum might be
more efficacious [52, 69]. UV-4B (N-(9′-methoxynonyl)-1-deoxynojirimycin),
another alpha-glucosidase inhibitor, also showed antiviral activity against
all four serotypes of dengue in vitro [70]. In vivo studies using immunosup-
pressed mice showed decreased viremia and viral burden and improved sur-
vival in a lethal ADE model of dengue disease [71]. A Phase 1a clinical trial
(NCT02061358) with healthy subjects, evaluating the safety, tolerability, and
pharmacokinetics of the drug, indicated that a single dose of up to 1000 mg
UV-4B was safe and well tolerated [72]. The efficacy of this drug in dengue
patients has yet to be determined.
Similar to oseltamivir mentioned earlier, Zanamivir, another neurami-
nidase inhibitor, has shown inhibition of DENV2 NS1-induced endothelial
hyperpermeability in vitro by inhibiting endogenous sialidase [73]. Consider-
ing that the TOTO trial failed to show any clinical benefit, the efficacy of zan-
amivir in vivo remains speculative. A phase 1 pilot randomized, double-blind,
placebo-controlled clinical trial for the evaluation of the safety and efficacy
38 

of five days of intravenous zanamivir treatment to treat vascular permeability

syndrome (NCT04597437) is currently on-going.
There are several other direct-acting antivirals and host-directed anti-
virals (reviewed by others [74–77])—both novel and repurposed drugs,
which are still in varying stages of pre-clinical development.

Monoclonal therapeutics
An obstacle for the development of monoclonal antibody (mAb) thera-
peutics against DENV has been the identification of antibodies capable
of cross-neutralizing DENV1-4, which make up a minority of antibod-
ies induced by natural infection [78]. Many of the dominant antibod-
ies following natural infection target the immunodominant epitopes of
the E protein fusion loop and the prM proteins, which can be involved
in ADE [79]. Most mAb development pipelines have focused on the
goals of either developing broadly cross-neutralizing antibodies or pro-
ducing antibody cocktails [80]. Cross-reactive neutralizing antibodies
can be formed against domains I, II, and III of the E protein, yet those
against the quaternary structure of E protein dimers are more likely to be
potently cross-neutralizing [78, 79]. However, even highly potent neu-
tralizing antibodies can induce ADE at intermediate concentrations [8,
81], emphasizing the importance of safety testing of mAbs to identify
the optimal therapeutic window and concentration. The risk of ADE can
also be mitigated by engineering LALA substitutions in the heavy chain
[82, 83]. Monovalent mAb therapeutics also have the risk of becoming
obsolete if viral immune evasion results in loss of neutralizing epitopes,
as has been shown in the real world during the SARS-CoV-2 pandemic
[84], and in animal models of DENV mAb testing [82]. Development of
mAb as therapeutics or prophylactics for dengue has also been compre-
hensively reviewed elsewhere [85, 86] and three candidates for human
use are currently in clinical trials.
VIS513, a humanized pan-serotype anti-DENV mAb developed by Vis-
terra (Cambridge, Massachusetts) has been engineered to bind domain III
of the E protein of all 4 DENV serotypes [87]. Administration of VIS513
either 24 h or 5 days post dengue infection in non-human primates was
found to diminish infectious DENV in circulation without altering the
endogenous antibody response [88]. In the murine model of antibody-
enhanced DENV infection, VIS513 had increased protection of immu-
nocompromised mice from lethal primary and secondary infection [87].
VIS513 is currently in phase 2, a single-blind, randomized, parallel-group,
dose-ranging, single-dose study in India to study its safety and efficacy
in adults with dengue fever (CTRI/2021/07/035290). AV-1, developed
by AbViro LLC (NCT04273217), and Dengushield, developed by Serum
Institute of India Pvt. Ltd. (NCT03883620) are other human monoclonal
antibodies currently in phase 1, placebo-controlled, clinical trials with
 Dengue: Update on Clinically Relevant Therapeutic Strategies and Vaccines Palanichamy Kala et al. 39

goals to determine the safety and pharmacokinetics in healthy adults. How-

ever, details on their preclinical development, target epitopes, and efficacy
against DENV have not yet been published.

Development of therapeutics targeting host

Many severe dengue symptoms are thought to result from a pathological
host immune response [8]. Mast cells, in particular, have been identified
as an important drug target for the treatment of severe dengue patholo-
gies including vascular permeability, plasma leakage, and thrombocytope-
nia [89, 90]. Mast cells are granulated innate immune cells located along
host-environment interfaces like epithelial and endothelial barriers such
that they can quickly respond to invading pathogens [91]. During DENV
infection in the skin, mast cells are activated in response to the virus and
degranulate to release an extensive array of preformed mediators like lyso-
somal enzymes (β-hexosaminidase), biogenic amines, histamine and sero-
tonin, mast cell-specific proteases–tryptase, chymase, and carboxypeptidase
A3 and cytokines, such as TNF. In addition, mast cell activation leads to the
de novo synthesis of lipid mediators—eicosanoids: leukotrienes and pros-
taglandins, and platelet activating factor (PAF), as well as other cytokines
and chemokines, that subsequently aid recruitment of cytotoxic cells that
help with viral clearance [92, 93]. In contrast to the localized protective
response, pre-clinical studies with immunocompetent and immunocom-
promised mice showed that widespread mast cell activation during sys-
temic DENV infection results in excessive release of vasoactive mast cell
mediators including leukotrienes, PAF [94], and proteases tryptase and
chymase [16, 18] that cause vascular leakage by disrupting the endothelium
[17•]. Importantly, injection of tryptase at similar concentrations detected
in the plasma of severe dengue patients was sufficient to induce a tempera-
ture drop indicative of shock in mice [17•]. Moreover, elevated tryptase
levels correlated with increasing severity of DHF and DSS in humans [17•].
Tryptase inhibiting drug, nafamostat mesylate significantly reduced vascu-
lar leakage in DENV infected mice and was effective even after the delayed
treatment [17•]. While tryptase function is specific to the vascular endothe-
lium, serotonin released peripherally by mast cells during DENV infection
was shown to induce thrombocytopenia [34•]. Activation of platelets by
serotonin, sensed using 5HT2 receptors, triggered aggregation and destruc-
tion of platelets during DENV infection [34 •]. Accordingly, treatment of
mice using 5HT2 receptor antagonists, ketanserin and sarpogrelate reversed
thrombocytopenia in DENV-infected mice [34•]. These studies highlighted
that mast cell degranulation and mast cell products can be targeted in vivo
with already clinically available drugs like mast cell stabilizers ketotifen
and cromolyn [18], and inhibitors of mast cell products like nafamostat
mesylate [17•] (for tryptase), montelukast (for leukotrienes) [18], ketan-
serin (for peripheral serotonin) [34•], and rupatadine (for PAF and hista-
mine-1-receptor block) [94]. Ketotifen is currently in a phase 4 randomized
40 

clinical trial in Singapore that has concluded patient enrollment, where

the primary endpoint of clinical fluid accumulation has been measured by
MRI (NCT02673840). A preliminary randomized placebo-controlled clini-
cal trial (SLCTR/2014/023) testing efficacy of rupatadine for acute dengue
patients revealed improved platelet counts, reduction in liver transaminases
suggesting reduced tissue inflammation, and reduction in volume of plural
effusions on certain days of the study protocol in their post hoc analyses
despite failing to meet its primary endpoint of reduction in fluid leakage
(pleural effusion or ascites) [94]. Further studies are needed to evaluate
the efficacy of rupatadine against dengue vasculopathy. A preliminary open
labeled, randomized clinical trial in Pakistan provided some early evidence
towards the efficacy of montelukast in reducing risk for DSS, as defined
by narrow pulse pressure < 20 mmHg and hypotension for age [95]. Mon-
telukast 10 mg was given once daily for 5 days. There was no change in
hemoconcentration, or platelet counts although the overall DSS frequency
reported in the cohort was very high (40%). The authors reported reduced
incidence and relative risk of DSS in patients treated with montelukast,
however the study lacks power analysis and a predefined significant statis-
tical difference between the groups. A phase 2/3 multicentre, randomized,
double-blind, placebo controlled, superiority trial (NCT04673422) is cur-
rently on-going in Thailand to study the effect of montelukast in preventing
dengue with warning signs in dengue patients.
As metabolic disorders like obesity and diabetes are increasingly rec-
ognized risk factors for severe dengue [96 •, 97•, 98, 99], metabolic drugs
are being investigated as potential dengue therapeutics. For example,
Metformin, is a well-established oral anti-hyperglycemic agent adminis-
tered to diabetic patients. Its primary mechanism of action is to activate
adenosine monophosphate (AMP)-activated protein kinase (AMPK), an
important cellular energy sensor that is activated in conditions of low
cellular energy levels to maintain homeostasis by upregulating lipid,
protein, and glucose metabolism [100]. Interestingly, in vitro studies
show that DENV impairs AMPK phosphorylation, which leads to down-
stream upregulation of HMG-CoA reductase activity, the rate-limiting
step in cholesterol biosynthesis [101]. DENV proteins NS3 and NS4A
colocalize in this resultant lipid-enriched environment which is shown
to be conducive to enhanced DENV replication complex formation [101,
102]. Consistent with this mechanism of DENV replication, metformin
showed a significant dose-dependent antiviral effect in DENV-infected
cells in vitro [101]. Correspondingly, a retrospective study in confirmed
dengue patients with diabetes showed that metformin use was associated
with decreased risk of developing severe dengue, and further, there was
a dose-dependent inverse relationship between metformin intake and
dengue severity [103•]. However, it is unclear from this study whether the
effects of metformin on diabetic control or on DENV replication may be
linked to the use of this drug. Currently, an open-label, two-phase dose
escalation trial (NCT04377451) of metformin in dengue patients with
obesity (MeDO) is on-going in Vietnam [104], which should clarify the
therapeutic utility of metformin in dengue patients during acute disease.
 Dengue: Update on Clinically Relevant Therapeutic Strategies and Vaccines Palanichamy Kala et al. 41

Other potential therapy–bioactive compounds

Many plant-based bioactive compounds have also been recognized to have
anti-dengue activity in vitro and in vivo and have been summarized in a
recent review [105]. Among these, Carica papaya leaf extract (CPLE) has
been recognized for its platelet augmenting effect in both pediatric and
adult dengue patients [107, 108]. Results from these randomized, placebo-
controlled clinical trials showed that administration of CPLE thrice daily
enhanced platelet recovery rate, with a statistically significant increase in
platelet levels in the intervention group from day 3 of treatment. While
the mechanism of action is not yet completely understood, a recent study
indicates that CPLE increases the expression of thrombopoietin receptor,
CD110, also known as the myeloproliferative leukemia protein (cMpl),
on platelets and megakaryocytes which is important for megakaryocyte
proliferation and platelet formation [109]. Micronutrients are signifi-
cant immunomodulators [110] and thus are often prescribed as supple-
ments in addition to standard supportive care for dengue patients [111,
112]. Clinical trials showed a reduction in liver derangements [113] and
increased platelet recovery [114] upon vitamin E supplementation in
addition to supportive therapy in dengue patients when compared to the
control group. Other smaller RCTs with vitamin D [115] and zinc sup-
plementation (TCTR20151110001) [116] showed reduced relative risk of
DHF and decreased duration of hospital stay respectively. A retrospective
observational study investigating the effect of vitamin C supplementation
in dengue fever reported increased platelet recovery and reduced hospi-
talization duration in patients receiving vitamin C [117]. Currently, two
phase-II clinical trials have been registered to study the efficacy of vita-
min C (SLCTR/2017/028, Sri Lanka) and vitamin C and B1 combination
(CTRI/2019/09/021244, India) in reducing morbidity in dengue patients.

Vaccine development
Given the lack of specific dengue therapeutics and significant economic
and public health burden, WHO considers dengue vaccine development
an urgent priority [121]. Two main challenges prevail in dengue vaccine
development. Firstly, the vaccine should confer effective and balanced pro-
tection against all four dengue serotypes. Tetravalent vaccine formulations
developed with this aim are hindered by antigenic competition, wherein
the immune response is skewed towards more immunodominant serotype-
specific dengue antigens. Secondly, ADE poses a significant challenge in
dengue vaccine development since vaccine-mediated sub-optimal protec-
tion to any of the dengue serotypes can confer a risk of severe dengue in
a subsequent infection. Currently, there are at least seven dengue vaccines
42 

in various stages of development and clinical trials [122, 123•, 124–129].

We will discuss selected vaccine candidates that have progressed furthest
in clinical development here.
CYD-TDV (chimeric yellow fever virus–DENV–tetravalent dengue vaccine)
aka Dengvaxia, developed by Sanofi Pasteur, was the first dengue vaccine to
be licensed based on three clinical trials [130–132] and has been approved
in certain countries, but is limited for use in individuals with prior dengue
infection. It is a tetravalent live attenuated vaccine that uses the yellow fever
YF17D vaccine strain as the backbone, substituting the prM and E proteins
with the corresponding genes of the four wild-type dengue serotypes. It is
administered subcutaneously as a 3-dose regimen scheduled 6 months apart
in the population aged 9–45 years. In the pooled analysis of 25-month effi-
cacy data from phase 3 trials in population aged 2–16 years (CYD14, CYD15
and CYD57) overall vaccine efficacy for symptomatic virologically confirmed
dengue (VCD) was 60.3% (95% CI: 55.7–64.5). It has been proposed that
the limited efficacy of the vaccine could result from the mismatched non-
structural proteins from the YF17D backbone, potentially limiting the effi-
cacy of the vaccine in inducing a protective T cell response against DENV
[8]. Interestingly, for children, the vaccine efficacy was higher for those in
older age groups with 65.6% (95% CI: 60.7–69.9) in those aged 9–16 years,
than the younger age group with 44.6% (95% CI: 31.6–55.0) for those aged
2–8 years old [122]. For both age groups, specific vaccine efficacy for DENV1
and DENV2 was 40–50%, whereas it was 70–85% for DENV3 and DENV4.
The vaccine seemed to be most efficacious against hospitalization and severe
dengue with pooled vaccine efficacy across all age groups as 72.7% (95% CI:
62.3–80.3) and 79.1% (95% CI: 60.0–89.0) respectively, not stratified by
serostatus [122]. Increased relative risk of hospitalization in children aged
2–9 years of 1.58% (95% CI: 0.83–3.02) versus 0.5% (95% CI: 0.29–0.86) in
children aged 9–16 years was observed. Since 80% of the 9–16 years popula-
tion were baseline seropositive, it was hypothesized that baseline serostatus
of the patient could possibly influence dengue risk wherein the vaccine could
potentially precipitate severe dengue in seronegative patients via ADE [133].
Indeed, vaccine efficacy was higher for seropositive individuals (70–80%)
than for seronegative individuals (14.4–52.5%) for both age groups. A fol-
low-up case-cohort study re-analyzing data from the three trials along with
retrospective inference of serostatus of the individuals based on blood taken
at 13 months post-vaccination, found that there was an increased risk of
hospitalization and severe dengue in seronegative individuals [134]. The haz-
ard ratio (HR) (vaccine vs. control) for hospitalization was 1.75 (95% CI:
1.14–2.70) and that for severe dengue was 2.87 (95% CI:1.09–7.61) in seron-
egative patients compared to corresponding HRs of 0.32 (95% CI: 0.23–0.45)
and 0.31 (95% CI: 0.17–0.58) in seropositive patients. In accordance with
this, the latest WHO Strategic Advisory Group of Experts on immunization
recommends pre-vaccination screening as the preferred strategy for countries
considering CYD-TDV vaccination as part of their dengue control program.
With this strategy, only seropositive individuals with evidence of a labora-
tory or antibody test confirmed past dengue infection would be vaccinated. If
pre-vaccination screening is not feasible, vaccination can still be considered if
Dengue: Update on Clinically Relevant Therapeutic Strategies and Vaccines Palanichamy Kala et al. 43

the recent seroprevalence rate in the area has been documented to be at least
80% by 9 years of age [135].
QDENGA® or TAK-003 by Takeda Pharmaceuticals is another live-attenuated
tetravalent dengue vaccine that has been recently licensed for use in Indonesia
for individuals aged 6 to 45 [136], and has received marketing authorization
in the European Union for individuals aged 4 and above [137], regardless of
their prior dengue exposure status. It is currently undergoing regulatory review
in other dengue-endemic countries in Asia and Latin America [138, 139]. Using
attenuated DENV2 PDK-53 virus as backbone, the other chimeric dengue virus
were engineered by substituting the prM and E genes of DENV2 for that of
wild-type DENV1 16007, DENV3 16562, or DENV4 1036 virus [140]. It is
administered subcutaneously as a 0.5 mL dose in a two dose regimen scheduled
3 months apart [136, 137]. The approval is based on the Tetravalent Immuni-
zation against Dengue Efficacy Study (TIDES) trial which included more than
28,000 participants. The primary endpoint of the study was the overall vac-
cine efficacy against VCD in the first 11 months and was found to be 80·2%
(95% CI: 73·3–85·3) [141]. However, subsequent follow-up studies at 18-,
24- and 36-months vaccination showed waning of vaccine efficacy over time
with cumulative vaccine efficacy against VCD at 62% (95% CI: 56.6–66.7)
[123•, 124–143]. Nonetheless, vaccine efficacy against hospitalized VCD was
more robust and maintained from 90.4% (95% CI: 82.6–94.7) at 18 months
to 83.6% (95% CI: 76.8–88.4) at 3 years after the second dose. Importantly, the
year 3 cumulative data indicated no age effect and showed comparable overall
vaccine efficacy against VCD (65% vs 54.3%) and hospitalized VCD (86% vs
77.1%) for seropositive and seronegative individuals. When cumulative vaccine
efficacy was analyzed for specific serotypes, similar vaccine efficacy regardless
of baseline serostatus was observed for DENV-1 (seropositive: 56.2% (95% CI:
43.7–66.0) vs seronegative: 43.5% (95% CI: 21.5–59.3)) and DENV2 (seroposi-
tive: 83.4% (95% CI: 76.4–88.3) vs seronegative: 91.9% (95% CI: 83.6–96.0)).
However, while vaccine efficacy was 52.3% (95% CI: 36.6–64.2) for DENV-3
and 60.7% (95% CI: 16.0–81.6) for DENV-4 in seropositive individuals, no
efficacy was observed for DENV-3 (− 23.4% (95% CI: − 125.3–32.4)) and effi-
cacy against DENV-4 was inconclusive in seronegative patients [123•]. Notably
seronegative patients showed higher hospitalization rate (0.2%) compared to
placebo (< 0.1%) for DENV-3 infection [123•], raising concerns that serostatus
might also affect safety outcomes with this vaccine, similarly to Dengvaxia [144].
While this relative risk was inconclusive and was attributed by the authors to the
small number of DENV-3 cases and differences in clinical practice geographi-
cally, further analyses are warranted to ensure no increased hazard risk due to
ADE in seronegative patients. Moreover, the gradual waning efficacy needs to be
addressed. A new clinical trial (NCT03999996) to assess the impact of a booster
dose 15- and 24-months post 1 ­ st dose of vaccine is currently on-going. In addi-
tion, the presence of non-structural (NS) proteins from the DENV-2 backbone
in Qdenga was shown to elicit NS-proteins specific T-cell mediated immunity
in samples from phase 2 trial [145], however, it is notable that the protection
offered by this vaccine is highest against DENV2, the strain from which the virus
backbone originates. This might point to the importance of ensuring that future
DENV vaccine development prioritizes generating tetravalent immunity with
respect to both antibodies and T cell epitopes.
44 

TV003/TV005, developed by National Institute of Allergy and Infectious

Diseases (NIAID), is a live attenuated virus vaccine in clinical testing. TV003/
TV005 was developed by introducing 30 nucleotide deletions in the 3’ untrans-
lated region and additional mutations in non-structural proteins to engineer live
attenuated dengue virus—rDEN1Δ30, rDEN3Δ30/31 and rDEN4Δ30. Attenu-
ated DENV-2 virus was engineered as a chimeric virus by substituting the prM
and E proteins in rDEN4Δ30 with that of DENV-2 [146]. TV003 ­(103 PFU) and
TV005 ­(104 PFU) differ in the dosage of rDEN2/4Δ30 component. Two rand-
omized placebo controlled phase I trials evaluating safety and immunogenic-
ity of TV003 and TV005 found a low grade rash as the most frequent adverse
reaction [147, 148]. Importantly, pooled analysis from both the trials showed
between 64%-100% seroconversion following a single dose of TV003 [149].
Compared to placebo, TV003 induced serotype specific neutralizing antibodies
and showed protection against viremia, rash, and neutropenia when challenged
with an attenuated DENV2 strain, rDEN2Δ30, 6-months post vaccination [150].
TV003 has since been licensed by the Butantan Institute in Brazil and manufac-
tured as a lyophilized TDV named Butantan-DV. A double blind, randomized,
placebo-controlled phase II trial showed seroconversion for all four dengue sero-
types 91-days post single dose of Butantan-DV in both seronegative (76%-92%)
and seropositive (77–82%) individuals with rash as the main adverse reaction
[124]. Seroconversion was defined by PRNT50 cutoff titers (≥ 1/10) for seronega-
tive individuals and as a four-fold or higher increase in pre-existing neutralizing
antibody titer after immunization for the seropositive individuals. Butantan-DV
elicited neutralizing antibodies against all four DENV serotypes with 75% of
the participants developing tetravalent neutralizing humoral response after a
single vaccine dose. Notably, the neutralizing antibody geometric mean titer was
significantly higher in DENV-exposed individuals than DENV-naive participants
for DENV-1, DENV-2, and DENV-3, but not for DENV-4 (p = 0·077). Presence
of non-structural proteins of three different serotypes in Butantan-DV also ini-
tiated cellular immune response as evidenced by antigen specific CD8 + T cell
responses when stimulated ex vivo with DENV-derived peptide pool in 94% of
the vaccinated individuals as compared to 13% in placebo 91 days post first dose
of vaccination [124]. This vaccine is currently in phase III clinical trial in Brazil
with 16,944 participants divided into three age groups (18–59 years, 7–17 years,
and 2–6 years).

Conclusion
The current standard of care for dengue remains supportive care. Timely fluid
management has shown to be effective in lowering deaths due to severe dengue.
However, due to the late onset of warning signs, it can be difficult to manage
severe dengue solely guided by symptomatic interventions and is often too late
too little for the interventions to be effective. Therefore, there is a dire need for
effective drugs that can reduce dengue viral infection and reduce the likelihood
of developing severe disease. Moreover, an integrated approach utilizing both
efficacious vaccines and drugs will be required to combat dengue globally. As
 Dengue: Update on Clinically Relevant Therapeutic Strategies and Vaccines Palanichamy Kala et al. 45

highlighted in this review, there are new and promising drugs and vaccines for
the control of dengue at various stages of clinical development.

Funding
The authors acknowledge funding from the National Medical Research Council of Singapore (OFIR-
G22jul-0018 ) and National Research Foundation of Singapore (NRF-CRP27-2021-0003).

Declarations
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.

Conflict of Interest
Dr. Rathore has patents related to dengue therapeutics, PCT/US11426408 and PCT/US11219616.
Dr. St. John has patents related to dengue therapeutics, PCT/US11426408 and PCT/US9730921B2.
Ms. Monica Palanichamy Kala declares no competing interests.

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